Open Access

Good syndrome and other causes of cytomegalovirus retinitis in HIV-negative patients—case report and comprehensive review of the literature

  • Kenneth M. Downes1Email author,
  • Dariusz Tarasewicz2,
  • Laurie J. Weisberg3 and
  • Emmett T. CunninghamJr1, 4, 5, 6
Journal of Ophthalmic Inflammation and Infection20166:3

https://doi.org/10.1186/s12348-016-0070-7

Received: 24 September 2015

Accepted: 4 January 2016

Published: 25 January 2016

Abstract

We describe a 65-year-old Thai woman who developed cytomegalovirus retinitis (CMVR) in the setting of Good syndrome—a rare, acquired partial immune deficiency caused by thymoma. The patient subsequently developed vitritis with cystoid macular edema (CME) similar to immune recovery uveitis (IRU) despite control of the retinitis with antiviral agents. A comprehensive review of the literature through December, 2014, identified an additional 279 eyes of 208 patients with CMVR in the absence of human immunodeficiency virus (HIV) infection. Including our newly reported case, 9 of the 208 patients (4.3 %) had Good syndrome. Twenty-one of the 208 patients (10.1 %) had CMVR related to intraocular or periocular corticosteroid administration. The remaining 178 patients (85.6 %) acquired CMVR from other causes. Within the subset of patients who did not have Good syndrome or did not acquire CMVR followed by intraocular or periocular corticosteroid administration, there were many other factors contributing to a decline in immune function. The most common included age over 60 years (33.1 %), an underlying malignancy (28.7 %), a systemic autoimmune disorder requiring systemic immunosuppression (19.1 %), organ (15.2 %) or bone marrow (16.3 %) transplantation requiring systemic immunosuppression, and diabetes mellitus (6.1 %). Only 4.5 % of the patients had no identifiable contributor to a decline in immune function. While the clinical features of CMVR are generally similar in HIV-negative and HIV-positive patients, the rates of moderate to severe intraocular inflammation and of occlusive retinal vasculitis appear to be higher in HIV-negative patients.

Keywords

Herpetic retinitis Immunosuppression Thymoma Uveitis Good syndrome

Review

Introduction

Thymoma is an uncommon and slow-growing neoplasm that accounts for approximately 20 to 30 % of mediastinal masses in adults and 1 % in children [1]. Thymic tumors not only usually present with respiratory symptoms due to compression of the upper airways and/or superior vena cava syndrome but also can produce paraneoplastic or parathymic syndromes [14], and the most common of which are myasthenia gravis (MG), pure red cell aplasia (PRCA), and acquired partial immune deficiency or Good syndrome [5, 6].

Good syndrome was first described by the American hematologist-oncologist Dr. Robert Good in 1956 [7]. Good noted a direct relationship between the presence of thymoma and hypogammaglobulinemia causing immunosuppression in those patients. Good syndrome typically occurs in middle-aged adults and is associated most commonly with recurrent sinus and pulmonary infections, cytomegalovirus (CMV) disease (most often retinitis), fungal infections, pure red cell aplasia, and myasthenia gravis [8]. While hypogammaglobulinemia in the setting of thymoma defines Good syndrome, other, often partial, immune deficiencies have also been described, including decreased T cell function [9].

We describe a 65-year-old woman who developed CMV retinitis (CMVR) in the setting of Good syndrome. The patient subsequently developed vitritis with cystoid macular edema (CME) despite control of the retinitis with antiviral agents. Cases of CMVR in human immunodeficiency virus (HIV)-negative patients, including those with Good syndrome, identified in PubMed through December, 2014, were reviewed and are summarized. Search terms included “Cytomegalovirus AND eye” and “cytomegalovirus retinitis.” Additional publications were identified by reviewing collected references.

Case report

A 65-year-old Thai woman presented for evaluation of suddenly decreased vision with floaters in her right eye. Past ocular history was unremarkable. Past medical history was notable for PRCA diagnosed 2 years prior to presentation and for which she was treated for four months with erythropoietin and systemic corticosteroids. She also had two prior episodes of oropharyngeal candidiasis, which were treated successfully. There was no history of recent or current corticosteroid use.

The best-corrected vision was 20/100 on the right eye and 20/25 on the left eye. Intraocular pressure (IOP) was 15 mmHg bilaterally. No afferent pupillary defect was noted. Anterior segment examination of the right eye showed trace anterior chamber cell but was otherwise normal. Anterior segment examination on the left eye was unremarkable. Posterior segment examination on the right showed moderate vitreous inflammation and an advancing edge of necrotizing retinitis associated with scattered intraretinal hemorrhages and retinal vascular telangiectasis (Fig. 1a). Posterior segment examination of the left eye was unremarkable. The patient was diagnosed clinically with viral retinitis, an anterior chamber paracentesis was performed for viral DNA testing, a laser barrier was applied immediately posterior to the area of active retinitis, and the patient was given an intravitreal injection of 2 mg of ganciclovir followed by treatment with high-dose oral valaciclovir, 2 g three times daily. Analysis of the anterior chamber paracentesis was positive for CMV DNA, and the patient was switched from valaciclovir to valganciclovir, which resulted in resolution of the area of retinitis.
Fig. 1

Color photograph of the patient’s right eye showing the active edge of cytomegalovirus retinitis (a), which became inactive following treatment with an intravitreal injection of 2 mg of ganciclovir followed by high-dose oral valaciclovir, 2 g three times daily (b). Fluorescein angiography (c) and SD-OCT imaging (d) showed the development of cystoid macular edema consistent with the diagnosis of immune recovery uveitis

The patient subsequently underwent HIV and syphilis testing, colonoscopy, chest X-ray, bone marrow biopsy, and abdominal CT, all of which were negative. Testing of immune function revealed a markedly decrease total B cell (CD19) cell count and panhypogammaglobulinemia (Table 1).
Table 1

Immunologic profile over time of currently reported case of cytomegalovirus retinitis in the setting of thymoma (Good’s syndrome)

Immunologic profile

At time of retinitis

At time of CME diagnosis and 5 months after thymoma resection

6 months after CME and 11 months after thymoma resection

Reference range

T cells CD3

1079 (70 %)

N/A

1284 (81 %)

672–2638 cells/mL (54–83 %)

T helper cells CD4

480 (31 %)

N/A

437 (28 %)

292–1366 cells/mL (23.1–51.0 %)

