Case Report

Subepithelial Corneal Immunoglobulin Deposition as a Manifestation of Multiple Myeloma: A Case Report and Literature Review Trent P. Wang,1,2 Steven G. Safran,3 Joshua R. Richter,1 David S. Siegel,1 David H. Vesole1 Clinical Practice Points  Crystalline deposition in the cornea can be an early

manifestation of paraproteinemia, which may parallel disease activity.  Local treatment with superficial keratectomy or penetrating keratoplasty provides symptomatic but only transient improvement.

 Treatment of systemic disease often leads to resolu-

tion of corneal involvement.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 1, e39-42 ª 2014 Elsevier Inc. All rights reserved. Keywords: Autologous stem cell transplantation, Corneal crystalline deposition, Multiple myeloma

Introduction Multiple myeloma (MM) and other paraproteinemias may rarely cause subepithelial crystalline deposition disease in the cornea.1-3 These deposits have been shown to be immunoglobulins, usually IgG, although rare cases of other immunoglobulins have been reported.4,5 There are limited reports in the literature regarding the treatment and prognosis of patients with subepithelial corneal crystals. We report the diagnosis and treatment of a patient whose presenting manifestation of symptomatic MM was blurry vision with corneal involvement secondary to paraprotein-associated subepithelial corneal crystalline deposits.

Case Report A 63-year-old male with a history of age-related macular degeneration was seen by his primary care physician for progressively worsening blurry vision associated with a gritty sensation. On referral to an ophthalmologist, he was noted to have visual acuity of 20/60 bilaterally, vision of 20/200 in the presence of glare, and 1 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 2 Rutgers New Jersey Medical School, Newark, NJ 3 Capital Health System, Pennington, NJ

Submitted: Jun 17, 2013; Revised: Sep 10, 2013; Accepted: Sep 24, 2013; Epub: Oct 1, 2013 Address for correspondence: David H. Vesole, MD, PhD, John Theurer Cancer Center at Hackensack Medical Center, 92 Second Street, Hackensack, NJ 07601 Fax: 551-996-0582; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.09.012

significant amounts of subepithelial corneal crystals in both corneas (Fig. 1). He was subsequently referred to a hematologist/oncologist for workup of a plasma cell dyscrasia. His initial laboratory results revealed the following: serum electrophoresis showed an M spike of 1.35 g/dL; quantitative immunoglobulin levels of IgG—1778 mg/dL; IgA—56 mg/dL, and IgM—15 mg/dL; and normal creatinine and hemoglobin concentrations. A bone marrow aspirate showed a kappa-light-chaine restricted plasma cell population with < 5% marrow plasmacytosis and a normal metaphase karyotype. A metastatic skeletal survey was negative. He was diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and was followed at 6-month intervals without therapeutic intervention. For his visual complaints, he twice underwent superficial keratectomy, but the subepithelial corneal crystals returned within 3 months after each procedure. Two years after the initial MGUS diagnosis, he was referred to the Myeloma Division at the John Theurer Cancer Center at Hackensack University Medical Center. A repeated bone marrow aspiration was performed and showed 20% to 30% marrow plasmacytosis. His skeletal survey result remained negative, and the M spike on serum electrophoresis was 1.48 g/dL; there was no evidence of renal impairment, anemia, or hypercalcemia (no CRAB [hypercalcemia, renal insufficiency, anemia or bone lesions]). Although he did not meet the classic CRAB criteria for treatment of his MM, the recurrent subepithelial corneal immunoglobulin deposition was considered a manifestation of active MM requiring therapeutic intervention.

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Corneal Manifestations in Multiple Myeloma Figure 1 (A) Right Eye at Presentation With Significant Corneal Crystals (Arrow) Seen Clearly on Retroillumination at the Slit Lamp. (B) Slit-Lamp View Showing Corneal Crystals (Arrow) Throughout Cornea Before Treatment. They Were Affecting the Patient’s Vision

The patient was treated with oral lenalidomide (25 mg on days 1-21) and oral low-dose dexamethasone (40 mg on days 1, 8, 15, and 22 on a 28-day cycle) for 4 cycles. He responded to this induction regimen with an improvement in his M-protein level from 1.35 g/dL to 0.19 g/dL. To further consolidate his response, he underwent stem cell mobilization followed by high-dose melphalan (200 mg/m2) with autologous stem cell transplantation. At his 3-month posttransplantation evaluation, he was noted to have a partial remission with a decrease in his M protein to 0.16 g/dL. However, he had clearing of his subepithelial corneal immunoglobulin deposition (Fig. 2). Two years after transplantation, his MM remains in biochemical complete remission, and he has not had recurrence of his crystalline deposits.

