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Paraproteinemic keratopathy: recognizing the ocular significance

Published:September 17, 2022DOI:https://doi.org/10.1016/j.jcjo.2022.08.011
      Multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance (MGUS), are disorders of plasma cell proliferation and immunoglobulin production. Although an uncommon presentation, paraproteinemic keratopathy, originally called immunotactoid keratopathy,
      • Garibaldi DC
      • Gottsch J
      • Cruz Z
      • de la
      • Haas M
      • Green WR.
      Immunotactoid keratopathy: a clinicopathologic case report and a review of reports of corneal involvement in systemic paraproteinemias.
      may be the first manifestation.
      • Nobacht S
      • Kusters B
      • Breukink MB
      • Rongen GA
      • Cruysberg JRM.
      Recurrence of paraproteinemic crystalline keratopathy after corneal transplantation: a case of monoclonal gammopathy of ocular significance.
      ,
      • Bharath V
      • Hsia CC
      • Minuk L
      • Mather R
      • Nichols BD.
      Ocular crystal deposition leading to a diagnosis of multiple myeloma: a report of 2 cases and review of the literature.
      Patients may present with photophobia, glare, and decreased visual acuity or remain asymptomatic with crystals and opacities detected incidentally. Optimal treatment is not yet established, but chemotherapy, superficial keratectomy, and penetrating keratoplasty (PKP) have been reported.
      • Nobacht S
      • Kusters B
      • Breukink MB
      • Rongen GA
      • Cruysberg JRM.
      Recurrence of paraproteinemic crystalline keratopathy after corneal transplantation: a case of monoclonal gammopathy of ocular significance.
      • Bharath V
      • Hsia CC
      • Minuk L
      • Mather R
      • Nichols BD.
      Ocular crystal deposition leading to a diagnosis of multiple myeloma: a report of 2 cases and review of the literature.
      • Karakus S
      • Gottsch JD
      • Caturegli P
      • Eghrari AO.
      Monoclonal gammopathy of “ocular” significance.
      We present 3 cases of paraproteinemic keratopathy and provide follow-up on 2 patients, documenting the potential for long-term success of treatment.
      • Bharath V
      • Hsia CC
      • Minuk L
      • Mather R
      • Nichols BD.
      Ocular crystal deposition leading to a diagnosis of multiple myeloma: a report of 2 cases and review of the literature.
      The first case is a 65-year-old female with blurred vision who was noted to have superficial refractile corneal crystals 2 months after cataract extraction with lens implantation. Her best corrected visual acuity (BCVA) in both eyes was 20/50. She was investigated with protein electrophoresis, which confirmed IgG kappa monoclonal protein. Because her symptoms were mild with no systemic features, no treatment was initiated. Two years later (Fig. 1A), her vision had worsened with increasing glare. There continued to be no signs of hypercalcemia, renal failure, anemia, or lytic lesions, but VMP chemotherapy (bortezomib, melphalan, and prednisone) was initiated for worsening keratopathy. The tolerated chemotherapy well but did experience fatigue and occasional nausea. She was also started on granulocyte colony-stimulating factor to maintain her neutrophil levels. After 6 cycles of chemotherapy, the crystals almost completely resolved. Four months after chemotherapy, uncorrected visual acuity improved to 20/25 OD and 20/30 OS. The patient reported significant improvement in driving and other visual tasks. Fifteen months after treatment, the patient experienced a recurrence of symptoms and crystals with an associated biochemical relapse but no other systemic features. She is now undergoing treatment with daratumumab, lenalidomide, and dexamethasone and has again experienced complete resolution of her crystalline deposits OU.
      Fig 1
      Fig. 1Colour slit-lamp photographs: (A) the first patient's cornea showing refractile crystals of the cornea including the visual axis (the small slit-lamp beam shows crystals within the superficial cornea); (B) the second patient's right cornea showing a peripheral ring of dense white opacification (neovascularization of the cornea is also seen); and (C) the third patient's left cornea showing crystalline and fibrillar deposits within the deep stroma and epithelium (there a is relative concentration of these deposits within the central cornea and sparing the limbus).