Cytotoxic T cells CD 8

540 (35 %)

N/A

817 (51 %)

240–1028 cells/mL (17.9–47.5 %)

CD4 to CD8 ratio

0.88

N/A

0.53

0.6–2.5

B cells CD19

40 (3 %)

N/A

26 (2 %)

82–560 cells/mL (5.1–20.8 %)

Natural killer cells CD16/56

413 (27 %)

N/A

277 (17 %)

130–938 cells/mL (7.1–38.0 %)

Immunoglobulin G

2.24

1.91

N/A

8–18 (g/L)

Immunoglobulin M

<0.06

<0.06

N/A

0.5–2.2 (g/L)

Immunoglobulin A

<0.04

0.6

N/A

1.1–5.6 (g/L)

Abbreviations: CME cystoid macular edema, CMV cytomegalovirus, NR not reported, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, CD cluster designation, NK natural killer, N/A not available

Within 1 month of the diagnosis of CMVR, the patient was hospitalized for acute pneumonia. During this hospitalization, a mediastinal mass was discovered on chest X-ray and evaluated further by chest CT (Fig. 2). Computer tomography guided thymus biopsy and subsequent thymectomy were performed, revealing histological changes consistent with thymoma that lead to the diagnosis of Good syndrome. Immunoglobulin A, G, and M levels remained low at the last testing 5 months following removal of the thymus. The patient then returned with worsening vision in the eye with CMVR while on maintenance valganciclovir therapy, 450 mg twice daily.
Fig. 2

Chest CT showing a large mediastinal mass outlined in red and found subsequently to be a thymoma

The best-corrected vision was 20/125 on the right eye and 20/25 on the left eye. Intraocular pressure was normal. No afferent pupillary defect was noted. Anterior segment examination on the right showed several stellate keratic precipitates on the corneal endothelium, one cell per high powered field in the anterior chamber, and occasional anterior vitreous cells. Anterior segment examination on the left was unremarkable. Posterior segment examination on the right showed mild to moderate vitreous inflammation, a posterior vitreous detachment, a large area of inactive retinal necrosis (Fig. 1b), continuous laser barrier scars immediately posterior to the area of retinitis, and loss of the foveal light reflex suggestive of CME. Posterior segment examination on the left was unremarkable. Fluorescein angiography confirmed the presence of severe CME on the right (Fig. 1c). Spectral domain optical coherence tomography (SD-OCT) imaging showed marked CME on the right (Fig. 1d) with a central macular thickness of 743 um. SD-OCT imaging of the left fovea revealed a normal contour with no evidence of subretinal or intraretinal fluid. The patient was treated with topical difluprednate four times daily for 1 month. The CME persisted, the difluprednate was stopped, and the patient was given two injections of 1.25 mg of intravitreal bevacizumab, 1 month apart. The CME failed to respond, and so the patient was given an intravitreal injection of triamcinolone acetonide, 2.0 mg, following which the CME resolved and vision improved to 20/80 in the affected eye. The CME subsequently recurred and the vision decreased to 20/100, but the patient refused further treatment. The retinitis remained inactive.

Comprehensive literature review

We describe a patient who developed CMVR in the setting of Good syndrome, a rare occurrence reported in eight previous patients to date (Tables 2 and 3) [1016]. Including our patient, reported ages of the nine patients ranged from 48 to 68 years, with both a mean and median of 56 years. Women constituted just over half of the reported patients (55.5 %), with retinitis occurring unilaterally in all but one patient (88.9 %) and involving zone 1 in nearly two thirds of the affected eyes (62.5 %). When reported, anterior chamber inflammation was present in 62.5 % of cases; vitritis was present in 88.8 % of cases and was reported to be moderate to severe in five cases (55.5 %). The diagnosis was confirmed in all but one patient (89.9 %) by polymerase chain reaction (PCR)-based testing of intraocular fluids, and all cases responded to antiviral therapy, which was administered both intravitreally and systemically in six of nine (66.6 %) patients. While the CMVR in our patient occurred 1 month prior to the identification of thymoma, a thymic tumor was identified prior to the development of CMVR in the other eight patients, with a time ranging from 1 month to just over 6 years prior to the occurrence of retinitis. Visual acuity at the initial CMVR diagnosis was between 20/40 and 20/200 in 77.8 and worse than 20/200 in 22.2 % of eyes, whereas visual acuity at last follow-up (median 6 months; range 1.5–7 months) was between 20/40 and 20/200 in 55.5 and worse than 20/200 in 44.4 % of eyes. Other common opportunistic infections reported in these nine patients with Good syndrome and CMVR included respiratory infections (77.8 %), non-ocular CMV (22.2 %), and herpes zoster dermatitis (33.3 %), whereas other autoimmune diseases (Table 3) included MG (25.0 %) and PRCA (22.2 %).
Table 2

Summary of the current and previously reported cases of cytomegalovirus (CMV) retinitis in the setting of immunodeficiency associated with thymoma (Good syndrome)

 

Author (year)

Age (years)

Gender

Unilateral (U) or bilateral (BL)

Timing of CMV retinitis relative to thymoma diagnosis (months)

Associated opportunistic infectionsa

Zone (involved)b

Retinitis treatmentc

CMV testing

Vision when retinitis was first diagnosed

Follow-up (months)

Vision at the last visit

Previously published cases

Ho et al. (2010) [10]

68

M

U

75 months after thymoma

Recurrent pneumonia; disseminated CMV; CMV colitis

Zone I

IV ganciclovir and then PO valganciclovir

Lung biopsy

20/200

1

20/100

Mateo-Montoya et al. (2010) [11]

57

M

U

NR. “Long time after thymoma”

Recurrent pneumonia; Camplyobacter sepsis

Zone I

IVT ganciclovir, IVT foscarnet, and IV ganciclovir then PO valganciclovir

Aqueous PCR; vitreous PCR

20/100

6

20/40

Park et al. (2009) [12]

56

M

BL

3 months after thymoma

NR

Zone I and zone II

IVT ganciclovir and IV ganciclovir, then PO valganciclovir

Aqueous PCR; serum IgG

20/800 OD, 20/125 OS

6

CF at 30 cm OD, NLP OS

Sen et al. (2005)1 [13]

48

M

U

60 months after thymoma

Pneumocystis jiroveci pneumonia; history of retinitis and optic neuropathy

Zone I

IVT ganciclovir and IVT ganciclovir implant (Vitrasert)