Discussion Paraproteinemias, including MGUS, Waldenstrom macroglobulinemia, amyloidosis, and MM may be associated with a variety of ophthalmic conditions, including corneal deposits, conjunctival deposits, proptosis, diplopia, lid ecchymosis, scleritis, episcleritis, and retinopathy associated with hyperviscosity.3,6,7 Our patient’s presenting sign of MM was symptomatic bilateral corneal crystalline deposits. Although many patients have minimal visual impairment

and do not require intervention, those with significant visual symptoms have been treated with several modalities, including superficial keratectomy,8 penetrating keratoplasty,9 and systemic therapy.4,5,8-13 Table 1 presents a summary of cases reported in the literature. One of the initial cases of corneal involvement of immunoglobulin deposition was described by Firkin et al regarding a 69-year-old male who was diagnosed with IgG lambda MM after complaining of glare in his vision and was found to have bilateral golden corneal crystals.10 Treatment with vincristine, melphalan, and prednisolone resulted in improvement of both paraprotein levels and corneal deposits. Years later, Hill et al reported a 46-year-old woman with IgG lambda disseminated myeloma with corneal deposits. Despite treatment with irradiation of upper and lower body halves, paraprotein levels and corneal deposits remained unchanged.11 Chong et al described a 52-year-old woman presenting initially with vortex keratopathy and diagnosed with IgG-kappa MM.12 After undergoing unspecified chemotherapy, this patient had mild improvement in stroma deposits but persistent blurry vision. Shuttleworth at al described a 64-year-old man found to have pancorneal epithelial crystalline keratopathy with IgG-kappa MM. Epithelial debridement provided improvement of visual symptoms for several weeks only before recurrence. He was being treated with

Figure 2 (A) Right Eye Seen After Being Treated for Multiple Myeloma. There is Complete Resolution of the Corneal Crystals as Seen Here on Retroillumination (Arrow). An Intraocular Lens can be Seen Centered Within the Capsular Bag. (B) Slit-Lamp Image Showing Clear Cornea With Resolution of Corneal Crystals (Arrow) After Systemic Treatment for Multiple Myeloma

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Trent P. Wang et al Table 1 Corneal Deposition Characterization and Treatment Type of Immunoglobulin

Surgical Treatment

Edmunds et al4

IgD-kappa

e

Hsueh et al5

IgA-kappa

Nakatsukasa et al8

IgG-kappa

Font et al9

IgG-kappa

Firkin et al10

IgG-lambda

Hill et al11

IgG-lambda

Chong et al12

IgG-kappa

Shuttleworth et al13

IgG-kappa

Wang et al (current study)

IgG-kappa

Author

Systemic Treatment

Ophthalmic Response

Thalidomide, dexamethasone, Possible improvement cyclophosphamide e Melphalan, prednisone No improvement in visual crystals Superficial keratectomy Melphalan, prednisone Improvement from surgical treatment only Corneal transplantation ASCT, pulsed Improvement after dexamethasone dexamethasone and corneal transplantation e Vincristine, melphalan, Improvement in corneal prednisolone haze/crystals e Upper and lower body No improvement irradiation e Unspecified Mild improvement in chemotherapy stromal crystals Corneal epithelial ABCM, CIDEX, thalidomide, Improvement of corneal debridement and dexamethasone crystals Penetrating keratoplasty Lenalidomide and Marked improvement of dexamethasone, corneal haze/crystals followed by ASCT

Biochemical Response Not available Stable disease Not available Not available

Partial response Not available Not available Complete response Very good partial response

Abbreviations: ACBM ¼ Adriamycin (doxorubicin); ASCT ¼ autologous stem cell transplantation; BCNU (carmustine) ¼ cyclophosphamide, and melphalan; CIDEX ¼ CCNU (lomustine), idarubicin, and dexamethasone.

