Retinopathy in a Patient With IgM MGUS: Causal Association or an Epiphenomenon?

Case Report

Clinical presentation and medical history. A 72-year-old man presented with progressive worsening blurred vision since few months. He complained about reduced visual acuity mainly in high-light conditions. From his past medical history, he was diagnosed with IgM MGUS 22 years ago. The most recent IgM level was 1,450 mg/dl, compared to 400 mg/dl at diagnosis before 22 years (Figure 1). The current bone marrow biopsy revealed 8-10% infiltration of monoclonal plasma cells. The evaluation for MYD88 gene mutational status showed MYD88 wild type. The patient also had a history of hypertension, dyslipidemia, thyroid disease, gastritis, bilateral cataract surgery, and a transient ischemic attack 15 years ago. He was a current smoker (40 pack-years) and he did not drink alcohol. His medications included levothyroxine, acetylsalicylic acid, atorvastatin and olmesartan with amlodipine and hydrochlorothiazide. He had reported no other personal or familial history of ocular disease.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1.

Sequential evaluation of IgM kinetics during and after treatment with DRC. BM: Bone marrow; PCs: plasma cells; IgM: immunoglobulin M. DRC: Dexamethasone, rituximab, cyclophosphamide.

Ocular findings. The ophthalmological examination revealed reduced vision in high light conditions and in bright environment. The best corrected visual acuity was 6/10 in the right eye and 6.5/10 in the left eye. The optical fields examination revealed an arc-shaped scintillating scotoma. The ophthalmoscopy (fundoscopy) and color photographing of the fundus showed no particular alterations on the retina. The optical coherence tomography and the fluorescent angiography showed no abnormal findings. However, the classic electroretinography (light and dark) demonstrated an electronegative electroretinogram, which was compatible with inner retinal dysfunction at the retinal layer of bipolar cells.

Imaging findings. The brain and eye magnetic resonance imaging (MRI) did not detect any abnormal findings in the optic nerves, the optic chiasm and the optic tracts. There were minimal small vessels lesions in the subcentral loci of the right frontal lobe.

Differential diagnosis and further workup. In this context, the patient underwent further examination to rule out occult malignancy and cancer-associated retinopathy, as well as autoimmune-related retinopathy. The clinical examination did not reveal any clinical manifestation of autoimmune disease, whereas serum markers were negative for auto-antibodies suggestive of autoimmunity, except for the previously known thyroid disease. The upper and lower endoscopy of the gastrointestinal tract showed grade 1 gastritis and the colonoscopy showed a colon polyp which was removed completely and the biopsy showed no signs of malignancy. The dermatological examination demonstrated no lesions suspicious for melanoma or other skin cancer and positron emission tomography/computed tomography (PET/CT) was negative for hypermetabolic lesions suggestive of malignancy. The cerebrospinal fluid analysis was negative for the presence of B-cells or plasma cells, whereas there was a T-cell population consisted of CD3+/CD4+ (60%) and CD3+/CD8+ (40%) T-lymphocytes, which is non-disease specific. The glucose levels were normal, total protein level increased at 83 mg/dl (normal range 15-45 mg/dl), and no red blood cells or other cells were present.

Taking into consideration the above, an association between the patient’s retinopathy and the IgM MGUS emerged as a potential diagnosis and an ocular immunology panel for cancer-associated retinopathy and autoimmune retinopathy was evaluated. The investigation included testing for antibodies against carbonic anhydrase II, heat shock protein 27, heat shock protein 60, aldolase, enolase, arrestin, tubulin, pyruvate kinase M2, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), recoverin, Rab6 and TULP1. The patient was positive for antibodies against carbonic anhydrase II and arrestin, whereas immunohistochemistry on human retina using patient’s serum was positive with moderate staining of the outer and inner segment of photoreceptor cells.

Treatment and patient outcomes. Based on the above results, ophthalmologic examination, clinical presentation, and history we set the diagnosis of IgM-related retinopathy and the patient started treatment with dexamethasone 20 mg on day 1, rituximab 375 mg/m2 on day 1 and cyclophosphamide 100 mg/m2 on days 1 to 5 (DRC regimen) administered every 3 weeks for 6 cycles. The patient tolerated treatment well except for gastrointestinal toxicity, but dose modifications or treatment delay were not necessary. The IgM level was gradually reduced, and the patient had a minor hematological response (>25% IgM reduction) at one month post treatment completion and a partial hematological response (>50% IgM reduction) at three months post treatment completion (Figure 1). The bone marrow biopsy following treatment revealed a reduced percentage of 3% clonal plasma cells. The patient reported a gradual improvement of ocular symptoms. The electroretinography showed an improvement by 50% for the cones and by 75% for the rods along with a reversal of the previously electronegative phenotype. There was also an improvement in best corrected visual acuity to 7/10 in both eyes. At one-and-a-half-year post treatment completion, the patient’s condition remains stable. However, regarding the ocular immunology profile, the patient remained positive for carbonic anhydrase II and arrestin, whereas he was also positive for enolase post treatment. The patient gave his written informed consent for the publication of this Case Report.