What is Paraproteinemic Keratopathy?
Ocular monoclonal gammopathy, also known as paraproteinemia, is a condition where damage to the eye occurs due to a buildup of specific proteins, called monoclonal immunoglobulins, in different parts of the eye. This buildup is caused by high levels of these proteins circulating in the blood, a phenomenon often associated with diseases like multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of unknown significance (MGUS). Other diseases like B-cell lymphoma and primary amyloidosis can also cause this condition. Although eye symptoms due to gammopathy are rare, they can sometimes be among the first signs of these systemic diseases.
Several eye diseases can result from systemic gammopathy, including paraproteinemic keratopathy, retinal vein occlusion, paraproteinemic maculopathy, and others. Paraproteinemic keratopathy (PPK) is one of the best-studied eye conditions linked with monoclonal gammopathy. Also known as corneal crystalline deposition, MGUS keratopathy, or MGUS associated corneal opacification. PPK is a condition where deposits of these proteins build up in the cornea and potentially leading to vision loss.
Systemic gammopathy can also result in a condition called retinal vein occlusion. This condition frequently occurs in Waldenström macroglobulinemia due to high levels of a specific type of protein, IgM, leading to increased blood thickness and a greater risk of blood clotting.
Another eye condition, paraproteinemic maculopathy, occurs due to fluid accumulation behind the retina, potentially leading to retinal detachment and vision loss. This condition is most common in Waldenström macroglobulinemia and has also been associated with multiple myeloma and MGUS.
Certain extremely rare conditions can also occur due to ocular gammopathy. Ocular crystal storing histiocytosis (CSH) is one such. Here, protein deposits form crystals that accumulate in multiple tissues, including the conjunctiva, periorbital fat, and extraocular muscles of the eye, which can cause masses. Similarly, corneal copper aggregation occurs due to buildup of monoclonal gammopathy of IgG proteins that have a high affinity for copper. These proteins gather along the Descemet membrane and the anterior lens capsule.
A few cases of conditions like open-angle glaucoma and anterior uveitis have also been linked to monoclonal gammopathies. It’s important to remember that while these conditions are possible, they are rare, and the main focus of this discussion is the condition of paraproteinemic keratopathy.
What Causes Paraproteinemic Keratopathy?
Gammopathy is a condition caused by the buildup of a type of protein called immunoglobulin, or Ig, in different parts of the body. This buildup can occur in many parts of the eye, like the cornea (the clear front surface of the eye) or the retina (the back part of the eye that sends visual signals to the brain) and cause different eye issues. This happens because the proteins disrupt the normal workings of these eye tissues.
One specific eye problem caused by this is paraproteinemic keratopathy, where immunoglobulins create crystal-like inclusions in the cornea. These inclusions cloud up the cornea and can lead to problems with vision clarity.
Many studies also show that patients with monoclonal gammopathy, a form of gammopathy, have notable decreases in the clearness of their corneas, as shown by a technique called corneal densitometry. It’s still not certain whether these changes in the cornea lead to paraproteinemic keratopathy. However, these results suggest that protein deposits may be present and not detected in the early stages in all patients with monoclonal gammopathy. The mystery remains as to why some patients go on to develop paraproteinemic keratopathy, defined by crystal-like deposit formation and visual impairment, while most do not.
Risk Factors and Frequency for Paraproteinemic Keratopathy
Corneal deposition in paraproteinemic keratopathy (PPK), which is a problem related to the eyes, is quite rare and it’s estimated to impact fewer than 1% of patients with systemic gammopathies, a group of diseases that affect the immune system. The older a person gets, the higher the chances are of them having monoclonal gammopathy, a blood disorder, and it’s thought that PPK follows the same pattern. According to research, people tend to be diagnosed around the age of 67, though it can vary widely. In one particular case, a person as young as 24 was diagnosed with PPK, showing just how different each case can be. There’s no specific gene associated with this disease, and it seems to affect men and women equally.
Signs and Symptoms of Paraproteinemic Keratopathy
Paraproteinemic keratopathy is a condition that often doesn’t show any symptoms. However, some patients may experience light sensitivity (photophobia) and a slowly worsening vision due to changes in the surface and clarity of the cornea. These symptoms may persist for several years and typically affect both eyes, although their effect may vary in each eye or even occur in only one eye.
Sometimes, problems with vision may be one of the first signs of a systemic gammopathy (a group of diseases involving proteins in the blood) or may appear ten or more years after the diagnosis. Other signs that might suggest gammopathy include:
- Fever
- Night sweats
- Weight loss
- Bone pain
- Unexplained problems with kidney function
- High levels of calcium in the blood (hypercalcemia)
Testing for Paraproteinemic Keratopathy
If you’re showing symptoms of an eye condition called paraproteinemic keratopathy or other conditions related to gammopathy (which involves a problem with proteins in your blood plasma), your doctor may need to run several tests. These could include tests for serum protein and serum free light chains, as well as specific processes known as serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP), flow cytometry, and bone marrow biopsy with aspirate. These tests help the doctor see if there’s a buildup of proteins in your bloodstream that might be causing your symptoms.
To help confirm a diagnosis, doctors use a special microscope called a slit-lamp or another type of microscope, called confocal microscope. Through this, they can see if there are protein deposits known as paracrystalline proteins in your cornea (which is the clear, front surface of your eye). Along with the tests mentioned before, this can give the doctor a thorough understanding of what might be happening in your body.
