Paraproteinemic Keratopathy Research Articles

Paraproteinaemic keratopathy simulating a crystalline keratopathy

BackgroundParaproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy.Case presentationa 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity.ConclusionsParaproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.

Does Systemic Hematological Therapy Influence the Course of Paraproteinemic Keratopathy?

The purpose of this article is to evaluate the course of paraproteinemic keratopathy (PPK) in patients undergoing systemic therapy for the underlying hematological disease. Baseline and follow-up examinations included hematological work-up, best-corrected visual acuity, slit-lamp biomicroscopy, and in vivo confocal laser scanning microscopy (IVCM). We included 22 patients with bilateral PPK (aged 68 ± 10.4 years, 11 males). Ten patients with multiple myeloma (MM) underwent on-label systemic therapy. During follow-up, we observed a regression of corneal opacities in three patients under slit-lamp examination and under IVCM, while PPK remained unchanged in seven patients. In three patients with monoclonal gammopathy of ocular significance (MGOS), systemic therapy was initiated off-label to reduce the serum paraprotein load before penetrating keratoplasty (PKP). These patients showed no signs of PPK recurrence for up to 24 months after PKP. In one patient without systemic therapy, a recurrence in corneal grafts occurred within 12 months of PKP. In eight patients without systemic therapy, PPK remained stable. In conclusion, systemic therapy for MM patients reduced corneal opacity in 30% of treated patients. Furthermore, systemic therapy performed before PKP in patients without conventional systemic therapy indication (MGOS) likely postpones PPK recurrence in the corneal graft.

CLINICAL AND IN VIVO CONFOCAL MICROSCOPY FINDINGS IN MGUS - A CASE REPORT

Purpose The purpose of this study was to describe a case of paraproteinemic keratopathy (PPK) in a patient with monoclonal gammopathy of undetermined significance (MGUS) Methods A 56 years old man was assessed using a slit lamp and in vivo confocal microscopy (IVCM) with Heidelberg HRT Rostock II. Results The patient showed bilateral diffuse, symmetric, non-polychromatic, punctiform crystals in all layers of the cornea. The remaining part of the ophthalmic clinical assessment was normal. Esthesiometry was normal in all quadrants. Anterior segment OCT confirmed diffused hyperreflectivity of the epithelium and corneal stroma. IVCM was then executed, showing polymorphic (granular, needle-like, stellate) hyperreflective crystals in all layers of corneal epithelium and anterior stroma, subbasal plexus nerves beading, cytoplasmatic hyperreflectivity of the keratocytes of the posterior stroma without any endothelial involvement After considering the age, health status, and ocular signs the primary entities to be investigated were adult benign cystinosis and paraproteinemic disorder. All the diagnostic tests were negative except for a monoclonal component IgG/k of 1.37 d/dl. A hematological examination was then performed with the resulting diagnosis of MGUS. In this paper, we analyzed 11 articles about IVCM in PPK in MGUS and other paraproteinemias highlighting IVCM features compatible with our findings allowing us to generalize a first diagnostic IVCM pattern for PPK. Conclusions In this case report we suggest the IVCM diagnostic patterns that may be used to identify PPK without corneal biopsy.

Two Cases of Paraproteinemic Keratopathy

Purpose: To report two cases of paraproteinemic keratopathy (PK).Case summary: A 57-year-old man visited the ophthalmology clinic complaining of decreased visual acuity since 1 year earlier. White crystalline deposits were observed on both corneas and the best corrected visual acuity (BCVA) of both eyes was 1.0. After 3 months, the BCVA decreased to 0.8 in the right and 0.6 in the left. Increased corneal deposits were observed. To rule out PK, his medical records were checked. The patient had been diagnosed with lymphoplasmacytic lymphoma 3 years earlier. Diagnosing PK, the patient was referred back to the Hemato-Oncology department. After 3 months of chemotherapy, the corneal deposits decreased and BCVA returned to 1.0. A 69-year-old woman presented complaining of decreased visual acuity for 2 years. The uncorrected visual acuity (UCVA) was 0.4 in the right and finger count at 30 cm in the left. Brown deposits were observed on both corneas and lenses. The serum copper level was elevated. She was referred to the internal medicine department and diagnosed with multiple myeloma. After treatment, the laboratory results returned to normal, but the UCVA decreased to hand motion in the left. A left white cataract was noted and cataract surgery was performed. 1 month postoperatively, the BCVA was 0.9, with no change in the corneal deposits.Conclusions: When there are corneal deposits, we should consider PK in the differential diagnosis. In such cases, systemic treatment is the first line. Therefore, diagnosing and referring PK patients to the internal medicine department is crucial.