      The second case is a 79-year-old female with IgG kappa MGUS who was referred for blurred vision. There was bilateral dense peripheral corneal stromal opacification (Fig. 1B). Corneal biopsy revealed strongly positive IgG deposition consistent with paraproteinemic keratopathy. At this time, the patient had mildly elevated creatinine (thought to be an incidental finding) and mild but progressive anemia with no hypercalcemia or lytic lesions. She was started on cyclophosphamide and prednisone for progressive anemia and keratopathy. Visual acuity was 20/400 OD and 20/150 OS at the initiation of treatment. After 8 cycles, visual acuity improved to 20/200 OD and 20/60 OS, but corneal appearance did not change. The patient decided to stop cyclophosphamide and prednisone after 9 cycles because of ongoing nausea and vomiting but remained on dexamethasone. Treatment with bortezomib and autologous stem cell transplantation (ASCT) were recommended, but she declined therapy.
      The third case is a 59-year-old male with chronic lymphocytic leukemia who presented with 9 months of blurred vision OD. BCVA was 20/30 OD and 20/20 OS. There were diffuse, deep stromal crystalline and fibrillar deposits in both corneas, concentrated in the central axis and sparing the limbus (Fig. 1C). While lost to follow-up for 4 years, the patient was found to have CD5+ B-cell lymphoproliferative disorder with elevated small IgG kappa monoclonal protein. On re-presentation, visual acuity was 20/200 OD and 20/30 OS with bilateral crystalline depositions throughout the stroma. Within months, the patient developed bone marrow infiltration, spleen enlargement, and worsening cell counts and IgG levels. He was started on 6 cycles of fludarabine and rituximab and later switched to rituximab, cyclophosphamide, vincristine, and prednisone because of suboptimal response. However, corneal opacities persisted, and BCVA declined to counting fingers OS. The patient underwent combined right PKP and cataract extraction with lens implantation. Histopathology of the corneal button found granular acellular eosinophilic deposits with a suggestion of an organized structure anterior to Descemet's membrane (Fig. 2). At 1-year after PKP, BCVA was 20/40 with no recurrence in the corneal graft.
      Fig 2
      Fig. 2(A) Histopathologic examination of the third patient's corneal button found granular acellular eosinophilic deposits (arrow) with a suggestion of an organized structure anterior to Descemet's membrane. (B) This deposit was proteinaceous and stained with trichrome red. (C) Negative for staining with periodic acid–Schiff. (D) Immunohistochemical analysis found that this deposit was positive for IgG kappa. (E, F) Monoclonality was demonstrated on light-chain restriction immunohistochemistry with positive staining with kappa but not lambda. (G, H) Electron microscopy shows proteinaceous and crystalline material anterior to Descemet's membrane (arrow) consisting of tubular, electron-dense, crystalloid deposits with a central lucent core.
      The fourth case is a previously reported 53-year-old female with numerous bilateral iridescent whorl-like crystals in the corneal subepithelium and anterior stroma.
      • Bharath V
      • Hsia CC
      • Minuk L
      • Mather R
      • Nichols BD.
      Ocular crystal deposition leading to a diagnosis of multiple myeloma: a report of 2 cases and review of the literature.
      She was diagnosed with multiple myeloma with IgG kappa monoclonal protein and 3 years later developed mild anemia. Treatment with bortezomib and dexamethasone followed by high-dose melphalan and ASCT completely resolved the crystals. We report that 11 years after treatment, the patient continues to have no recurrence of corneal crystals despite a relapse of multiple myeloma.
      The fifth case is a previously reported 50-year-old female with bilateral crystal formation at the flap interface after LASIK surgery.
      • Bharath V
      • Hsia CC
      • Minuk L
      • Mather R
      • Nichols BD.
