Autoimmune Retinopathy in Benign Thymoma after Good Syndrome-associated Cytomegalovirus Retinitis

Abstract

We report a case of anti-40kDa protein autoimmune retinopathy developing 9 years after thymoma excision on a background of Good Syndrome-associated cytomegalovirus (CMV) retinitis that suggests a separate pathogenetic pathway from that of previously reported thymoma-associated autoimmune retinopathies.

KEYWORDS::

• Autoimmune retinopathy
• Thymoma
• Good Syndrome
• Cytomegalovirus retinitis
• Autoantibodies
• Uveitis

A 51-year-old Chinese woman had a benign thymoma excised in 2001. No chemotherapy or radiotherapy was instituted. Pure red cell aplasia developed in 2006 and she was treated with immunosuppression. Good syndrome was diagnosed in 2008 after recurrent sinopulmonary infections and she was treated with monthly intravenous immunoglobulin (IVIg). Prior to treatment with IVIg, PCR for CMV DNA from plasma was negative. She subsequently lost vision in the left eye due to chronic retinal detachment secondary to presumed fungal endophthalmitis.

In 2009, she was diagnosed and treated for CMV enterocolitis. Three months later, she presented with right eye floaters and blurring of vision. Examination showed infero- and superonasal areas of yellowish necrotic retinitis along blood vessels with adjacent flame hemorrhage and vasculitis, and minimal vitritis (Figure 1) clinically consistent with cytomegalovirus (CMV) retinitis and corroborated on polymerase chain reaction (PCR) for CMV DNA from vitreous fluid. She was commenced on valganciclovir induction therapy but developed cytopenia. Attempted tapering of antiviral dosing resulted in multiple relapses and she required regular weekly intravitreal ganciclovir maintenance therapy (2 mg/0.01 mL) that successfully controlled her CMV retinitis.

FIGURE 1  (A) Fundus photo showing superior cytomegalovirus (CMV) retinitis characterized by yellowish necrotic retinitis along blood vessels with adjacent flame hemorrhage and vasculitis. (B) Fundus photo of posterior pole with drusen but no retinitis and minimal vitritis.

Visual acuity in the right eye gradually declined 6 months later from 6/12 to 6/60 over 6 weeks despite quiescent CMV retinitis and no complications of vitritis or cystoid macular edema, confirmed on OCT imaging. Fundus fluorescein angiography showed a normal foveal avascular zone with no capillary ischemia. Phacoemulsification with intraocular lens implantation temporarily improved vision to 6/15 but eventually deteriorated to counting fingers. An MRI of her brain and anterior visual pathway did not reveal any abnormalities that could account for the progression. Automated Humphrey visual field analysis and microperimetry confirmed decreased sensitivities in the retina and macula. Qualitative serum Western blot revealed anti-40-kDa protein antibodies (Oregon Health Sciences, USA). Electrophysiology assessment could not be performed, as she succumbed to pneumonia 3 months later.

In the absence of inflammation, compression, or vascular compromise, the findings in our patient were consistent with autoimmune retinopathy, a diagnosis of exclusion. Cancer-associated retinopathy (CAR) antiretinal antibodies are postulated to occur in response to aberrant tumor antigens that cross-react with retinal antigens. Four cases of thymoma-associated autoimmune retinopathy have been reported in the literature.^1–4 In thymoma CAR, antigens that cross-react with retinal antigens (molecular mimicry) may cause retinal apoptosis,^5–8 as evidenced by serum anti-recoverin antibodies being detected in 75% of reported cases and in 50% of resected thymomas. Interphotoreceptor retinoid-binding protein (IRBP) was detected in 1 reported case. In contrast to previously reported cases, autoimmune retinopathy in our patient involved anti-40-kDa protein and was associated with a long period of chronic relapsing CMV retinitis on a background of thymoma-associated paraneoplastic immune dysfunction viz. pure red cell aplasia and Good syndrome.

The normal thymus plays an important role in the concept of central immune tolerance. Bone marrow-derived precursor cells undergo positive and negative selection in the thymus before differentiating into thymocytes. Thymic epithelial cells mediate the positive selection process in particular. Thymomas, being abnormal proliferations of thymic epithelial cells, disrupt this process, resulting in paraneoplastic autoimmune disorders or immunodeficiencies such as Good syndrome. Studies conducted on patients with thymomas in relation to myasthenia gravis suggest that thymoma-associated autoimmunity may develop due to a defect of T-cell regulatory function or failure of intrathymic selection resulting in export of autoreactive CD4⁺ T cells.^9–11 Furthermore, thymoma-associated loss of immunological memory has been implicated in the development of CMV retinitis.¹²

Immune tolerance to recoverin is normally induced by expression of retina-specific recoverin within the newborn thymus.² Hence, aberrant expression of recoverin within thymomas in the presence of normal immune tolerance should not result in production of anti-recoverin antibodies. A multihit mechanism involving both thymoma-associated loss of T-cell immune regulatory function and aberrant recoverin expression may be required to explain the resultant production of circulating anti-recoverin antibodies.

The role of 40-kDa antigen is uncertain. Antiretinal antibodies can be present even in healthy subjects.⁷ However, in some autoantibodies associated with autoimmune retinopathy, such as anti-enolase, the antibodies found in patients with autoimmune retinopathy targeted apoptogenic epitopes, whereas those found in healthy subjects did not.⁷ Anti-40-kDa auto-antibodies that possess specificity to the amino-terminus of rod transducin-alpha have been found to develop months to years after tumor excision. They are theorized to originate from release of aberrant expressed antigens during excision.¹³ However, the 9-year duration between tumor excision and the onset of her ocular symptoms far exceeded that of previously reported cases. The relatively sudden onset and rapid progression following a course of chronic relapsing CMV retinitis suggests that CMV infection may be the second hit in the pathogenesis of autoimmune retinopathy in our patient. CMV has been associated with autoantibody development, particularly in immunodeficiency.^14,15 Anti-endothelial cell antibodies have been noted in transplant recipients after CMV infections, while anti-neurofilament and anti-retinal antibodies have been detected in HIV patients with CMV retinitis.^14,15 The relapsing CMV retinitis would have led to bouts of retinal necrosis and inflammation releasing sequestered retinal antigens to the immune system. Inflammatory co-stimulation and thymoma-associated loss of tolerance would have resulted in an inappropriate response to the antigenic stimulation, activating B lymphocytes to produce specific anti-retinal antibody that resulted in autoimmune retinopathy and rapid loss of vision.

Electrophysiological studies such as electroretinography and electrooculography are useful adjuncts in the diagnosis of autoimmune retinopathy. However, reports on electrophysiological criteria for the diagnosis of autoimmune retinopathy remains inconclusive, and such definite diagnostic criteria have yet to be established.⁷ The rapid clinical deterioration of our patient precluded such studies and this is a limitation of our case report. Nonetheless, given the overall clinical presentation and investigations, we feel that the diagnosis of autoimmune retinopathy remains valid.

In summary, the pathogenesis of thymoma-associated autoimmune retinopathy is likely to result from a multiple-hit mechanism involving thymoma-associated loss of immune tolerance as well as abnormal exposure of retinal antigens to the immune system that can result from either aberrant tumor expression or retinal inflammation. In the setting of a previous thymoma, aggressive treatment to stem any cause of ocular inflammation, such as CMV retinitis, would be prudent in order to forestall the development of thymoma-associated autoimmune retinopathy.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.