Bilateral corneal opacities and surface irregularity: role of contact lenses in a case of paraproteinemic keratopathy and multiple myeloma

Introduction: This report features an interdisciplinary approach to diagnose and manage a case of paraproteinemic keratopathy and multiple myeloma. In addition, it suggests that rigid gas-permeable contact lenses (RGP CLs) may be a viable alternative to corneal surgery to reduce visual symptoms. Patient and clinical findings: A 57-year-old man symptomatic for progressive blur and glare over 2 years presented with an outside diagnosis of corneal dystrophy. An examination revealed bilateral diffuse subepithelial corneal crystals in conjunction with peripheral annular deposits with demarcated ridges. Corneal topography revealed central irregular astigmatism induced by these peripheral corneal opacities. Diagnosis, intervention, and outcomes: A hematological workup confirmed IgG Kappa monoclonal gammopathy and multiple myeloma. Visual rehabilitation for paraproteinemic keratopathy was achieved with RGP CLs, which are expected to maintain stable visual acuity while the patient undergoes systemic chemotherapy. Conclusions: This report emphasizes the value of thoroughly investigating dystrophy-like corneal deposits of unknown etiology as monoclonal gammopathy can have adverse or even fatal systemic implications. To the authors’ knowledge, this is the first study to directly suggest RGP CL as an adaptable and economical means to improve acuity in certain cases of paraproteinemic keratopathy without resorting to surgical intervention.

Monoclonal gammopathy of ocular significance (MGOS) – a short survey of corneal manifestations and treatment outcomes

Monoclonal gammopathy of ocular significance (MGOS) is a rare subset of monoclonal gammopathy of clinical significance occurring secondary to plasma cell disorders and causing ocular manifestations. We identified 23 patients with paraproteinemic keratopathy (PPK) in the setting of monoclonal gammopathy of unknown significance (MGUS, 10), smoldering multiple myeloma (SMM, 3) or multiple myeloma (MM, 10). Many of these patients with PPK (11/23) presented decreased vision. All patients with MM and 40% of those with other diagnoses such as SMM and MGUS received systemic therapy with or without autologous stem cell transplantation. Four eyes of four patients were treated by penetrating keratoplasty. In most cases, neither ocular nor hematologic treatment afforded a durable improvement in the visual acuity (recurrence after a median of 11 months), despite initial responses. Further studies will be required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with PPK.

Monoclonal Gammopathy of Ocular Significance (MGOS) - a Series of Corneal Manifestations and Treatment Outcomes

IntroductionMonoclonal gammopathy of ocular significance (MGOS) is a rare subset of monoclonal gammopathy of clinical significance (MGCS) occurring secondary to plasma cell dyscrasia resulting in ocular manifestations. Given the rarity of these conditions, optimal management strategies are not defined; the approach is dependent upon the underlying cause of the monoclonal gammopathy and whether or not the patient's vision is affected. We report our review of 23 cases with MGOS, more specifically on paraproteinemic keratopathy (PPK) the most common form, to obtain a better understanding of the patient characteristics, diagnosis and treatments.MethodsWe report an international retrospective series of patients with MGOS. Data was collected on patients with MGOS:there were no other inclusion criteria besides monoclonal gammopathy with an ophthalmologic manifestation; however, this report focuses only on patients with PPK. Efficacy outcomes were the hematologic and the ocular responses in patients with PPK. Hematologic responses were reported according to the IMWG response criteria. The ophthalmologic response to treatment was assessed by each contributing physician and reported as either complete, partial or no sight recovery.ResultsWe identified 23 patients with PPK in the setting of monoclonal gammopathy of unknown significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM) diagnosed between 2006 and 2019 in 7 countries. Table 1 summarizes the patients' characteristics. The ocular diagnosis was typically made at the same time or after the hematologic diagnosis. Eleven of 23 patients presented decreased vision. Four were treated by penetrating keratoplasty with or without systemic therapy, including chemotherapy with new generation anti-MM agents with or without autologous stem cell transplantation (ASCT). All patients with MM and 40% of those with other diagnoses such as SMM or MGUS received systemic therapy. In most cases, neither ocular nor hematologic treatment, even when ASCT was performed, afforded a durable improvement in the visual acuity despite initial responses. MGOS typically relapsed within one year of the initial response (Table 2).ConclusionTo date, this is the largest retrospective study focusing on MGOS patients with monoclonal immunoglobulin deposits accumulating in the cornea and resulting in visual impairment. Further studies will be required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with PPK and specifically to address the timing of keratoplasty and systemic chemotherapy and the role of maintenance therapy. Patients with corneal manifestation of unknown origin should undergo a hematologic check-up and patients with paraproteinemia should have a periodic ocular health assessment. [Display omitted] DisclosuresGarderet: Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. Gozzetti: AbbVie: Honoraria; Janssen: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau.