      Ocular crystal deposition leading to a diagnosis of multiple myeloma: a report of 2 cases and review of the literature.
      Operative lifting of the flap and scraping of the crystals improved visual acuity, but crystals continued to accumulate. Work-up revealed an IgG kappa monoclonal gammopathy and kappa light-chain proteinuria and possible myeloma. Treatment with melphalan, prednisone, and plasmapheresis produced marginal improvement of the crystals, and visual acuity improved to 20/25 OU. We report that 12 years after treatment, visual acuity was maintained at 20/20 OU. The corneal deposits continued to gradually aggregate at the LASIK interface and extend into the visual axis zone.
      We present 3 cases of paraproteinemic keratopathy and 2 long-term follow-ups. Patterns of paraproteinemic keratopathy have been described previously in 5 categories by Lisch et al.,
      • Lisch W
      • Saikai P
      • Pitz S
      • et al.
      Chameleon-like appearance of immunotactoid keratopathy.
      ,
      • Lisch W
      • Wasielica-Poslednik J
      • Kivela T
      • et al.
      The hematologic definition of monoclonal gammopathy of undetermined significance in relation to paraproteinemic keratopathy (An American Ophthalmological Society Thesis).
      later expanded to 17 subcategories. Within this framework, our cases are described as: the first case 1: crystalline-like; the second case 2: peripheral circular band-like; the third case 3: superficial geographic-like; the fourth case: verticillata-like, and the fifth case: peripheral granular-like. Symptoms of paraproteinemic keratopathy may range from nonexistent to significantly decreased visual acuity, photophobia, and glare. Importantly, changes in vision may be the first symptoms of the disease, as in our first, fourth, and fifth cases. This should prompt a hematology referral for investigation.
      • Hall RB
      • Yeung SN
      • Yenson PR
      • Moloney G.
      A series of 4 cases of distinct keratopathy secondary to dysproteinemia: Immunotactoid keratopathy.
      In our second and fourth cases, the patients also developed mild anemia but no other signs of end-organ damage. Keratopathy may develop years before other end-organ damage and may present an opportunity for early intervention.
      • Lindemann C
      • Enders P
      • Brinkkoetter PT
      • Völker LA.
      Crystalline deposits in the cornea and various areas of the kidney as symptoms of an underlying monoclonal gammopathy: a case report.
      Ocular symptoms are not yet an indication for systemic therapy of paraproteinemic keratopathy, even when the ocular disease is sight threatening and affects activities of daily living. Currently, cases of isolated paraproteinemic keratopathy are classified as monoclonal gammopathy of undetermined significance (MGUS), implying the absence of end-organ damage.
      • Lisch W
      • Wasielica-Poslednik J
      • Kivela T
      • et al.
      The hematologic definition of monoclonal gammopathy of undetermined significance in relation to paraproteinemic keratopathy (An American Ophthalmological Society Thesis).
      We instead support the use of monoclonal gammopathy of ocular significance, suggested by Karakus et al.
      • Karakus S
      • Gottsch JD
      • Caturegli P
      • Eghrari AO.
      Monoclonal gammopathy of “ocular” significance.
      and Nobacht et al.,
      • Nobacht S
      • Kusters B
      • Breukink MB
      • Rongen GA
      • Cruysberg JRM.
      Recurrence of paraproteinemic crystalline keratopathy after corneal transplantation: a case of monoclonal gammopathy of ocular significance.
      which reflects the significant visual impairment that may result.
      Optimal treatment for crystal deposition is not yet established. Observation may be appropriate if the patient is asymptomatic. Chemotherapy, superficial keratectomy, and PKP have been described. Given the reported significant risk of recurrence and the inherent risks associated with keratoplasty, PKP might only be considered if chemotherapy has failed, as in our third case.
      • Nobacht S
      • Kusters B
      • Breukink MB
      • Rongen GA
      • Cruysberg JRM.
