Paraproteinemic Keratopathy

Etiology

Gammopathy is caused by the aggregation of immunoglobulin (Ig) in various tissues. Ig can accumulate in most ocular tissues, including the cornea or retina, resulting in various pathologies due to the interference of normal tissue functioning by protein invasion. In paraproteinemic keratopathy, immunoglobulins form paracrystalline inclusions that impair corneal transparency, resulting in reduced visual acuity.[12]

Multiple studies have additionally shown that patients with monoclonal gammopathy have significant decreases in corneal transparency as measured by corneal densitometry. It is unclear if these corneal changes lead to paraproteinemic keratopathy; however, these findings suggest that corneal deposition may be present subclinically in all patients with monoclonal gammopathy. It is not understood why some patients develop PPK, defined by paracrystalline deposit formation and visual impairment, while most do not.[12][13]

Epidemiology

Corneal deposition is a rare finding in paraproteinemic keratopathy (PPK), estimated to affect less than 1% of patients with systemic gammopathies.[14][15][16] The incidence of monoclonal gammopathy increases with age, and PPK likely follows a similar trend. One study found the average age at diagnosis to be 67 (50 to 87), although another study reported a case of PPK in a 24-year-old patient, emphasizing the highly varied presentation of this disease.[17] No specific genetic mutation has been associated with the disease, and men and women appear to be affected equally.[7]

Pathophysiology

The pathophysiology of paraproteinemic keratopathy, including how immunoglobulins reach the cornea, is currently poorly understood. One study measured an increase in the densitometry of the anterior and central parts of the cornea compared with the posterior aspect of the cornea. This study suggests that the immunoglobulin light chains in these cases may be washed over the cornea while dissolved in tears and subsequently diffuse into the tissue of the cornea itself from the epithelial side.[13] 

Other studies found deposition affecting the posterior cornea as well, emphasizing the high degree of variability that characterizes this disease. Other mechanisms also have been studied, including deposition from limbal vasculature and immunoprotein production by keratocytes.[1][3] The most common type of immunoglobulin is IgG-kappa, suggesting that this isotype is more prone to corneal deposition and crystal formation.[3]

Histopathology

As with most elements of this disease, histopathologic findings vary widely. Ig deposition may occur intracellularly or extracellularly and has been seen in limbal vascular endothelium, corneal stroma, corneal keratocytes, and conjunctival fibroblasts. An immunohistochemical evaluation may be the most specific histopathological assay, as these deposits are usually reactive for Ig light chain, Ig heavy chain, or both. They are eosinophilic on H&E stain and fuchsinophilic with Masson trichrome.[8]

Electrophoresis performed on the deposits will also reveal immunoglobulin deposits, which can distinguish paraproteinemia from other disease processes causing protein deposition, such as cystinosis.[18] Immunoglobulin deposits are also non-birefringent, PAS-positive, and Congo red negative, which allows them to be distinguished from amyloid deposits such as those found in lattice corneal dystrophy.[1][8]

The corneal copper deposition may be seen on histology as well due to the high affinity of some types of immunoglobulin for copper. While this does occur in monoclonal gammopathies and is also mediated by immunoglobulin deposition, it occurs via a separate mechanism and presents differently than PPK. Copper deposition disease and will not be addressed at length in this article.[17]

History and Physical

Patients with paraproteinemic keratopathy are often asymptomatic; however, many experience photophobia and gradual worsening of vision due to corneal irregularity and opacification. These symptoms progress over several years and are usually bilateral, although they may also be asymmetric or monocular.[1][3][8][19] 

Ocular dysfunction may be among the first presenting symptoms of systemic gammopathy or may develop in patients ten or more years after diagnosis. Other findings suspicious of gammopathy include fever, night sweats, weight loss, bone pain, unexplained renal dysfunction, and hypercalcemia.

Evaluation

Patients presenting with signs of paraproteinemic keratopathy or other signs and symptoms suspicious of gammopathy should be worked up for a systemic monoclonal proliferation. Serum protein, serum free light chains, serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP), flow cytometry, and bone marrow biopsy with aspirate should be obtained.[20]

Diagnosis is made via slit-lamp exam or confocal microscopy by the identification of paracrystalline protein deposits seen throughout the cornea, in addition to serum findings described above. Immunohistochemistry and electrophoresis are also effective methods of diagnosis if corneal specimens have already been obtained during surgery; however, less invasive methods should be used where possible. The specific findings in PPK vary widely. The deposits may be iridescent and vary in color from white to grey or yellow and may affect any or all layers of the cornea. Deposits may be diffuse or sporadic, vary in density, and usually affect bilateral corneas. They may be central or peripheral.[3][17]

On electron microscopy, areas of normal corneal stroma containing crystalline protein deposits are found. Of note, in patients with multiple myeloma and paraproteinemic keratopathy, nearly identical crystalline structures may be found within bone marrow cells, as seen on light and electron microscopes.[3]

