Calciphylaxis a Giant Cell Arteritis Mimic: A Case Report and Review of the Literature

Acute pallid disc edema is frequently seen with giant cell arteritis (GCA) in elderly patients. Elevated acute phase reactants (e.g., erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) can support diagnosis of GCA but is typically confirmed with a temporal artery biopsy (TAB) and treated with high-dose corticosteroid therapy to preserve vision. Calciphylaxis (CPA), or calcific uremic arteriolopathy, can mimic GCA, especially in the setting of chronic kidney disease (CKD).

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Calciphylaxis a Giant Cell Arteritis Mimic: A Case Report and Review of the Literature Anne A. Duong, MD, Nita Bhat, MD, Shruthi H. Bindiganavile, MD, Patricia ChevezBarrios, MD, Andrew G. Lee, MD A cute pallid disc edema is frequently seen with giant cell arteritis (GCA) in elderly patients. Elevated acute phase reactants (e.g., erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) can support diagnosis of GCA but is typically confirmed with a temporal artery biopsy (TAB) and treated with high-dose corticosteroid therapy to preserve vision. Calciphylaxis (CPA), or calcific uremic arteriolopathy, can mimic GCA, especially in the setting of chronic kidney disease (CKD). The true diagnosis can be elucidated with TAB. Clinicians should be aware that CPA can produce pallid optic disc edema mimicking GCA. This article reports a patient who had calciphylaxis presenting with signs and symptoms similar to GCA and a review of other similar cases in the literature. CASE REPORT A 72-year-old African American man with a medical history of end-stage renal disease (ESRD) on hemodialysis, peripheral arterial disease, hypertension, and hyperlipidemia presented with acute painless loss of vision in his left eye. He had previous optic atrophy that was long-standing in his right eye from presumed previous ischemic optic neuropathy. He was admitted for management of dry gangrene of his left middle finger and on review of symptoms, denied headache, jaw claudication, weight loss, temple pain, or scalp tenderness. On eye examination, his visual acuity was 20/200 in the right eye and hand motions in the left eye. Pupils measured 2 mm bilaterally (both eyes) with a poor light reaction in both eyes but no relative afferent pupillary defect (RAPD). Anterior segment, motility, and intraocular pressure were within normal limits. Dilated fundus examination revealed a pale, atrophic nerve in the right eye and pallid disc edema in the left eye. ESR and CRP were both elevated at 104 mm/h and 6.78 mg/L, respectively. Testing for sarcoidosis, tuberculosis, Lyme disease, syphilis, aquaporin-4 antibodies, and myelin oligodendrocyte glycoprotein was negative. Contrast-enhanced MRI of the head and orbit showed no lesion. The vision loss and the pallid disc edema in the setting of elevated acute phase reactants raised suspicion for GCA, and intravenous (IV) methylprednisolone 1 gm was started. A dry gangrenous-appearing lesion was noted on his left middle finger, and a necrotic ulcer with a black eschar was noted on his right knee (Fig. 1). An X-ray study of the left hand revealed dense vascular calcifications and a suspected large partially calcified aneurysm adjacent to the radius. Parathyroid hormone (PTH) was elevated at 883 pg/mL (normal ,55), and serum calcium was normal at 9.3 mg/dL. McGovern Medical School at the University of Texas Health Science Center (AD), Houston, Texas; Department of Ophthalmology (NB, SHB, PC-B, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine (PC-B), Houston Methodist Hospital, Houston, Texas; Department of Pathology and Laboratory Medicine (PC-B), Weill Medical College of Cornell University, New York, New York; Department of Pathology and Laboratory Medicine (PC-B), the University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Ophthalmology (PC-B, AGL), Baylor College of Medicine. Houston, Texas; The Houston Methodist Research Institute (AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology Weill Cornell Medicine (AGL), New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), the University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street Suite 450, Houston, TX 77030; E-mail: [e-mail] e362 FIG. 1. Cutaneous lesions of a calciphylaxis-dry gangrenous lesion on the finger (A) and a necrotic knee lesion with black eschar (B). Duong et al: J Neuro-Ophthalmol 2022; 42: e362-e366 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Although the gangrenous lesion and CKD were previously known in this patient, neuro-ophthalmology