Aqueous PCR

20/200

7

20/200

Wan et al. (2012) [14]

51

F

U

60 months after thymoma

Recurrent sinopulomary infections; CMV enterocolitis

Zone II

PO valganciclovir then IVT ganciclovir weekly

Vitreous PCR

20/40

6

20/50 then subsequently to CF due to the development of autoimmune retinopathy

Yong et al. (2008) [15]

50

F

U

6 months after thymoma

Herpes zoster (T10 dermatome)

NR

IV ganciclovir, then PO valganciclovir

Vitreous PCR

NR

2

NLP

Assi et al. (2002) [16] case 1

45

F

U

24 months after thymoma

Recurrent pneumonia; zoster dermatitis

Zone II and zone III

IV valaciclovir, then IVT ganciclovir implant

Vitreous PCR

20/40

6 weeks

NR

Assi et al. (2002) [16] case 2

65

F

U

24 months after thymoma

Recurrent pneumonia

Zone I

IVT foscarnet then PO ganciclovir

Vitreous PCR

HM

NR

HM

Current case

Downes, et al. (2016)

65

F

U

1 month before thymoma

Oropharyngeal candidiasis; Candida esophagitis; pneumonia

Zone II and zone III

IVT ganciclovir, then PO valganciclovir

Aqueous PCR

20/100

7

20/80

Summary

Total n = 9

Mean: 56 years

Male: 4/9 (44.4 %)

8/9 (88.9 %) unilateral

Retinitis diagnosed after thymoma: 8/9 (88.9 %)

Respiratory infections: 7/9 (77.8 %)

Zone I: 5/8 reported (62.5 %)

Intravitreal therapy alone: 1/9 (11.1 %)

Positive aqueous PCR: 4/9 (44.4 %)

Acuity better than 20/40: 0/9 eyes (0.0 %)

Mean = 4.56 months

Acuity better than 20/40: 0/9 eyes (0.0 %)

Median: 56 years

Female: 5/9 (55.5 %)

Mean = 31.4 months after thymoma

Non-ocular CMV: 2/9 (22.2 %)

Zone II: 4/8 reported (50 %)

Systemic therapy alone: 2/9 (22.2 %)

Positive vitreous PCR: 5/9 (55.5 %)

Acuity between 20/40 and 20/200: 7/9 eyes (77.8 %)

Median = 6 months

Acuity between 20/40 and 20/200: 5/9 eyes (55.5 %)

Range: 48–68 years

Male to female ratio 0.8:1

Median = 24 months after thymoma

Other opportunistic infections: 3/9 (33.3 %)

Zone III: 2/8 reported (25 %)

Combo intravitreal and systemic therapy: 6/9 (66.6 %)

Confirmed by other means: 1/9 (11.1 %)

Acuity worse than 20/200: 2/9 eyes (22.2 %)

Range = 1.5–7 months

Acuity worse than 20/200: 4/9 eyes (44.4 %)

Range = 75 months after to 1 month before

Abbreviations: IgG immunoglobulin G, M male, F female, U unilateral, BL bilateral, CMV cytomegalovirus, NR not reported, CF count fingers, NLP no light perception, LP light perception, HM hand motion, IV intravenous, PO per oral, IVT intravitreal, PCR polymerase chain reaction

aAll patients were tested for HIV and found to be negative

bZone definitions are as follows: zone I defined as macula or optic nerve involvement; zone II defined as mid-periphery; and zone 3 defined as outer periphery. Zone definitions referenced in this paper: Cunningham ET Jr, Hubbard LD, Danis RP, Holland GN. Proportionate topographic areas of retinal zones 1, 2, and 3 for use in describing infectious retinitis. Arch Ophthalmol. 2011;129(11):1507–8 [115]

cDosing with each modality varied widely across studies

Table 3

Summary of autoimmune conditions and immunologic parameters in current and previously reported cases of cytomegalovirus (CMV) retinitis in the setting of immunodeficiency associated with thymoma (Good syndrome)

 

Author (year)

Myasthenia gravis

Pure red cell aplasia

Other conditions encountered

Lymphopeniaa

Low CD3+ T cells (<672 cells/mL or <54 %)

Low CD4+ count (<360/μL or <36 %)

A low CD8+ count (<240 cells/μL)

Low CD4+/CD8+ ratio (<0.6)

Low NK cells (<130 cells/mL or <7.1 %)

Hypogammaglobulinemia IgG (IgG < 8 g/L)

Hypogammaglobulinemia IgM (IgM <0.5 g/L)

Hypogammaglobulinemia IgA (IgA < 1.1 g/L)

Panhypogammaglobulinemia (I gG < 8 g/L, IgM <0.5 g/L, IgA < 1.1 g/L, or total Ig < 9.6 g/L)

Previously published cases

Ho et al. (2010) [10]

None

+

+

+

+

+

+

+

+

+

Mateo-Montoya et al. (2010) [11]

+

None

NR

NR

+

NR

NR

NR

NR

NR

NR

+

Park et al. (2009) [12]

None

+

NR

NR

NR

NR

NR

+

+

+

+

Sen et al. (2005) [13]

?neurosensory hearing loss and optic neuropathy

NR

NR

+

NR

+

NR

+

+

+

+

Wan et al. (2012) [14]

NR

+

Autoimmune retinopathy (many years after diagnosis of retinitis)

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Yong et al. (2008) [15]

None

+

+

+

NR

+

+

+

+

Assi et al. (2002) [16] case 1

+

None

NR

+

NR

+

NR

+

Assi et al. (2002) [16] case 2

None

NR

NR

NR

+

NR

+

+

+

+

Current case

Downes, et al. (2013)

+

None

+

+

+

+

Summary

Total n = 9

+2/8 reported (25.0 %)

+2/9 cases (22.2 %)

No other definite autoimmune conditions encountered at the time of diagnosis of retinitis

+3/5 reported (60.0 %)

+1/3 reported (33.3 %)

+5/6 reported (83.3 %)

+0/4 reported (0.0 %)

+5/6 reported (83.3 %)

+1/2 reported (50.0 %)

+7/8 reported hypo IgG (87.5 %)

+7/8 reported hypo IgM (87.5 %)

+8/8 reported hypo IgA (87.5 %)

+7/8 reported panhypogammaglobulins (87.5 %)