      Recurrence of paraproteinemic crystalline keratopathy after corneal transplantation: a case of monoclonal gammopathy of ocular significance.
      ,
      • Lisch W
      • Wasielica-Poslednik J
      • Kivela T
      • et al.
      The hematologic definition of monoclonal gammopathy of undetermined significance in relation to paraproteinemic keratopathy (An American Ophthalmological Society Thesis).
      ,
      • Milman T
      • Kao AA
      • Chu D
      • et al.
      Paraproteinemic keratopathy: the expanding diversity of clinical and pathologic manifestations.
      • Wasielica-Poslednik J
      • Gericke C
      • Desuki A
      • et al.
      Recurrence of paraproteinemic keratopathy after penetrating keratoplasty and its assessment with confocal microscopy.
      • Skalicka P
      • Dudacova L
      • Palos M
      • et al.
      Paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance (MGUS): clinical findings in twelve patients including recurrence after keratoplasty.
      There are no guidelines as to which systemic treatment is best. Several chemotherapies, plasmapheresis, and ASCT have been used. Our cases found varied success with chemotherapy. Further research is needed to elucidate which disease and treatment characteristics result in resolution without recurrence. Our fourth case is the first to show that crystal resolution achieved by chemotherapy and ASCT can be maintained long term (11 years). Crystal resolution was maintained despite a relapse in multiple myeloma. There are few other reported cases of patients with paraproteinemic keratopathy undergoing ASCT.
      • Wang TP
      • Safran SG
      • Richter JR
      • Siegel DS
      • Vesole DH.
      Subepithelial corneal immunoglobulin deposition as a manifestation of multiple myeloma: a case report and literature review.
      ,
      • D'Costa MR
      • Dalvin LA
      • Manohar S
      • et al.
      Crystalglobulin-induced nephropathy and keratopathy.
      A patient reported by Wang et al.
      • Wang TP
      • Safran SG
      • Richter JR
      • Siegel DS
      • Vesole DH.
      Subepithelial corneal immunoglobulin deposition as a manifestation of multiple myeloma: a case report and literature review.
      experienced complete clearing of the crystalline deposits with no recurrence after 2 years of follow-up.
      • Wang TP
      • Safran SG
      • Richter JR
      • Siegel DS
      • Vesole DH.
      Subepithelial corneal immunoglobulin deposition as a manifestation of multiple myeloma: a case report and literature review.
      Our cases also highlight the importance of long-term follow-up both in clinical practice and in reporting cases. Because multiple myeloma often relapses, reporting longer follow-up periods will allow for a better understanding of disease course with and without treatment.
      Because patients with paraproteinemic keratopathy may have no other end-organ damage at the time of presentation, the decision to treat may be challenging. Our second and fourth cases also developed anemia, which contributed to the decision to treat. It is important to recognize the limitations of chemotherapy, including the possibility of recurrence. Furthermore, there can be significant side effects to chemotherapy and ASCT. Depending on the regimen, side effects may include fatigue, gastrointestinal symptoms, neuropathy, and hair loss. Possible risks include low blood counts predisposing to infection or bleeding and graft-versus-host disease after ASCT. Therefore, the decision to treat with chemotherapy or ASCT must be taken in the context of symptom severity, other indications for treatment, and ultimately, the patient's own preferences. Our first case, for example, was significantly affected by her corneal disease and elected to undergo treatment with chemotherapy twice, whereas our second and fifth cases did not wish to undergo further therapy.
      Although there is now a growing number of reports on paraproteinemic keratopathy, these case reports are limited in terms of their generalizability. Prospective multicentre studies involving ophthalmologists and hematologists with adequate follow-up periods are required to better understand the efficacy of different treatment options. Until such studies are available, eye care providers should continue to partner with hematologists and patients when considering treatments on a case-by-case basis.

      Footnotes and Disclosure

      Consent to include case details has been obtained from all patients or their next of kin.
      The authors have no proprietary or commercial interest in any materials discussed in this correspondence.
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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