Workup, Diagnosis and Treatment
At presentation, the patient had already undergone an initial serologic evaluation for several forms of infectious retinitis by an outside ophthalmologist. HIV testing was negative, QuantiFERON-TB Gold was negative for tuberculosis and RPR/FTA-ABS tests for syphilis were nonreactive. Serum IgG testing returned positive for HSV-1, CMV and VZV, but IgM testing was negative for all three. Both IgG and IgM testing were negative for HSV-2. Complete blood count, basic metabolic panel and liver function tests were unremarkable.

Fundus photographs and OCT of the macula OU were taken in the office, and can be seen in Figures
 
Figure 2. OCT macula of the right and left eyes demonstrating macular thickening and edema on the right.
1 and 2, respectively. Anterior chamber paracentesis with removal of 0.1 ml of aqueous fluid was performed on the right eye and sent for viral PCR studies. The patient was started empirically on oral valganciclovir 900 mg twice per day due to concern for cytomegalovirus retinitis.

The patient returned two weeks later with slight subjective improvement in his vision and fewer floaters. Visual acuity had improved to 20/50 in the right eye. The anterior chamber reaction was improved. Repeat dilated fundus examination revealed less vitreous haze and stability in the area of retinitis OD (See Figure 3). PCR from the anterior chamber sample returned positive for CMV (377,000 copies/ml) and negative for HSV-1 and -2, VZV and Toxoplasma gondii.  

Discussion
Diabetes mellitus leads to a state of relative immune compromise through complex mechanisms, including dysfunction of host immune cells and increased virulence of pathogenic organisms in a high-glucose environment.1-3 Although cytomegalovirus (CMV) retinitis is classically associated with acquired immune deficiency syndrome (AIDS) with CD4 counts below 50 cells/ul,4 it has been reported in a variety of other conditions of immune dysfunction. A recent review identified 208 HIV-negative patients who developed CMV retinitis in one or both eyes. Nearly 80 percent of the patients included in the review had a clear cause for immune dysfunction such as malignancy, severe autoimmune condition requiring immunosuppression or a history of bone marrow or solid organ transplantation requiring long-term immunosuppressive therapy.5 However, in 6.1 percent of patients, the only identified cause of immune dysfunction was diabetes.  A total of 10.1 percent of patients developed CMV retinitis after injection of intraocular or periocular corticosteroids. Intraocular corticosteroids are a therapeutic option for diabetic macular edema, but they also lead to local immunosuppression within the eye. The patient presented here received multiple intraocular injections of corticosteroids that may have contributed to a degree of local immunosuppression sufficient for the development of CMV retinitis.

Cystoid macular edema is a frequent cause of decreased vision among patients with diabetes, but it is rarely encountered in patients with AIDS-related CMV retinitis.6-9 Diabetes likely contributed to the macular edema seen in this case, but it may not have been the only causative factor. In contrast to AIDS-related CMV retinitis, HIV-negative patients with CMV retinitis may develop CME. HIV-negative patients with CMV retinitis develop more pronounced intraocular inflammation in response to the infection, and it is theorized that this inflammation may lead to the development of macular edema.9 With treatment of the CMV retinitis, the CME seen in this case improved, though it did not completely resolve.

While medications active against vascular endothelial growth factor (VEGF) have become the first-line intravitreal pharmacologic agent in the treatment of diabetic macular edema based on the results of several large trials demonstrating their efficacy,10-12 as previously
 
Figure 3. Repeat montage fundus photographs of both eyes showing less vitreous haze and stability of the retinitis OD after two weeks of oral valganciclovir therapy for CMV retinitis.
stated, intravitreal corticosteroid agents are another therapeutic option. Investigations have shown that visual acuity gains in pseudophakic patients with DME treated with intravitreal triamcinolone may be similar to those treated with intravitreal ranibizumab, though the risk of intraocular pressure elevation is greater in those receiving corticosteroid injections.10 Therefore, intravitreal steroid injection may be considered in patients with DME who have shown poor treatment response to injection of an anti-VEGF agent, as was the case with the patient presented above. Though these medications provide extended local anti-inflammatory action that is helpful in improving edema, they also cause extended local immunosuppression that can lead to intraocular infection. A large retrospective cohort study comparing the rates of development of bacterial endophthalmitis following intravitreal injection of a corticosteroid versus an anti-VEGF agent found a significantly increased odds ratio (6.92) among patients receiving a corticosteroid.13 While the reasons for this increase are likely multifactorial, the study’s authors felt that local immunosuppression played an important role.

In the patient presented, relative systemic immune compromise from diabetes as well as local immune suppression from intravitreal corticosteroid injections likely contributed to the development of CMV retinitis. CMV retinitis should be kept in the differential diagnosis when the typical funduscopic findings of the infection are seen, even among patients without HIV who are traditionally described as immunocompetent. The risk of intraocular infection should be considered in patients receiving repeated intravitreal corticosteroid injections.  REVIEW


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