Treatment / Management

Treatment of paraproteinemic keratopathy consists of first addressing the underlying cause of the systemic monoclonal gammopathy. Immediate referral to a hematologist or oncologist upon discovery of the disease is essential. Systemic treatments may include plasma exchange, rituximab, chemotherapy (alkylating agents, purine analogs, bortezomib, and thalidomide), and stem cell transplantation. The resolution of the underlying disease may stop the progression of the disease. Some studies have shown regression in ocular symptoms after chemotherapy, while others report continued progression of the disease despite the resolution of the systemic process.[1][2][7][8][17](B3)

In some systemic processes, such as MGUS, systemic treatment is not always indicated. In these cases, close cooperation between hematology/oncology and ophthalmology is necessary for the determination of appropriate treatment. Findings of ocular dysfunction may be an indication for the initiation of systemic therapy.[8]

After managing the systemic disease, the treatment of paraproteinemic keratopathy is only necessary when vision is significantly impaired. Patients with minimal visual impairment do not need additional treatment, although they should be monitored for the progression of the disease. Where visual acuity is significantly affected, there is no consensus on the appropriate course of treatment. Surgical correction of the affected corneas may resolve visual impairment; however, there may be a high risk of recurrence, depending on the procedure being used.[3][8] Potential therapies are summarized below:

• Phototherapeutic keratectomy (PTK) may be useful in treating loss of visual acuity due to deposits in the anterior cornea. Because PTK only treats the anterior layers of the cornea, it is only useful for superficial treatments of the disease. It is unlikely to be a definitive treatment, as deposition of Ig will continue as long as systemic levels remain elevated; however, it may allow systemic treatment to be delayed where chemotherapy is not otherwise indicated (ex. MGUS).[8]

• For severe cases, penetrating keratoplasty (PK) or Deep Anterior Lamellar Keratoplasty (DALK) may restore visual acuity; however, there is a high likelihood of rapid recurrence if serum Ig levels remain elevated. These recurrences occur rapidly, usually between one month and three years after PK. Treatment of the systemic disease is aimed at reducing Ig levels and may reduce the likelihood of recurrence.[1][8] Careful consideration should be given the risks of recurrence in patients with systemic gammopathy, and some sources suggest that this may be a contraindication for these procedures.[8]
(B3)

• Primary keratoprosthesis implantation may be used as a second-line therapy if penetrating keratoplasty fails. This procedure remains the second line to PK due to the limited data on risks vs. benefits in the general population; however, one study suggests that it may have better long-term outcomes in patients with PPK.[1] Primary keratoprosthesis procedures may not be offered at all surgical centers. Complications include increased intraocular pressures, vitritis, endophthalmitis, and retroprosthetic membrane formation.[1] 
(B3)

• Topical steroids have not shown any measurable benefit in treating or slowing the progression of deposits in MGUS keratopathy.[7]

Differential Diagnosis

Paraproteinemic keratopathy is often initially misdiagnosed as other corneal pathologies, with misdiagnosis becoming apparent after initial treatment fails. In suspected corneal dystrophy, for example, recurrent disease within a year of penetrating keratoplasty is evidence that a systemic process may be involved. In all cases where systemic gammopathy is suspected, SPEP or UPEP should be obtained, along with further workup as described above. Differential diagnosis is broad and includes:[1][7][8][21]

• Amyloidosis
• Arcus lipoides
• Schneider corneal dystrophy
• Lattice corneal dystrophy
• Gelatinous, drop-like corneal dystrophy
• Granular corneal dystrophy
• Diffuse stromal corneal dystrophy
• Reis-Bucklers corneal dystrophy
• Pre-Descemet corneal dystrophy
• Cystinosis
• Peripheral hypertrophic degeneration
• Limbal stem cell deficiency
• Cornea farinata
• Posterior corneal pigmentation
• Interstitial keratitis
• Salzmann nodular degeneration
• Lecithin cholesterol acyltransferase (LCAT) enzyme deficiency

Prognosis

Paraproteinemic keratopathy is a correctible cause of vision loss and therefore has an excellent prognosis with treatment. Where the systemic gammopathy is successfully treated, ocular disease progression usually ceases. If treatment occurs early enough, corneal damage may be kept to a minimum and require no further intervention. Where there is significant visual impairment, the corneal transplant has a high degree of success in returning short-term functional vision. If the systemic gammopathy is not resolved, there is a high probability of recurrence after a corneal transplant. With the resolution of systemic disease, ocular symptoms may regress on their own, and patients requiring corneal transplants are likely to have more durable results.[1][3][8]

Complications

Paraproteinemic keratopathy is a progressive disease often resulting in loss of visual acuity. Rapid recurrence of disease after corneal transplant is a common complication in patients with ongoing systemic gammopathy. Treatment of the underlying disease may reduce the risk of recurrence.[1]