Localized retinal degeneration secondary to Waldenström's macroglobulinemia.

A 52-year-old man, treated for Waldenström's macroglobulinemia (WM), continued to experience decreased vision even after 24 months. He was evaluated using multimodal imaging and electroretinography. The retina did not show any hyperviscosity changes but revealed a yellow lesion at macula with atrophic changes causing a pattern on fluorescein angiography similar to a leopard's skin. Optical coherence tomographic imaging revealed uniformly reflective material deposited in the outer retina with degeneration of outer retinal layers. Full-field electroretinography was normal, but multifocal electroretinography revealed reduced foveal responses. This case highlights the degenerative effects of long-standing immunogammopathy maculopathy in WM.

Introduction

Waldenström's macroglobulinemia (WM) is a chronic lymphoproliferative disorder, characterized by heterogeneous lymphoplasmacytic bone marrow infiltrate and high IgM production. Hyperviscosity is caused by the overproduction of IgM, and the deposition of this immunoglobulin-derived material leads to various ocular manifestations. The retinal changes, collectively known as the “dysproteinemic fundus,” include retinal hemorrhages, dilated retinal veins, cotton wool spots, optic disc swelling, and serous macular detachments.[1] The serous macular detachments are considered to be caused by the accumulation of immunoglobulins in the subretinal space. Friedman et al.[2] demonstrated immunoglobulin immunofluorescence within all layers of the retina. The immunoglobulins may persist in the subretinal space; however, it is unknown how long they may persist and to what extent they can affect the retinal pigment epithelial (RPE) layer and photoreceptors. We present a case that shows the degenerative effects of the long-standing immunogammopathy maculopathy on the retinal cells.

Case Report

A 52-year-old man was diagnosed to have WM 2 years ago. At that time, the complaints of diminution of vision led to the discovery of serous retinal detachments in macular area of both the eyes and retinal hemorrhages suggestive of a hyperviscosity state. The diagnosis of WM was confirmed with bone marrow biopsy. The patient was treated with multiple cycles of chemotherapy for over a year. Thereafter, the blood counts were stable. However, the vision did not improve. He was reexamined at this stage, 2 years from the diagnosis and 1 year after the chemotherapy was over.

His best-corrected vision was 20/60 in both the eyes. The anterior segments were normal. Retinal examination revealed a circular punctate yellowish lesion at macula, with atrophic pigmentary changes in both the eyes. The temporal rim of these lesions appeared to reveal a slightly elevated serous detachment. This was more clearly evident in autofluorescence images that showed a complete absence of autofluorescence at the fovea covering about 1 disc area. The outer area showed spotted appearance similar to a leopard's skin with hypoautofluorescence in the center surrounded by hyperautofluorescence. The outermost rim showed tiny hyperfluorescent specks. The same pattern was seen in fluorescein angiography. There was neither leakage nor pooling of the dye. The spectral-domain optical coherence tomography (OCT) images showed the elevation of retina, with retinal thickening and small cystoid spaces. There was disorganization of the outer retinal layers. The inner segment–outer segment junctional photoreceptor layer and external limiting membrane layers were absent. The RPE layer was thinned out and atrophic. The area between the outer retinal layers and the RPE showed moderately reflective, nearly homogeneous material. Along the RPE, a few clumps of highly reflectile material were seen [Figure 1].

Figure 1

Fundus images of the right (a) and left (b) eyes showing round yellow-speckled area of atrophy at the macular region. The temporal rims of this circular area are slightly elevated. (c and d) Show autofluorescence images of right and left eyes, respectively. Centrally, there is absence of autofluorescence indicating retinal pigment epithelial atrophy. The surrounding area shows spotted pattern of hypo- and hyper-autofluorescence resembling a leopard's skin. Temporal rims show tiny speckled hyperautofluorescence. (e and f) Show mid-phase photographs of fluorescein angiography showing a similar pattern without any leakage or pooling of dye. Spectral-domain optical coherence tomography images of the right (g) and left (h) eyes show retinal thickening, intraretinal fluid spaces, disorganization of the outer retina, and thinning and atrophy of the photoreceptor and retinal pigment epithelial layers. Deposition of moderate reflective material can be seen under the retina

Electroretinographic studies showed normal rod and cone responses, but multifocal electroretinography revealed reduced foveal and parafoveal responses and minimally reduced perifoveal responses. Blood tests revealed normal blood counts and no abnormal cells. In view of the degenerative and atrophic changes at macula, no intervention was advised, and the patient was offered visual rehabilitation with spectacles.

Discussion

The most common retinal change seen in WM is retinal hemorrhage owing to venous stasis retinopathy or frank vein occlusions. Many times, these changes are the presenting signs of this disease. The hyperviscosity state caused owing to the deposition and cryoprecipitation of the abnormal immunoglobulins leads to venous stasis. The vascular changes have been used as an index to help grade the hyperviscosity levels.[3] These changes are seen to be completely reversible on correction of the hyperviscosity state.

Serous retinal detachment is often reported in WM. However, these lesions are angiographically silent.[4] They do not show any leakage. The reason for this is postulated to be deposition of immunoglobulins in the subretinal space, which increases the osmotic gradient leading to transudation of fluid into the subretinal space.[5]

These detachments are known to persist even after the disease is in remission. Only one report has mentioned the occurrence of RPE atrophy following such a detachment in WM.[5] Our patient showed the destruction of photoreceptors and the RPE layer in the area of the detachment. Such a pattern of atrophy has never been reported. In addition, from the OCT, there appears to be deposition of some material under the retina. We have no means to confirm the nature of these deposits. Brolly et al.[6] have reported a similar case wherein they have postulated the subretinal deposits to be caused by the accumulation of immunoglobulins. Friedman et al.[2] have confirmed the deposits in the outer layers of the retina to be immunoglobulins by immunofluorescent staining. Discontinuity in outer retina had been demonstrated on OCT by Baker et al.[7] which may enable the immunoglobulins to flow out into the subretinal space. In WM, deposition of amyloid has also been reported in dermis, optic nerve, etc.[89]

The destruction of photoreceptors and RPE cells could be a result of various factors. Toxic effects owing to the deposition of immunoglobulins on the cells leading to interference with the passage of micronutrients and increased intracellular osmotic pressure have been considered to be the reason for destruction. Another mechanism could involve an autoimmune response owing to the circulating immunoglobulins reacting to the photoreceptor proteins. Sen et al.[10] showed progressive paraneoplastic retinopathy in a patient with WM. The patient's visual acuity, visual fields, and electroretinogram showed progressively worsening changes. However, the retinal examination throughout the follow-up period was normal in their patient.

These serous detachments have been variably treated with intravitreal injections of antivascular endothelial growth factor antibodies and dexamethasone implants without much change in the subretinal fluid.[111213] They only helped in reducing intraretinal fluid and retinal thickness associated with hyperviscosity. We did not offer any active intervention to our patient owing to the extensive atrophic changes.

Conclusion

Although previous reports have discussed the possibility of photoreceptor damage owing to persistence of serous detachment, none have shown so clearly the extent of photoreceptor and RPE atrophy that is possible. This case demonstrates the potential of immunogammopathy maculopathy to cause irreversible visual loss owing to localized degeneration of photoreceptors and RPE long after the disease has been inactive.

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Conflicts of interest

There are no conflicts of interest.