Hypercupremia refers to an elevation in serum copper levels, typically secondary to Wilson's disease or lymphoproliferative disorders. Although most cases of intraocular copper deposition occur secondary to chalcosis and Wilson's disease, intraocular copper deposition can result from hypercupremia. In these rare variants, copper deposition has been noted to occur in the lens capsule and Descemet's membrane.1–6 However, in each case report deposition was limited to the cornea and lens capsule. Thus far, copper deposition within the vitreous and intraocular copper causing retinal toxicity has only been described in cases of chalcosis. The degree of retinal toxicity can be measured through electroretinogram (ERG), which shows decrease in response amplitude. However, if the intraocular copper levels can be returned to normal, this retinopathy can be reversible.7 In this case report, we describe a patient who developed retinal toxicity and deposition of copper within the vitreous due to hypercupremia from multiple myeloma.
A 46-year-old woman presented for evaluation of worsening glare during the past 18 months. Initial visual acuity (VA) was 20/30 in both eyes (OU), which decreased to 20/400 on glare testing OU. The patient was found to have dense copper deposition in Descemet's membrane and lens capsule OU. The patient underwent systemic workup, which revealed significantly elevated serum copper but normal serum ceruloplasmin. Ultimately, a diagnosis of multiple myeloma was established via serum protein electrophoresis and bone marrow biopsy. The patient underwent successful Descemet stripping automated endothelial keratoplasty (DSAEK) and cataract extraction with intraocular lens implantation OU, with glared VA improving to 20/20 OU.8 Following these surgeries, a green discoloration of the vitreous and posterior lens capsule was observed. Fundus autofluorescence and optical coherence tomography macula were unremarkable. A baseline ERG was performed, which showed mild changes associated with ganglion cell response.
The patient returned for follow-up 6 months later. Repeat ERG at that time showed stable-to-improved rod response but decreased cone response (25% to 30%), with the left eye (OS) greater than the right eye (OD). Green discoloration of the vitreous and posterior lens capsule was again noted. During the next 2 years, repeat ERGs demonstrated decreasing amplitude compared to initial recordings, with amplitude at 1-year follow-up showing a 20% reduction. Additionally, decreasing photopic negative response was noted, suggesting decreased macular function. A multifocal ERG performed at 2-year follow-up demonstrated central and paracentral decrease in macular functioning OU. Second and third multifocal ERGs performed at 3- and 4-year follow-ups demonstrated further decline in response amplitude, particularly OS (Figure 1). These findings were reflected in VA recordings, which decreased to 20/30 OD and 20/50 OS at last follow-up. Although the patient underwent treatment for multiple myeloma, serum copper levels remained elevated throughout the followup interval (Table 1).
Effects of elevated serum copper levels on the full-field electroretinogram (ERG) (A, B) and on multifocal ERG (C). (A) Full-field ERG tracings from the first recording in 2015 (from top to bottom): Dark-adapted 0.01 ERG, Dark-adapted 10 ERG, Light-adapted 3 ERG, Light-adapted 30 Hz flicker. (B, from top to bottom) Amplitude change of dark-adapted responses over time, peak time changes of darkadapted responses over time, amplitude changes of light-adapted responses over time, peak time changes of light-adapted responses over time. Please note the difference in the range of the horizontal axis values between dark-adapted and light-adapted responses. (C) Top response density values of P1 amplitude from the five rings reflecting grouped responses from the 61 hexagons for each of the recordings made in 2016, 2017, and 2018; middle: peak times of P1 for each ring; bottom: three-dimensional representation of response density plots from both eyes (top – right eye, bottom – left eye, years of recording indicated over each pair of eyes).
Serum Copper Levels Throughout Follow-Up
To date, retinal toxicity secondary to elevated intraocular copper deposition has only been described in ocular chalcosis. Ocular chalcosis refers to the deposition of copper within various ocular tissues including Descemet's membrane, iris, the crystalline lens, vitreous, and in the internal limiting membrane of the retina due to an intraocular copper foreign body. Vision loss from chalcosis can result from corneal deposition of copper, cataract formation, and retinal toxicity, as well as significant inflammatory reaction to an intraocular copper foreign body. The degree of inflammation incited by a copper foreign body is dependent on the copper content. A foreign body with greater than 85% copper composition tends to produce more widespread dissemination and thus elicit a strong inflammatory response. Due to the potentially intense nature of this inflammatory response, all intraocular foreign bodies containing copper are typically removed. However, if left in the eye, foreign bodies with less than 85% copper composition tend to cause more localized copper deposition, little to no immune response, and ultimately chronic chalcosis.9,10 The degree of retinal toxicity can be measured through ERG, which shows reduction in photopic and scotopic responses and increased implicit times. However, if the intraocular copper levels can be returned to normal, this retinopathy can be partially reversible.7
A second well-known cause of elevated intraocular copper is Wilson's disease, in which a mutation in the Wilson's disease gene (ATP7B) restricts the transportation and excretion of copper through bile. In Wilson's disease, copper can accumulate within the eye to form Kayser-Fleshier rings, a pathognomonic deposition of copper in Descemet's membrane, and sunflower cataracts. Wilson's disease has also been shown to cause retinal toxicity diagnosed by ERG. In particular, patients with Wilson's disease have been found to have reduced amplitude of photopic a- and b-waves, prolonged photopic and scotopic a-waves, and prolonged oscillatory potentials on flash ERG. Similar to retinal toxicity in chalcosis, these ERG findings can be partially or sometimes completely reversed with normalization of serum and intraocular copper levels.11,12
Unlike chalcosis and Wilson's disease, the deposition of copper in patients with hypercupremia has been limited to the cornea and lens capsule in previously described cases.1–6,13 This case represents the first description of retinal toxicity and copper deposition in the vitreous in a patient with hypercupremia. Much like previously described cases of retinal toxicity from chalcosis and Wilson's disease, our patient also demonstrated decreased ERG amplitude and delayed implicit times. The decreasing response amplitude and poor photopic negative response were particularly pronounced in the left eye. Best-corrected VA showed an analogous decline throughout follow-up. Although VA improved to 20/20 OU following initial DSAEK and cataract surgery, VA had declined to 20/30 OD and 20/50 OS at last follow-up. In patients with chalcosis and Wilson's disease, the decreased response amplitude found on ERG has been observed to partially reverse following removal of the copper foreign body.7 However, in our case ERG findings and VA continued to decline despite treatment of the underlying cause of hypercupremia and reduction in serum copper levels (Figure 1, Table 1).