Sometimes, if small samples of cornea tissue have already been taken during surgery, the doctors can use methods called immunohistochemistry and electrophoresis to look for paracrystalline proteins. However, less invasive methods are always preferred if possible. The signs of paraproteinemic keratopathy can vary a lot between different people, in aspects such as the color, location, and density of the deposits, or how much of the cornea they affect.
Additional examination using a high-powered electron microscope can show areas of regular corneal tissue containing these crystalline protein deposits. Interestingly, in patients who have both multiple myeloma (a type of cancer affecting plasma cells) and paraproteinemic keratopathy, nearly identical crystalline structures can be found both in the cornea and within cells in the bone marrow as seen under microscope.
Treatment Options for Paraproteinemic Keratopathy
When treating paraproteinemic keratopathy, a condition affecting the cornea, addressing the root cause – a condition called systemic monoclonal gammopathy – is crucial. This condition often requires an immediate referral to a specialist doctor, such as a hematologist or oncologist. Treatment options can range from plasmapheresis (a process to filter the blood) and targeted therapies (like rituximab), to chemotherapy and stem cell transplantation.
Effective treatment of the underlying disease can potentially halt the progression of paraproteinemic keratopathy. Some studies have noted an improvement in eye symptoms following chemotherapy, though others indicate continued eye disease progression despite the underlying cause being resolved.
In some cases, as with a condition known as Monoclonal Gammopathy of Undetermined Significance (MGUS), treatment may not always be required. Instead, close collaboration between hematologists/oncologists and ophthalmologists becomes necessary to determine the next steps. Should the eyes reveal signs of dysfunction, this may indicate the need to initiate treatments directed at the systemic disease.
Once the underlying disease is managed, additional treatment for paraproteinemic keratopathy is only needed if vision is significantly impaired. For patients with minimal vision changes, additional treatments might not be necessary, although ongoing monitoring for disease progression is important. There isn’t a consensus on the best course of action if visual acuity is significantly affected. Surgical interventions can improve vision, but there could be a high risk of the disease coming back, depending on the procedure used.
Specific therapies might include Phototherapeutic Keratectomy (PTK), which might be helpful for treating visual loss due to deposits in the front part of the cornea. However, as PTK only treats the front part of the cornea, it’s only useful for superficial treatments of the disease and is unlikely to be a definitive treatment.
More severe cases might require surgeries known as Penetrating Keratoplasty (PK) or Deep Anterior Lamellar Keratoplasty (DALK). While these procedures can restore visual acuity, there is a high chance of quick recurrence if immunoglobulin (Ig) levels in the bloodstream remain high. Effective systemic disease treatment is aimed at reducing these Ig levels and may reduce recurrence likelihood.
In cases where penetrating keratoplasty fails, a procedure called primary keratoprosthesis implantation might be considered. However, this procedure isn’t offered at all surgical centers, and it might carry certain risks, such as increased eye pressure, inflammation, and infection.
Lastly, the use of topical steroids has not shown any clear benefit in treating or slowing the deposit progression in MGUS keratopathy.
What else can Paraproteinemic Keratopathy be?
Paraproteinemic keratopathy, a disease affecting the cornea of the eye, is often mistaken for other eye conditions. This misdiagnosis usually becomes evident when the initial treatment doesn’t work. For instance, if a corneal dystrophy (a disease of the cornea) reoccurs within a year after surgery, it’s a sign that a body-wide process could be taking place. In such cases where a disorder in the proteins in Plasma (gammopathy) is suspected, certain tests (SPEP or UPEP) should be carried out, alongside other necessary examinations.
There is a wide range of conditions that could be confused with paraproteinemic keratopathy. These include:
- 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
What to expect with Paraproteinemic Keratopathy
Paraproteinemic keratopathy, a condition that can cause vision loss, can be corrected and has a good outlook when treated. When the underlying generalised abnormality of the immune system (systemic gammopathy) is effectively treated, the eye condition usually stops worsening. If treated early enough, any damage to the cornea, the clear, curved surface on the front of your eye, can be minimal and may not need further treatment.
For advanced cases that significantly affect your vision, a corneal transplant can be very successful in restoring clear short-term vision. However, if the immune system abnormality continues, there’s a high chance that the eye condition will reoccur after a corneal transplant. If the immune system issue is treated and resolved, the eye symptoms may subside on their own, giving patients, that had a corneal transplant, a better chance for a long-lasting improvement.
Possible Complications When Diagnosed with Paraproteinemic Keratopathy
Paraproteinemic keratopathy is a disease that gets worse over time, often causing vision loss. A common issue patients face after a corneal transplant is the quick return of the disease, especially in those with continuous systemic gammopathy. However, treating the underlying disease may lower the chances of the disease coming back.
Common issues:
- Progression of disease resulting in vision loss
- Rapid return of disease after corneal transplant
- Higher risk of recurrence in patients with ongoing systemic gammopathy
- Potential reduction in recurrence risk by treating the underlying disease
Preventing Paraproteinemic Keratopathy
If you’ve been diagnosed with diseases such as multiple myeloma, Waldenström macroglobulinemia, MGUS, or other systemic gammopathies, it’s critical to understand the potential eye-related risks of these conditions. These diseases can affect your eye health, so it’s crucial to follow your treatment plan closely and have regular check-ups. Multiple myeloma is a cancer of plasma cells, Waldenström macroglobulinemia is a rare blood disease, and MGUS is a condition which may potentially develop into cancer. Systemic gammopathies refer to disorders associated with abnormal proteins in the blood. Adhering to therapy and undergoing regular check-ups can help you manage these conditions and prevent or manage any associated ocular risks effectively.