was not consulted until the visual loss occurred. A TAB was performed, which revealed extensive calcification of all the layers of the artery but predominantly in the muscularis, compatible with a diagnosis of calciphylaxis (1) (Fig. 2). IV methylprednisolone was subsequently discontinued after 2 days of therapy. DISCUSSION CPA is a rare but increasingly recognized condition that can mimic GCA. There are 10 other reported cases of acute optic neuropathy due to calciphylaxis (Table 1) (2–10). Common ophthalmic manifestations include acute visual loss, a RAPD, and pallid optic disc edema. Some patients may have symptoms that are usually associated with GCA including jaw claudication and temporal headache. Four patients had concurrent soft tissue manifestations of calciphylaxis (2,4,5,9) with another 2 developed them within a year of vision change (6,8). Soft tissue involvement was confirmed directly with biopsy or seen on imaging. Common patient characteristics included 7 patients with CKD (2–6,8,10). Of the 3 patients without CKD, 1 was on hemodialysis for uremia and volume overload with laboratory findings of improper phosphorus balance (3), 1 was on chronic steroids for her rheumatoid arthritis (9), and 1 patient’s medical history was unknown (7). Multiple patients were on warfarin (3,4,6,9). TAB results revealed diffuse calcification of the temporal artery media and sometimes lamina, with no signs of inflammation confirming the diagnosis of CPA. ESR was commonly elevated as was either parathyroid hormone or phosphorus. Eight patients were on a course of steroids (7 on high dose (2,3,5–8)) for presumed GCA but were discontinued when no improvement in vision was seen or when biopsy indicated CPA (10). Sodium thiosulfate was given to 2 patients, as well as our patient, but again, no improvement was observed (9,10). Three of the 7 patients, whose clinic outcomes are known, died within a year of visual presentation (3,6,8). Given our patient’s age and comorbidities, acute, pallid edema normally is suggestive of GCA and must be ruled out given the severe complications. However, other causes of pallid disc edema, especially in the setting of ESRD, include uremia, ischemic optic neuropathy, and hyperparathyroidism. Acute phase reactants are often obtained but can confound diagnosis. In our patient, the increased ESR could have been due to his CKD, and the skin gangrene can produce elevated CRP levels (11). Thus, CPA should be considered in the differential diagnosis of any patient with the combination of these risk factors. Interestingly, the kidneys are not typically involved in GCA although it is considered to be a systemic inflammation (12); therefore, renal disease should be considered independent rather than a sequela of GCA. FIG. 2. Temporal artery biopsy with calciphylaxis. A. Low-power view of 2 cross sections of the medium size artery with chunky deposits of calcium (purple crystalline structures disrupting the tissue) in the wall. The lumen (*) is focally markedly narrowed by the deposits in the wall of the artery (hematoxylin and eosin, original magnification ·1.25). B. A close-up view shows irregular intimal (i) hyperplasia, calcification of the elastic lamina (arrows), and histiocytic reaction around calcifications in the media (m) and intima. The adventitia (a) is unremarkable (hematoxylin and eosin, original magnification ·10). C. Notice the narrowed lumen (*) secondary to the irregular intimal (i) hyperplasia and the chunky calcification in the intima and predominantly in the media (m) (hematoxylin and eosin, original magnification ·4). Duong et al: J Neuro-Ophthalmol 2022; 42: e362-e366 e363 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Previous reports of calciphylaxis mimicking giant cell arteritis Case # Author Patient PMH Laboratory Results Imaging, DFE, and Temporal Biopsy Results Treatment Outcomes IV MP VA stable and skin Calcification of the ESR 101 mm/h, ESRD 60 days and valvular media, minimal Ca. 8.0 mg/dL, Phos. bilateral temporal secondary to calcification inflam 7.5 mg/dL, PTH HTN and headaches, acute 1128 pg/mL, calcium– matory changes (no cocaine blurry vision, jaw giant cells). phosphorous product abuse claudication, Peripapillary atrophy 70–80. Negative arthralgias; but no papilledema, ANA and ANCA thickened, exudates, or tortuous, and hemorrhages tender TAs No ESRD, T2DM, Phos. 5.5–10 mg/dL and Calcification of the IV MP · 5 days 77 yo M Vision loss to improvement in PTH 950 pg/mL media and no IHD, and PVD light perception VA OD and OS inflammation. warfarin for only with RAPD OD stable at 6/24. Pale