Abbreviations: CMV cytomegalovirus, NR not reported, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, CD cluster designation, NK natural killer

aBased on each individual lab standards and if reported by authors

Although the retinitis in our patient responded promptly to intravitreal and systemic antiviral agents, the patient subsequently developed vitritis and CME of the type seen in patients with immune recovery uveitis (IRU) despite the fact that her total CD4+ T cell count was normal both before and after the occurrence of retinitis. In contrast, the total B cell count and immunoglobulin levels where low both before and after thymectomy. While hypogammaglobulinemia is required to diagnose Good syndrome and has been observed in all reported cases to date, including our patient, it is noteworthy that the total CD4+ T cell count was somewhat decreased in five of the eight previously reported cases with Good syndrome and CMVR (Table 3), indicating that partial CD4+ T cell depletion does occur in patients with Good syndrome and suggesting the possibility that selective loss of CMV-targeting CD4+ T cells may have occurred in our patient, facilitating the development of retinitis. To our knowledge, an IRU-like syndrome has not been reported previously following treatment of CMVR in a patient with Good syndrome.

Our review identified a total of 248 eyes of 178 patients previously reported with CMVR in the absence of either HIV infection, Good syndrome, or prior periocular or intraocular corticosteroid injection (Additional file 1: Table S1) [1786]. Reported ages ranged from 1 week to 84 years, with a mean and median of 45.7 and 48.0 years, respectively. Men outnumbered women approximately two to one (M to F ratio = 1.88:1), and the vast majority (95.5 %) had an identifiable cause of systemic immunosuppression. The most common factors contributing to a decline in immune function included age over 60 years (33.1 %), an underlying malignancy (28.7 %), a systemic autoimmune disorder requiring treatment (19.1 %), organ (15.2 %) or bone marrow (16.3 %) transplantation requiring systemic immunosuppression, and diabetes mellitus (6.1 %). The most commonly reported cancers included leukemia (35 patients; 19.7 %) and lymphoma (14 patients; 7.9 %). Three patients had multiple myeloma (1.7 %). One patient each (0.6 %) had breast cancer and angiocentric immunoblastic lymphadenopathy with dysproteinemia. Several patients had a primary immune deficiency other than Good syndrome, including three patients (1.7 %) with severe combined immunodeficiency, two patients each (1.1 %) with unspecified primary immune deficiency and common variable immune deficiency, and one patient (0.6 %) with idiopathic CD4+ T cell lymphopenia. Among the 26 reported patients less 18 years of age, 9 (34.6 %) had acute lymphoblastic leukemia, 8 (30.8 %) had undergone bone marrow transplantation, 5 (19.2 %) had congenital CMV infection, 3 (11.5 %) had severe combined immunodeficiency and 1 each (3.8 %) had common variable immune deficiency and immunoglobulin 2 (Ig2) deficiency.

The use of systemic immunosuppressive medication was reported in 105 of 160 cases (65.6 %). Seventy-eight of these 105 patients (74.3 %) were on two or more immunosuppressive agents. Corticosteroids were the most common immunosuppressive agent used in 69 patients (65.7 %), followed by cyclophosphamide in 33 patients (31.4 %), azathioprine in 17 patients (16.2 %), vincristine in 16 patients (15.2 %), methotrexate in 15 patients (14.3 %), cyclosporine in 13 patients (12.4 %), tacrolimus in 11 patients (10.5 %), 6-mercaptopurine in 9 patients (8.6 %), mycophenolate mofetil in 8 patients (7.6 %), fludarabine in 7 patients (6.7 %), and adriamycin in 6 patients (5.7 %). Five patients each (4.8 %) used intravenous immunoglobulin G and rituximab. One patient each (1.0 %) was on mitoxantrone, ibritumomab tiuxetan, and hydroxychloroquine. Within the 105 cases reporting medication use, the use of either an antimetabolite or a leukocyte signaling inhibitor as a group (methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, or cyclosporine) was reported in 46.7 % of cases, whereas chemotherapeutic agents as a whole (cyclophosphamide, vincristine, high-dose methotrexate, 6-mercaptopurine, adriamycin, rituximab, fludarabine, mitoxantrone, and ibritumomab tiuxetan) were reported in 48.6 % of cases. Clinically, the retinitis was unilateral in 108 out of 178 cases (60.7 %). Many case reports provided limited clinical information, but the location was either reported or illustrated in 97 out of the 248 eyes (39.1 %) and was found to involve zone 1 in 72 eyes (74.2 %). Additional clinical features were noted in 200 out of 248 eyes (80.6 %). Among these, 200 eyes, or just under one third (29.0 %), were noted to have anterior chamber inflammation, which was described as mild in 18 (9.0 %) and moderate in 13 (6.5 %), and severe in the remaining 27 (13.5 %). Just over one third of the reported eyes (37.5 %) were noted to have vitreous inflammation, among which inflammation was described as mild in 23 (11.5 %), moderate in 18 (9.0 %), and severe in 6 (3.0 %), with the remaining 28 (14.0 %) not quantifying severity. An occlusive vasculitis was noted in 47 eyes (23.5 %). Visual acuity at initial CMVR diagnosis was reported in 179 of 248 eyes (72.2 %). Among these 179 eyes, visual acuity at initial diagnosis was better than 20/40 in 34.1 %, between 20/40 and 20/200 in 39.1 %, and worse than 20/200 in 26.8 % of eyes. The method of diagnostic confirmation of CMVR was reported in 131 of the 178 cases (73.6 %), among which the diagnosis of CMVR was confirmed by PCR-based testing of intraocular fluids in 71.8 %. The retinitis responded to antiviral therapy in all cases. The treatment administered was reported in 126 of the 178 cases (70.8 %). Of these 126 cases, systemic treatment was administered in 45.2 % of patients, whereas both intravitreal and systemic therapy was given in 31.0 % of patients, and intravitreal treatment alone was employed in 23.8 % patients. Visual acuity at the last follow-up visit was reported in 171 eyes (mean 14.2 months; median 6.0 months; range 0 to 216 months) and was better than 20/40 in 30.4 %, between 20/40 and 20/200 in 37.4 %, and worse than 20/200 in 32.2 % of eyes.