ABCM (Adriamycin [doxorubicin], BCNU [carmustine], cyclophosphamide, and melphalan) for 7 cycles and CIDEX (CCNU [lomustine], idarubicin, and dexamethasone) for 6 cycles, in addition to regular epithelial debridement every 2 to 3 months. After discontinuation of CIDEX because of renal deterioration, he was treated with thalidomide and dexamethasone, which provided complete resolution of crystalline keratopathy within 7 months. There are several case reports of MM with corneal deposition in which patients were treated with autologous stem cell transplantation. Font et al reported “systemic chemotherapy” as treatment for a 52-year-old man with deep stromal corneal crystals. Despite initial improvement, the crystals recurred. The patient later received high-dose therapy with autologous stem cell transplantation without resolution of stromal opacities. It was not until therapy with pulsed dexamethasone and corneal transplantation that he experienced durable improvement. In another case, bilateral subepithelial corneal infiltrates at the level of the Descemet membrane were described by Edmunds et al.4 After being diagnosed with IgD-kappa MM, the patient was treated with cyclophosphamide, dexamethasone, and thalidomide. It was not until subsequent autologous stem cell transplantation that the patient achieved neuroophthalmic resolution of symptoms. Hsueh et al described a 62-year-old woman with IgA-kappa MM and bilateral diffuse stromal white crystalline deposits treated with melphalan and prednisone. She did not achieve remission of her MM or resolution of the corneal crystals. The manifestation of corneal crystals in the setting of MGUS may be associated with an accelerated progression into MM. Chou et al described a case of a 51-year-old man with crystalline deposits who had MGUS for at least 3 years before being diagnosed with MM. Our patient was found to have subepithelial corneal crystals and was diagnosed with MGUS at least 2 years before progressing to

MM. Given the paucity of well-described cases, however, it remains difficult to speculate whether corneal crystals in MGUS are a poor prognostic indicator.

Conclusion Corneal crystalline immunoglobulin deposition is a rare clinical manifestation of paraproteinemia. The differential diagnosis includes corneal dystrophies, cystinosis, and gout. The presenting symptom of ocular involvement for this patient’s MM is a very rare entity. In this case, systemic treatment of the underlying MM with lenalidomide and dexamethasone followed by autologous stem cell transplantation resulted in resolution of the subepithelial corneal crystalline deposition. Based on the few reported cases (Table 1), the highest likelihood of success is with systemic chemotherapeutic treatment of the underlying plasma cell dyscrasia rather than surgical intervention, which provides only transient improvement.

Disclosure The authors have stated that they have no conflicts of interest.

References 1. Knapp AJ, Gartner S, Henkind P. Multiple myeloma and its ocular manifestations. Surv Ophthalmol 1987; 31:343-51. 2. Chou JL, Sink ML. Corneal crystals: a precursor to cancer. Optom Vis Sci 2011; 88:E543-7. 3. Garibaldi DC, Gottsch J, Green WR, et al. Immunotactoid keratopathy: a clinicopathologic case report and a review of reports of corneal involvement in systemic paraproteinemias. Surv Opthalmol 2005; 50:61-80. 4. Edmunds M, Cikatricis P, Bowyer JD, et al. Ophthalmic manifestations of atypical IgD multiple myeloma. BMJ Case Rep 2012; bcr2012006486. doi:10.1136/bcr2012-006486. 5. Hsueh CM, Lin PY, Hsu WM, et al. Corneal crystalline deposits as the initial manifestation of IgA-kappa multiple myeloma. Eye (Lond) 2004; 644-5.

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Corneal Manifestations in Multiple Myeloma 6. Goldstein DA, Schteingart MT, Birnbaum AD, et al. Bilateral eyelid ecchymoses and corneal crystals: an unusual presentation of multiple myeloma. Cornea 2005; 24:757-8. 7. Omoti AE, Omoti C. Ophthalmic manifestations of multiple myeloma. West Afr J Med 2007; 26:265-8. 8. Nakatsukasa M, Sotozono C, Kinoshita S, et al. Diagnosis of multiple myeloma in a patient with atypical corneal findings. Cornea 2008; 27:249-51. 9. Font RL, Matoba AY, Prabhakaran VC. IgG-kappa immunoglobulin deposits involving the predescemetic region in a patient with multiple myeloma. Cornea 2006; 25:1237-9.

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10. Firkin FC, Lee N, Ramsay R, et al. Visual loss caused by corneal crystals in myeloma: rapid improvement and plasma exchange and chemotherapy. Med J Aust 1979; 2:677-8. 11. Hill J, Mulligan G. Subepithelial corneal deposits in IgG (lambda) myeloma. Br J Ophthalmol 1989; 73:552-4. 12. Chong EM, Campbell RJ, Bourne WM. Vortex keratopathy in a patient with multiple myeloma. Cornea 1997; 16:592-4. 13. Shuttleworth GN, Cook SD, Ropner JE. Vanishing corneal epithelial crystals following thalidomide induced resolution of myeloma related paraproteinaemia. Br J Ophthalmol 2002; 86:1315-6.

Subepithelial corneal immunoglobulin deposition as a manifestation of multiple myeloma: a case report and literature review.

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