- Edward DP, Patil AJ, Sugar J, Parikh M. Copper deposition in a variant of multiple myeloma: pathologic changes in the cornea and the lens capsule. Cornea. 2011;30(3):360–363. https://doi.org/10.1097/ICO.0b013e3181ee67fd PMID: doi:10.1097/ICO.0b013e3181ee67fd [CrossRef]
- Garg S, Jampol LM, Lewis RA, Penner JA. Corneal copper deposition secondary to a variant of multiple myeloma: 30-year catamnesis. Arch Ophthalmol. 2006;124(1):130–132. https://doi.org/10.1001/archopht.124.1.130 PMID: doi:10.1001/archopht.124.1.130 [CrossRef]16401799
- Hawkins AS, Stein RM, Gaines BI, Deutsch TA. Ocular deposition of copper associated with multiple myeloma. Am J Ophthalmol. 2001;131(2):257–259. https://doi.org/10.1016/S0002-9394(00)00657-7 PMID: doi:10.1016/S0002-9394(00)00657-7 [CrossRef]11228306
- Probst LE, Hoffman E, Cherian MG, et al. Ocular copper deposition associated with benign monoclonal gammopathy and hypercupremia. Cornea. 1996;15(1):94–98. https://doi.org/10.1097/00003226-199601000-00017 PMID: doi:10.1097/00003226-199601000-00017 [CrossRef]8907388
- Ellis PP. Ocular deposition of copper in hypercupremia. Am J Ophthalmol. 1969;68(3):423–427. https://doi.org/10.1016/0002-9394(69)90706-5 PMID: doi:10.1016/0002-9394(69)90706-5 [CrossRef]5807669
- Lewis RA, Falls HF, Troyer DO. Ocular manifestations of hypercupremia associated with multiple myeloma. Arch Ophthalmol. 1975;93(10):1050–1053. https://doi.org/10.1001/archopht.1975.01010020824017 PMID: doi:10.1001/archopht.1975.01010020824017 [CrossRef]1080996
- Dayan MR, Cottrell DG, Mitchell KW. Reversible retinal toxicity associated with retained intravitreal copper foreign body in the absence of intraocular inflammation. Acta Ophthalmol Scand. 1999;77(5):597–598. https://doi.org/10.1034/j.1600-0420.1999.770525.x PMID: doi:10.1034/j.1600-0420.1999.770525.x [CrossRef]10551310
- Shah S, Espana EM, Margo CE. Ocular manifestations of monoclonal copper-binding immunoglobulin. Surv Ophthalmol. 2014;59(1):115–123. https://doi.org/10.1016/j.survophthal.2013.03.002 PMID: doi:10.1016/j.survophthal.2013.03.002 [CrossRef]
- Friedman NJ, Kaiser PK. Essentials of Ophthalmology. 1st ed. Philadelphia, PA: Saunders; 2007.
- Rao NA, Tso MO, Rosenthal AR. Chalcosis in the human eye. A clinicopathologic study. Arch Ophthalmol. 1976;94(8):1379–1384. https://doi.org/10.1001/archopht.1976.03910040247018 PMID: doi:10.1001/archopht.1976.03910040247018 [CrossRef]60098
- Satishchandra P, Ravishankar Naik K. Visual pathway abnormalities Wilson's disease: an electrophysiological study using electroretinography and visual evoked potentials. J Neurol Sci. 2000;176(1):13–20. https://doi.org/10.1016/S0022-510X(00)00280-X PMID: doi:10.1016/S0022-510X(00)00280-X [CrossRef]10865087
- Langwińska-Wońko E, Litwin T, Szulborski K, Członkowska A. Optical coherence tomography and electrophysiology of retinal and visual pathways in Wilson's disease. Metab Brain Dis. 2016;31(2):405–415. https://doi.org/10.1007/s11011-015-9776-8 PMID: doi:10.1007/s11011-015-9776-8 [CrossRef]
- Martin NF, Kincaid MC, Stark WJ, et al. Ocular copper deposition associated with pulmonary carcinoma, IgG monoclonal gammopathy and hypercupremia. A clinicopathologic correlation. Ophthalmology. 1983;90(1):110–116. https://doi.org/10.1016/S0161-6420(83)34599-1 PMID: doi:10.1016/S0161-6420(83)34599-1 [CrossRef]6828304
Serum Copper Levels Throughout Follow-Up
|Date||Initial Presentation||39 Months||42 Months||45 Months||48 Months||53 Months|
|Copper Level (70–175 μg/dL)||1,942||494||522||544||514||553|