Recently, Takakura and colleagues reviewed the literature on patients who developed viral retinitis following intraocular or periocular administration of corticosteroids [87]. Out of a total of 30 reported cases, 21 (70.0 %) developed CMVR (Table 4) [33, 87100]. These 21 patients constituted 10.1 % of the total of 208 non-HIV-positive patients with CMVR identified in our review. Among the 21 patients with CMVR, reported ages ranged from 30 to 84 years, with a mean and median of 66 and 69 years, respectively, and men outnumbered women two to one (M to F ratio = 2:1). The most common underlying ocular diseases for which corticosteroids were injected included diabetes mellitus (38.0 %), retinal vein occlusion (33.3 %), and uveitic CME (33.3 %), followed by choroidal neovascularization secondary to age-related macular degeneration (9.5 %). In patients with uveitis and CMVR, Behcet’s disease and anterior uveitis comprised two cases each (28.5 %), followed by one case each (14.3 %) of anterior uveitis, Vogt-Koyangi-Harada disease, idiopathic posterior uveitis, and idiopathic panuveitis. The corticosteroid was administered intravitreally in 19 of the 21 eyes (90.5 %). Among these 19 patients who received intravitreal corticosteroids, 8 (38.0 %) were administered between 1.5 and 4 mg, 4 (19.0 %) were administered between 8 and 20 mg, and 1 (4.8 %) was administered 40 mg of triamcinolone acetonide. Two (9.0 %) were implanted with the fluocinolone acetonide intravitreal implant (Retisert®). Among the two patients who received periocular corticosteroids, one (4.8 %) was administered 20 mg triamcinolone acetonide while the other patient (4.8 %) was administered 40 mg. The median time to developing retinitis after corticosteroid administration was 4.3 months with a mean of 4.0 months and a range 7 days to 13 months. Clinically, the retinitis involved zone 1 in 20.0 % of the eyes and was both unilateral and ipsilateral to the injection in all cases. Twelve out of 21 cases (57.1 %) described some clinical features of the retinitis. Within these 12 eyes, 10 (83.3 %) were noted to have anterior chamber inflammation, among which the inflammation was described as mild in one case (8.3 %) and moderate in four cases (33.3 %)—with the remaining seven (58.3 %) not quantifying severity. Over ninety percent of the eyes (91.6 %) were noted to have vitreous inflammation, among which inflammation was described as moderate in four eyes (33.3 %) with the remaining seven (63.6 %) not quantifying the severity of the inflammation. An occlusive vasculitis was noted in seven eyes (58.3 %). Visual acuity at initial CMVR diagnosis was reported in all 21 eyes and was better than 20/40 in 2 eyes (9.5 %), between 20/40 and 20/200 in 11 eyes (52.3 %), and worse than 20/200 in 8 eyes (38.0 %). The diagnosis was confirmed by PCR-based testing of intraocular fluids in 95.2 % of cases, and all cases responded to antiviral therapy, which was administered both intravitreally and systemically in 11 patients (52.3 %). Visual acuity at the last follow-up visit (mean 11.8 months; median 5.5 months; range 1–84 months) was better than 20/40 in 2 eyes (9.5 %), between 20/40 and 20/200 in 8 eyes (38.0 %), and worse than 20/200 in 11 eyes (52.3 %).
Table 4

Summary of previously reported HIV-negative cases of cytomegalovirus retinitis following intraocular and periocular corticosteroid injection

Previously published cases

Author (year)

Age (years)

Gender

Unilateral (U) or bilateral (BL)

Indication for corticosteroid

Corticosteroid dose/route

Time from corticosteroid dosing to retinitis (months)

CMV testing

Zone involveda

Vision when retinitis was first diagnosed

Retinitis treatmentb

Follow-up (months)

Vision at the last Visit

 

Saidel et al. (2005) [88]

75

M

U

DME

4 mg IVTA

4.0

CMV retinitis (PCR)

Zone I

20/400

IV ganciclovir, then IV valganciclovir, repeated IVT ganciclovir

6

20/400

Delyfer et al. (2007) [89] Case 1

77

M

U

CNVM/AMD

20 mg IVTA

4.0

CMV retinitis (serology + PCR)

Zone II

CF at 1.8 m

IVT, IV valganciclovir

6

20/200

Delyfer et al. (2007) [89] Case 2

69

M

U

CRVO/DME

8 mg IVTA three times over a 3-month interval

3 (after the 3rd IVTA)

CMV retinitis (PCR)

Zone I

20/200

IV ganciclovir and IV valganciclovir

3

20/400

Furukawa et al. (2007) [90]

54

F

U

DME

10 mg IVTA

4.0

CMV retinitis (serology + PCR)

Zone II

1

IV ganciclovir; IVT foscarnet; vitrectomy and silicone oil tamponade

14

0.5

Hsu et al. (2007) [91]

77

M

U

DME

4 mg IVTA

1.5

CMV retinitis (PCR)

Zone II

3/200

Valganciclovir

1

20/400

Ufret-Vincenty et al. (2007) [92]

65

M

U

Uveitic CME/Behcet’s disease

FA implant

53 (after the 1st implant), 5 (after the 2nd implant)

CMV retinitis (“clinical diagnosis”)

Zone II

20/50

IVT foscarnet; ganciclovir implant

5

20/40

Park et al. (2008) [93]

77

F

U

CRVO/CME due to HTN

4 mg IVTA

4.0

CMV retinitis (PCR)

Zone II

LP

IVT ganciclovir

4

HM

Sekiryu et al. (2008) [94]

63

M

U

BRVO/DME

4 mg IVTA

7.0

CMV retinitis (PCR)

Zone II

0.1

IV ganciclovir, IV valganciclovir

1

0.6

Babiuch et al. (2010) [95]

77

M

U

Idiopathic iritis

40 mg PST TA

0.25

CMV retinitis (serology + PCR)

Zone II

20/40

Vitrectomy, endolaser; IVT ganciclovir; ganciclovir implant

NR

NR

Shah et al. (2010) [96]

62

M

U

BRVO/DME

20 mg IVTA × 2

6.5

CMV retinitis (PCR)

Zone II

20/400

IV valaciclovir; vitrectomy, endolaser and silicone oil; then IV valganciclovir

NR

NR

Toyokawa et al. (2010) [97]

83

M

U

CNVM/AMD

20 mg PST TA

3.0

CMV retinitis (PCR)

Zone II

0.3

PO valaciclovir, vitrectomy

5

0.1

Tugal-Tutkun et al. (2010) [98]

30

M

U

Behcet’s panuveitis

IVTA dose NR

3.5

CMV retinitis (serology + PCR)