optic disc with aortic valve and 6/24 OS Death from MI edema OD replacement IgG gamma 70 yo F Inferior field VA OD hand Phos = 7.0–10 mg/dL Calcification of the IV MP · 4 days monoclonal deficit 6/60 OD motion and OS and PTH ,100 pg/mL media and no gammopathy with RAPD and stable at 6/12 inflammation. bilateral temporal Optic disc edema OD and atheros headaches clerotic disease 75 yo M Subacute vision loss ESRD, IDT2DM, ESR 106 mm/h, Ca. Unknown Unknown Calcification of the 7.7 mg/dL, Phos. CAD, HTN, to CF with RAPD media and lamina 9.5 mg/dL, Cr and warfarin OS and skin and no 12.3 mg/mL, and and lesions. inflammation. calcium–phosphate Grade 2–3 pallor OD prednisone OD 6/60 product .70 mg2/dL2 andGrade 3 pallor OS 80 mg for optic nerve swelling No IV MP · 3 days First prese ESR 70 mm/h. CKD and 51 yo F First prese improvement followed by ntation: right Normal or negative parathyro ntation: central in VA optic oral predn temporal biopsy albumin, vitamin B12, idectomy scotoma 20/400 atrophy OD. isone taper inconclusive and folic acid, IgG, OD Cutaneous over 2 months optic disc edema cryoglobulins, syphilis, Second lesions. Died 6 OD ANA, presentation: acute years after Second presentation: ANCA, and ACA vision loss OS presentation calcification of the (20/200) media of left temporal biopsy Large diffuse Ca. 7.9 mg/dL, Phos. ESRD, HTN, 72 yo M First High-dose VA 20/200 OS calcification and no 6.6 mg/dL, T2DM, A. fib presentation: steroids stable and OD inflammation. calcium–phosphate with rightacute vision loss progressed to product 51.48 mg/dL, Optic disc edema with sided CHF; OS 20/200 20/200. PTH 164 pg/mL, warfarin for Second Developed venous dilation and ALP 636 IU/L, aortic presentation: acute cutaneous choroidal and PTH 374 pg/mL stenosis vision loss OD lesions with hypoperfusion OS valve and A. 20/80 bacterial fib infection. Died within 10 weeks of presentation Unknown IV MP · Calcification of the Unknown ESR 62 mm/h, BUN 82 yo F First 3 days media and lamina 0.56 g/dL, Cr 1.7 mg, presentation: followed by with narrowing of Ca 8.39 mg, Phos. diplopia oral lumen and no 2145 mg/24 h, Second prednisone inflammation. PTH 51.41 pg/mL, and presentation: acute taper Normal MRI of 15 pg/mL on repeat. vision loss OS for Negative or normal orbit and surrounding 7 days and doubtful areas blood cell count, temporal headache anticardiolipin, lupus anticoagulant, ANCA, and IgG 1 Al-Absi 50 yo M et al (2) 2 Korzets et al (3) 3 Korzets et al (3) 4 Awwad et al (4) 5 Huerva et al (5) 6 Shah et al. (6) 7 Roverano et al (7) e364 Presenting Symptoms Duong et al: J Neuro-Ophthalmol 2022; 42: e362-e366 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence (Continued ) Case # Author Patient Presenting Symptoms PMH Laboratory Results Imaging, DFE, and Temporal Biopsy Results No temporal biopsy. Calcified plaques in ciliary arteries seen on Doppler USG, calcified plaques in the right eye, and left eye cataract Treatment IV MP · 3 days followed by oral prednisone taper within 15 days; pentoxifylline, and aspirin IV sodium thiosulfate Outcomes No improvement in VA; Died of sepsis 8 months after acral gangrenes appeared 8 Komurcu 43 yo F et al (8) Acute vision loss CKD and severe with LP in OD and sensorimotor polyneu NLP OS with ropathy bilateral papilledema Ca 8.8 mg/dL, Phos 12.5 mg/dL, and PTH 137 pg/mL. Normal or negative ESR, CRP, and vasculitis or infectious markers 9 Sivertsen 72 yo F et al (9) Acute vision loss T2DM, RA, A. fib, HTN; to hand motion with RAPD OS warfarin for A. fib and chronic and chronic prednisone bacterial 5 mg/dL infections of leg ulcers 10 Farooqui 39 yo M Acute vision loss to et al hand movements (10) with RAPD OS 11 Our 72 yo M Acute vision loss to patient HM OS and chronic OD vision loss 20/200. Extensive cutaneous lesions No Calcifications of the ESR 57 mm/h, CRP improvement in media and intima 28 mg/L, Ca. VA and no 2/56 mmol/L, Phos. inflammation. 1.36 mmol/L, Cr 33 micromol/L, and PTH Pale optic disc with delayed choroidal 3.5 pmol/L perfusion of posterior ciliary arteries OS Calcification of the oral prednisone VA OD stable at ESR 120 mm/h, CRP 6/6, improved (short course, media and severe 74.1 mg/dL, Ca. to 6/60 OS with 40 mg/day) luminal occlusion, 1.55 mmol/L, Phos. severe optic with rapid and no 1.72 mmol/L, and PTH nerve atrophy taper; IV inflammation. 2.1 pmol/L. Normal or (2 yrs later) sodium Pale swollen disc negative blood cell thiosulphate count, coagulation, (c/d 0.1) and severe and vasculitis panel global depression OS Lost to IV MP · Calcification of the ESR 104 mm/h, CRP follow-up 2 days media and intima. 