The Spectrum of Ocular Manifestations in Patients with Waldenström’s Macroglobulinemia

ABSTRACT Purpose: To investigate the ocular manifestations in 91 Waldenström’s macroglobulinemia (WM) patients.Methods: Retrospective, cross-sectional, observational analysis.Results: Ocular impairments, detected in 19 patients, included flame-shaped hemorrhages, venous sausaging, papilledema, macular detachments, or central retinal vein occlusion in 16 patients; paraproteinemic keratopathy in 2; and a CANOMAD syndrome in 1. Best-corrected visual acuity was ≥0.5 logMAR units in 11 of 38 eyes. Intraocular pressure was increased in seven eyes. Genetic analysis in seven patients showed a mutation in the MYD88 gene in six patients and a nonsense mutation in the CXCR4 gene in five patients. Plasmapheresis followed by chemotherapy with or without the addition of rituximab resulted in improvement or normalization of the ophthalmological findings in 15 patients.Conclusion: The ocular manifestations of WM are protean and potentially sight threatening. Recent advances in genomic profiling and chemotherapy have remarkably improved the hematological and ophthalmological outcomes of these patients.

Multimodal imaging in paraproteinemic keratopathy.

Multimodal imaging in paraproteinemic keratopathy.

Clinical signs of paraproteinemic keratopathy

AbstractMonoclonal gammopathies are much more common than previously known in Ophthalmology. In the so‐called benign form or MGUS (Monoclonal Gammopathy of Undetermined Significance) different corneal opacities can be observed, in which the patients having no subjective symptoms or conspicuous systemic findings other than corneal opacities which were summarized as Paraproteinemic Keratopathy (PPK). It is therefore to be demanded that in all elderly patients with bilateral unclear corneal findings, Serum Protein Electrophoresis (SPE) should be performed to include or exclude monoclonal gammopathy.

Paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance (MGUS): clinical findings in twelve patients including recurrence after keratoplasty.

To describe the ocular findings of 12 subjects with paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance (MGUS). Ocular examination included corneal spectral domain optical coherence tomography. In three individuals with an initial diagnosis of a lattice or Thiel-Behnke corneal dystrophy, the TGFBI gene was screened by conventional Sanger sequencing. We confirmed a diagnosis of MGUS by systemic examination and serum protein electrophoresis in 12 individuals (9 males and 3 females), with a mean age at presentation of 52.2years (range 24-63years) and mean follow-up 6.4years (range 0-17years). The best-corrected visual acuity (BCVA) at presentation ranged from 1.25 to 0.32. In all individuals, the corneal opacities were bilateral. The appearances were diverse and included superficial reticular opacities and nummular lesions, diffuse posterior stromal opacity, stromal lattice lines, superficial and stromal crystalline deposits, superficial haze and a superficial ring of hypertrophic tissue. In one individual, with opacities first recorded at 24years of age, we documented the progression of corneal disease over the subsequent 17years. In another individual, despite systemic treatment for MGUS, recurrence of deposits was noted following bilateral penetrating keratoplasties. The three individuals initially diagnosed with inherited corneal dystrophy were negative for TGFBI mutations by direct sequencing. A diagnosis of MGUS should be considered in patients with bilateral corneal opacities. The appearance can mimic corneal dystrophies or cystinosis. In our experience, systemic treatment of MGUS did not prevent recurrence of paraproteinemic keratopathy following keratoplasty.

Paraproteinemic Keratopathy as a Clinical Sign of Monoclonal Gammopathy

Patients with monoclonal gammopathy can show paraproteinemic keratopathy (PPK) with an indication to treatment. PPK has to be differentiated from corneal dystrophies, systemic metabolic disorders with corneal involvement, as well as from immunologic and inflammatory corneal diseases.

Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations

To describe 7 patients with paraproteinemic keratopathy and to highlight the clinical and pathologic diversity of this rare entity and the importance of timely, systemic evaluation. Retrospective, multicenter collaborative case series. Seven patients with paraproteinemic keratopathy. Clinical and pathologic records were reviewed to identify patients with well-documented corneal immunoglobulin deposits. Detailed ophthalmologic and medical histories were assembled. In 6 patients, corneal tissue was evaluated histochemically and immunohistochemically; in selected cases, corneal tissue was evaluated by in situ hybridization and ultrastructurally. Visual acuity and anterior segment examination at presentation and follow-up; local therapy; systemic diagnosis and management; and histopathologic, immunohistochemical, in situ hybridization, and ultrastructural findings. Seven patients were identified with corneal immunoglobulin deposition. In addition to previously reported crystalline, nummular, patch-like, and lattice-like corneal opacities, prominent corneal vascularization was present in 2 patients mimicking interstitial keratitis and limbal stem cell deficiency. All patients had evidence of paraproteinemia in a setting of monoclonal gammopathy of undetermined significance, smoldering plasma cell myeloma, or Waldenström macroglobulinemia. Corneal findings were the first manifestation of systemic disease in 4 patients, and the diagnosis was not suspected in 3 of these patients. Pathologic evaluation of biopsied corneal and conjunctival tissues demonstrated immunoglobulin deposits. Previously unreported ultrastructural patterns in the cornea were noted: large scroll-like immunotactoid deposits, immune complex-like deposits, and randomly arranged fibrils morphologically intermediate between amyloid and immunotactoid deposits. Surgical intervention to improve vision was performed in 4 patients, with recurrence of deposits in 3 patients. Three patients underwent systemic therapy with diminution of the deposits and improvement in vision in 1 patient. The clinical and pathologic expressions of corneal immunoglobulin deposits are protean and present a diagnostic challenge. Early recognition of this rare entity is important to address the potentially serious associated systemic disease.

Localized conjunctival extra-nodal marginal zone B cell lymphoma with presumed paraproteinic crystalline keratopathy

Crystalline corneal deposits have been well reported in individual cases of lymphoproliferative disorders associated with hyper-gammaglobulinemia, hence called 'Crystalline Paraproteinemic Keratopathy'. This is the first report of corneal deposits in a case of localised conjunctival B-cell Lymphoma without paraproteinaemia/hyper-gammaglobulinemia, hence called 'Presumed Paraproteinic Crystalline Keratopathy'.

Crystalloidal Paraprotein Deposits in the Cornea: An Ultrastructural Study of Two New Cases with Tubular Crystalloids that Contain IgGk Light Chains and IgGγ Heavy Chains

The fine structure and immunoprotein content of the crystalloids are described in two cases of paraproteinemic crystalloidal keratopathy, both of which had clinical features thought by the referring ophthalmologists to be those of atypical lattice-type corneal dystrophy (presumably because of lattice-like lines). Most keratocytes in one case were surrounded by a mantle of densely packed tubular crystalloids. Individual tubules were annular in cross section with mean dimensions as follows: overall diameter, 29.32 nm (SD 1.26); internal diameter (core), 8.53 nm (SD 1.12); wall thickness, 10.39 nm (SD 0.85) (n = 10). Crystalloids were extracellular and found only in the corneal stroma, with none in Bowman's layer or Desce-met's membrane. In the second case, the tubules had a similar distribution but formed geometric arrays with no clear relationship to, or envelopment of, the keratocytes. The tubules were thin-walled, with mean dimensions as follows: overall diameter, 26.12 nm (SD 1.12); internal diameter (core), 15.46 nm (SD 1.12); wall thickness, 5.33 nm (SD 0) (n = 10). In both cases the tubules were K-light chain- and γ-chain-positive. Laboratory investigations revealed the presence of two IgM-k paraproteins and an IgG-K paraprotein in the serum of the first patient. The second patient had an IgG-K paraproteinemia and bone marrow changes consistent with low-grade non-Hodg-kin's lymphoma. These cases emphasize and extend the morphological range of corneal IgG crystalloids; the second case also demonstrates that corneal IgG crystalloids may be an early indicator of an underlying immunoproliferative disease.

Paraproteinemic Crystalline Keratopathy

Paraproteinemic crystalline keratopathy is an uncommon complication of multiple myeloma and other plasma cell dyscrasias. A case of 16 years' duration was associated with an IgG kappa monoclonal gammopathy and recurrent uveitis. The corneal changes were unusually extensive and distributed throughout all corneal layers. The deposits consisted of diffuse, small, polymorphic aggregates, which were iridescent in the superficial cornea, mat elsewhere, and associated with a diffuse stromal haze; specular microscopy showed additional features. Both corneas were thickened. The deposits failed to stain histochemically, except patchily with Masson Trichrome. There was extensive immunohistochemical labeling for IgG, kappa, and surprisingly, lambda. Ultrastructurally, pleomorphic deposits were found in every corneal cell; paracrystalline deposits with internal banding were seen only in the basal epithelium. Keratocytes and endothelial cells were damaged and reduced in number. Disease recurred in a corneal graft. Three main types of paraproteinemic keratopathy can be distinguished. The deposits probably represent various metabolic products of the monoclonal protein. This is not necessarily a benign condition; hematologic control may be necessary on purely ophthalmological criteria.