Zone I, zone II, zone III

20/200

IVT ganciclovir × 2; IV ganciclovir × 5 weeks; azathioprine changed to interferon alpha 2a

8

20/60

Vertes et al. (2010) [99]

78

F

U

BRVO/CME

4 mg IVTA

3.0

CMV retinitis (serology + PCR)

Zone II

20/40

IV ganciclovir; PO ganciclovir; IVT ganciclovir; then vitrectomy, endolaser

8

20/25

Zaborowski et al. (2013) [100]

56

F

U

Idiopathic panuveitis/Uveitic CME

4 mg IVTA

6.0

CMV retinitis (PCR)

Zone II

CF

Azathioprine discontinued; intravitreal ganciclovir twice weekly for 3 weeks (2 mg)

2

NR

Gupta et al. (2013) [32] case 1

70

F

U

DME

IVTA dose NR

4.0

CMV retinitis (PCR)

Zone II

CF

IVT foscarnet; IV valaciclovir; IVT foscarnet × 2; ganciclovir implant

32

CF

Gupta et al. (2013) [32] case 2

60

M

U

DME

IVTA NR

6.0

CMV retinitis (PCR)

NR

20/400

intravitreal foscarnet; IV valganciclovir; ganciclovir implant

NR

20/300

Gupta et al. (2013) [32] case 3

84

F

U

BRVO

IVTA NR

6.0

CMV retinitis (PCR)

Zone II

20/150

IVT foscarnet; IV valganciclovir

19

HM

Takakura et al. (2013) [87] case 1

66

M

U

VKH with steroid-induced cataracts and ocular hypertension, IVTA given during cataract surgery

4 mg IVTA and ASCTA

1.8

CMV retinitis (PCR)

Zone II

20/200

IVT ganciclovir, PO valganciclovir; methotrexate and low-dose oral prednisone

2

20/70

Takakura et al. (2013) [87] case 2

37

F

U

Bilateral idiopathic posterior uveitis complicated by CME/retinal vasculitis

FA implant

13.0

CMV retinitis (PCR)

Zone I

20/80

IVT foscarnet; PO valganciclovir

2

20/100

Takakura et al. (2013) [87] case 3

63

M

U

Granulomatous uveitis with CME

40 mg IVTA × 2

3.0

CMV retinitis (PCR)

Zone II

20/60

IV ganciclovir; PO prednisone; PPV

84

20/200

Takakura et al. (2013) [87] case 4

72

M

U

BRVO

4 mg IVTA

1.3

CMV retinitis (PCR)

Zone II

20/60

IVT ganciclovir

12

CF

Summary

N = 21

Mean, 66.4 years

Male, 14/21 (66.6 %)

21/21 (100 %)

RVO, 7/21 (33.3 %)

1.5–4 mg IVT, 8/21 (38.0 %)

Mean, 4.3 months

Positive aqueous or vitreous PCR, 20/21 (95.2 %)

Zone I, 4/20 reported (20.0 %)

Acuity better than 20/40, 2/21 eyes (9.5 %)

Intravitreal therapy alone, 5/21 (23.8 %)

Mean = 11.8 months

Acuity better than 20/40: 2/21 eyes (9.5 %)

Median, 69 years

Female, 7/21 (33.3 %)

DME, 8/21 (38.0 %)

8–20 mg, 5/21 (23.8 %)

Median, 4.0 months

Confirmed by other means: 1/21 (4.8 %)

Zone II, 17/20 reported (85.0 %)

Acuity between 20/40 and 20/200, 11/21 eyes (52.3 %)

Systemic therapy alone, 5/21 (23.8 %)

Median = 5.5 months

Acuity between 20/40 and 20/200: 8/21 eyes (38.0 %)

Range, 30.0–84.0 year

Male to female ratio, 2:1

Uveitic CME, 7/21 (33.3 %)

40 mg, 2/21 (9.0 %)

Range, 0.25–13.0 months

 

Zone III, 1/20 reported (5.0 %)

Acuity worse than 20/200, 8/21 eyes (38.0 %)

Intravitreal and systemic therapy, 11/21 (52.3 %)

Range = 1–84 months

Acuity worse than 20/200: 11/21 eyes (52.3 %)

  

CNVM due to AMD, 2/21 (9.5 %)

FA implant, 2/21 (9.0 %)

       

IRU, 0/21 (0.0 %)

Range, 1.5–40 mg

       

Data used from paper done by Takakura et al (2013) currently in peer review Ocular Immunology and Inflammation

Abbreviations: AMD age-related macular degeneration, BRVO branch retinal vein occlusion, CRVO central retinal vein occlusion, CME cystoid macular edema, CNVM choroidal neovascular membrane, DME diabetic macular edema, ERM epi-retinal membrane, FA fluocinolone acetonide, IRU immune recovery uveitis, IgG immunoglobulin G, CMV cytomegalovirus, NR not reported, PCR polymerase chain reaction, CD cluster designation, NK natural killer, N/A not applicable

aZone definitions are as follows: zone I defined as macula or optic nerve involvement; zone II defined as mid-periphery; and zone 3 defined as outer periphery. Zone definitions referenced in this paper: Cunningham ET Jr, Hubbard LD, Danis RP, Holland GN. Proportionate topographic areas of retinal zones 1, 2, and 3 for use in describing infectious retinitis. Arch Ophthalmol. 2011;129(11):1507-8 [115]

bDosing with each modality varied widely across studies

Table 5

Summary of cases of CMV retinitis in the literature without human immunodeficiency virus infection

 

CMV retinitis following intraocular and periocular corticosteroid injectiona

CMV retinitis in the setting of immunodeficiency associated with thymoma (Good syndrome)

CMV retinitis in immunocompetent adults (non-Good syndrome)

Number of cases

n = 21, n = 21 eyes

n = 9, n = 10 eyes

n = 178, n = 248 eyes

Age (years)

Mean, 66.4 years

Mean, 56 years

Mean, 45.7 years

Median, 69 years

Median, 56 years

Median, 48.0 year

Range, 30.0–84.0 year

Range, 48–68 years

Range, 1 week–84 years

Gender

Male, 14/21 (66.6 %)

Male, 4/9 (44.4 %)

Male, 113/173 reported (65.3 %)

Female, 7/21 (33.3 %)

Female, 5/9 (55.5 %)