6.78 mg/L, Ca. followed by 9.3 mg/dL, and PTH Pale, atrophic nerve oral OD and pallid 883 pg/mL. Negative prednisone disc edema OS. or normal TB, taper Negative MRI head sarcoidosis, Lyme and orbit disease, syphilis, AQP4, and MOG ESRD ESRD, HTN, peripheral artery disease, and A. fib A. fib, atrial fibrillation; ALP, alkaline phosphate; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; AQP4, aquaporin4; Ca., serum calcium; CAD, coronary artery disease; CF, counting fingers; CKD, chronic kidney disease; Cr, creatinine; CRP, C-reactive protein; DFE, dilated funduscopic examination; ESR, erythrocyte sedimentation rate; ESRD, end-stage renal disease; F, female; HTN, hypertension; IgG, immunoglobulin G; IHD, ischemic heart disease; IV- intravenous; M, male; MI, myocardial infarction; MOG, myelin oligodendrocyte glycoprotein; MP, methylprednisolone; Phos., phosphorous; PTH, parathyroid hormone; PVD, peripheral vascular disease; RA, rheumatoid arthritis; RAPD, relative afferent pupillary defect; T2DM, type 2 diabetes mellitus; TA (s), temporal artery (arteries); TB, tuberculosis; VA, visual acuity. Risk factors for CPA include CKD, defective calcium– phosphorus balance, other autoimmune disease, diabetes, alcoholic hepatitis, female sex, Caucasian ethnicity, and older age (13). CPA has also been implicated after medication use including warfarin, calcium supplements, and vitamin D (1,13). Corticosteroids, the mainstay of treatment for GCA, are an additional risk factor for CPA and were noted to be present in 61% of nonuremic patients who went on to develop CPA, in a 36-case systemic review (1). Although corticosteroid therapy before TAB is the standard approach for patients suspected of having GCA, steroids can worsen symptoms in CPA. Fortunately, our patient suffered no untoward effects of the short course of empiric steroids before the TAB result. Although CPA affects only around 1%–4% of patients with ESRD, in the presence of other manifestations of the disease, such as cutaneous lesions supported by arterial calcification on biopsy or imaging, CPA needs to be high on a provider’s index Duong et al: J Neuro-Ophthalmol 2022; 42: e362-e366 of clinical suspicion. CPA has a 1-year mortality of 45%–80%, and patients with ulcerated lesions have a higher risk due to superimposed infections and ensuing sepsis (1). Unfortunately, there is no known cure for CPA. Sodium thiosulfate is an antioxidant and a calcium chelator that has been used in the management of CPA. Retrospective studies showed some modest benefit; however, more studies are required (1,13). In the 2 patients who received sodium thiosulfate, 1 experienced improvement of their cutaneous lesions but neither saw any visual benefit (9,10). Owing to its high morbidity, there is a clear cognitive bias toward GCA when examining older patients with acute vision loss and pallid disc edema. GCA requires prompt treatment, which otherwise can lead to devastating consequences. However, in the setting of chronic renal disease, arterial calcifications with cutaneous manifestations (e.g., gangrene), and abnormalities in PTH or calcium levels, CPA should be e365 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence considered. Physicians should consider these potential cognitive biases and explore broader differentials, especially if therapy of one diagnosis (e.g., GCA) can be harmful to another diagnosis (e.g., calciphylaxis). Clinicians should be aware that CPA can mimic GCA. Both can cause headache, visual loss, pallid edema, and elevated acute phase reactants. However, corticosteroids are not useful in CPA and may worsen the disease. A TAB may be useful to confirm the diagnosis and exclude GCA. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. G. Lee and N. Bhat; b. Acquisition of data: N. Bhat and S. H. Bindiganavile; c. Analysis and interpretation of data: A. A. Duong, N. Bhat, and P. Chevez-Barrios. Category 2: a. Drafting the manuscript: A. A. Duong; b. Revising it for intellectual content: A. G. Lee, N. Bhat, and P. Chevez-Barrios. Category 3: a. Final approval of the completed manuscript: A. Duong, N. Bhat, S. H. Bindiganavile, P. Chevez-Barrios, and A. G. Lee. REFERENCES 1. Nigwekar SU, Kroshinsky D, Nazarian RM, Goverman J, Malhotra R, Jackson RA, Kamdar MM, Steele DJ, Thadhani RI. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66:133–146. 2. Al-Absi AI, Wall BM, Cooke CR. Medial arterial calcification mimicking temporal arteritis. Am J Kidney Dis. 2004;44:e73–e78. e366 3. Korzets A, Marashek I, Schwartz A, Rosenblatt I, Herman M, Ori Y. 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