Female, 60/173 reported (34.7 %)

Male to female ratio, 2:1

Male to female ratio, 0.8:1

Male to female ratio, 1.88:1

% unilateral

21/21 (100 %)

8/9 (88.9 %)

108/178 (60.7 %) unilateral

Indication for corticosteroid

RVO, 7/21 (33.3 %)

N/A

N/A

DME, 8/21 (38.0 %)

Uveitic CME, 7/21 (33.3 %)

CNVM due to AMD, 2/21 (9.5 %)

IRU, 0/21 (0.0 %)

Corticosteroid dose/route

1.5–4 mg IVT, 8/21 (38.0 %)

N/A

N/A

8–20 mg, 5/21 (23.8 %)

40 mg, 2/21 (9.0 %)

FA implant, 2/21 (9.0 %)

Range, 1.5–40 mg

Time from corticosteroid dosing to retinitis (months)

Mean, 4.3 months

N/A

N/A

Median, 4.0 months

Range, 0.25–13.0 months

Timing of CMV retinitis relative to thymoma diagnosis (months)b

N/A

Retinitis diagnosed after thymoma, 8/9 (88.9 %)

N/A

Mean, 31.4 months after thymoma

Median, 24 months after thymoma

Range, 75 months after to 1 month before

Associated systemic diseasesb

N/A

Respiratory infections, 7/9 (77.7 %)

No underlying systemic illness,

9/178 (5.1 %)

Non-ocular CMV, 2/9 (22.2 %)

Organ or bone marrow transplant, 61/178 (34.3 %)

Other opportunistic infections, 3/9 (33.3 %)

Autoimmune disease, 34/178 (19.1 %)

 

Leukemia or lymphoma, 51/178 (28.7 %)

Primary immune deficiency, 10/178 (5.6 %)

Other systemic medical conditions, 24/178 (13.5 %)

Immunosuppressive medication

N/A

N/A

No medication, 55/160 reported (34.4 %)

Using medication, 105/160 reported (65.6 %)

Using multiple immunosuppressive medication, 78/105 (74.3 %)

Using chemotherapy, 51/105 (48.6 %)

Using antimetabolites or leukocyte signaling inhibitors, 49/105 (46.7 %)

Associated autoimmune diseases

N/A

Myasthenia gravis, 2/8 reported (25.0 %)

N/A

Pure red cell aplasia, 2/9 cases (22.2 %)

Associated immunologic laboratory abnormalities

N/A

Generalized lymphopenia: 3/5 reported (60.0 %)

N/A

Low CD3+ T cells (<672 /mL), 1/3 reported (33.3 %)

Low CD4+ T cells (<360/μL), 5/6 reported (83.3 %)

Low CD 8 count (<240 /μL), 0/4 reported (0.0 %)

Low CD4+/CD8+ ratio (<0.6), 5/6 reported (83.3 %)

Low NK cells (<130 /mL), 1/2 reported (50.0 %)

Low serum IgG (<8 g/L), 7/8 reported (87.5 %)

Low serum IgM (<0.5 g/L), 7/8 reported (87.5 %)

Low serum IgA (<1.1 g/L), 8/8 reported (87.5 %)

Panhypogammaglobulinemia, 7/8 reported (87.5 %)

CMV testing

Positive aqueous or vitreous PCR, 20/21 (95.2 %)

Positive aqueous PCR, 4/9 (44.4 %)

Positive aqueous PCR, 65/131 reported (49.6 %)

Confirmed by other means, 1/21 (4.8 %)

Positive vitreous PCR, 5/9 (55.5 %)

Positive vitreous PCR, 29/131 reported (22.1 %)

 

Confirmed by other means, 1/9 (11.1 %)

Confirmed by other means, 37/131 reported (28.2 %)

Zone involvedc

Zone I, 4/20 reported (20.0 %)

Zone I, 5/8 reported (62.5 %)

Zone I, 72/97 eyes reported (74.2 %)

Zone II, 17/20 reported (85.0 %)

Zone II, 4/8 reported (50 %)

Zone II, 87/97 eyes reported (89.7 %)

Zone III, 1/20 reported (5.0 %)

Zone III, 2/8 reported (25 %)

Zone III, 39/97 eyes reported (40.2 %)

Vision when retinitis was first diagnosed

Acuity better than 20/40, 2/21 eyes (9.5 %)

Acuity better than 20/40, 0/9 eyes (0.0 %)

Acuity better than 20/40, 61/179 reported eyes (34.1 %)

Acuity between 20/40 and 20/200, 11/21 eyes (52.3 %)

Acuity between 20/40 and 20/200, 7/9 eyes (77.7 %)

Acuity between 20/40 and 20/200, 70/179 reported eyes (39.1 %)

Acuity worse than 20/200, 8/21 eyes (38.0 %)

Acuity worse than 20/200, 2/9 eyes (22.2 %)

Acuity worse than 20/200, 48/179 reported eyes (26.8 %)

Retinitis treatmentd

Intravitreal therapy alone, 5/21 (23.8 %)

Intravitreal therapy alone, 1/9 (11.1 %)

Intravitreal therapy alone, 30/126 reported (23.8 %)

Systemic therapy alone, 5/21 (23.8 %)

Systemic therapy alone, 2/9 (22.2 %)

Systemic therapy alone, 57/126 reported (45.2 %)

Intravitreal and systemic therapy, 12/21 (52.3 %)

Intravitreal and systemic therapy, 6/9 (66.6 %)

Intravitreal and systemic therapy, 39/126 reported (31.0 %)

Follow-up (months)

Mean = 11.8 months

Mean = 4.56 months

Mean = 14.2 months

Median = 5.5 months

Median = 6 months

Median = 6.0 months

Range = 1–84 months

Range = 1.5–7 months

Range = 0–216 months

Vision at the last visit

Acuity better than 20/40, 2/21 eyes (9.5 %)

Acuity better than 20/40, 0/9 eyes (0.0 %)

Acuity better than 20/40, 52/171 reported eyes (30.4 %)

Acuity between 20/40 and 20/200, 8/21 eyes (38.0 %)

Acuity between 20/40 and 20/200, 5/9 eyes (55.5 %)

Acuity between 20/40 and 20/200,:64/171 reported eyes (37.4 %)

Acuity worse than 20/200, 11/21 eyes (52.3 %)

Acuity worse than 20/200, 4/9 eyes (44.4 %)

Acuity worse than 20/200, 55/171 reported eyes (32.2 %)

Abbreviations: AMD age-related macular degeneration, BRVO branch retinal vein occlusion, CRVO central retinal vein occlusion, CME cystoid macular edema, CNVM choroidal neovascular membrane, DME diabetic macular edema, ERM epiretinal membrane, FA fluocinolone acetonide, IRU immune recovery uveitis, IgG immunoglobulin G, CMV cytomegalovirus, NR not reported, PCR polymerase chain reaction, CD cluster designation, NK natural killer, N/A not applicable

aData used from paper done by Takakura et al. [89] currently in peer review “Ocular Immunology and Inflammation”

bAll patients were HIV negative

cZone definitions are as follows: Zone I defined as macula or optic nerve involvement; Zone II defined as mid-periphery; Zone 3 defined as outer periphery. Zone definitions referenced in this paper: Cunningham ET Jr, Hubbard LD, Danis RP, Holland GN. Proportionate topographic areas of retinal zones 1, 2, and 3 for use in describing infectious retinitis. Arch Ophthalmol. 2011;129(11):1507–8 [115]

dDosing with each modality varied widely across studies

The most complete and standardized description of CMVR in HIV-positive patients comes from the studies performed by the Studies of the Ocular Complications of AIDS (SOCA) research group [101103]. Cytomegalovirus retinitis was the most frequently encountered complication of HIV infection in this cohort, occurring in 34.6 % of patients with CD4+ T cell counts <50 cells/μL and in 63.4 % of patients with CD4+ T cell counts <200 cells/μL [104]. Clinically, HIV-associated CMVR includes classic features of necrotizing retinitis with irregular sheathing of adjacent vessels and variable degrees of hemorrhage (sometimes referred to as “pizza pie retinopathy” or “cottage cheese with ketchup”), and which is sometimes coupled with a frost branch angiitis appearance without vascular occlusion and often associated with mild vitreous or anterior chamber inflammation [12, 20, 104]. In addition to these core clinical findings previously listed, the SOCA studies quantified the prevalence of a number of hallmark features of CMVR at presentation. Specifically, keratic precipitates were present in 36.8 % of the eyes with CMVR, anterior chamber inflammation in 46.2 %, and vitreous inflammation in 61.9 %. The prevalence of anterior chamber cells greater than 2+ was 1.9 % and vitreous haze greater than 2+ was 11.4 %. Macular edema, epiretinal membrane formation, and rhegmatogenous retinal detachment were each uncommon at presentation in the SOCA cohort, occurring in less than 10 % of the eyes, and posterior synechiae formation was not observed [104].

A number of studies have suggested that the clinical presentation of CMVR in HIV-negative patients can differ from that in HIV-positive patients [2023, 27, 36, 94]. In a small series of eyes with CMVR in HIV-negative patients complied by Maguire and associates in 1995, three eyes were found to have spontaneously regressed or indolent appearing CMVR associated with vitritis and CME. The authors suggested that HIV-negative CMVR was more often associated with moderate to severe vitreous inflammation and CME [21]. The tendency for HIV-negative CMVR to have more severe intraocular inflammation as compared to CMVR in HIV-positive patients has since been noted by a number of authors, including Silverstein and colleagues [23], Voros and associates [27], Tajunisah and colleagues [25], Panthanapitoon and associates [22], and Schneider and colleagues [36] with specific mention of a similarity to acute retinal necrosis (ARN) in some eyes, including both the severity of the inflammation and the presence of occlusive vasculitis. In most instances, the more severe inflammation and vascular occlusion was ascribed to relative retention of anti-CMV immunoreactivity. However, other studies have failed to identify consistent difference in clinical presentation based on HIV status [1820, 24, 26, 3033, 3740, 44, 94, 95]. In our review, of all the reported cases to date of HIV-negative CMVR not associated with Good syndrome or following intraocular or periocular administration of corticosteroids, clinical features of the inflammation were reported in 199 of the 248 eyes (80.2 %). Within these 199 eyes, 13 (6.5 %) were specifically described as having moderate to severe anterior chamber inflammation, 24 (12.1 %) as having moderate to severe vitreous inflammation, and 47 (23.6 %) were noted to have occlusive vasculitis. In HIV-negative CMVR associated with Good syndrome, clinical features of the inflammation were reported in all eyes. Within these 10 eyes, only 1 (10.0 %) was specifically described as having moderate to severe anterior chamber inflammation, whereas 5 out of 10 eyes (50.0 %) were described as having moderate to severe vitreous inflammation. None were noted to have occlusive vasculitis. In HIV-negative CMVR following intraocular or periocular administration of corticosteroids, clinical features of the inflammation were reported in 12 of the 21 eyes (57.1 %). Among these 12 eyes, 4 (33.3 %) each were described as moderate to severe anterior chamber inflammation or vitreous inflammation, and 6 (50.0 %) were noted to have occlusive retinal vasculitis. Hence, while an ARN-like picture including moderate to severe intraocular inflammation and the presence of occlusive vasculitis may be somewhat more common in HIV-negative as compared to HIV-positive CMVR, particularly in the setting of Good syndrome or following periocular or intraocular corticosteroids, the clinical presentation in these various cohorts appears, more often than not, to be fairly similar, with an overlapping clinical presentation (Table 5).

Immune recovery uveitis has been well characterized in HIV-positive patients and is currently one of the most common causes of vision loss in patients with CMVR receiving highly active antiretroviral therapy (HAART) [104, 105]. While the occurrence of IRU has varied widely in HIV-positive cohorts receiving HAART, with reported rates ranging from 3.0 to 63.3 % [106], the inflammation generally occurs several weeks to months after initiating HAART, as the number of circulating CD4+ T cells increases. The clinical spectrum of IRU includes vitritis, papillitis, CME, epiretinal membrane formation, vitreous hemorrhage, retinal neovascularization, vitreomacular traction syndrome, and proliferative vitreoretinopathy [104107].

Of the 248 eyes of 178 patients with CMVR in the absence of either HIV infection or Good syndrome that have been described in the literature (Additional file 1: Table S1), 16 eyes (6.5 %) of 10 patients had one or more features consistent with IRU [17, 20, 45, 50, 70]. Reported ages of these 10 patients ranged from 15 to 68 years, with a mean and median of 47.8 and 54 years, respectively. Men outnumbered women approximately two to one (M to F ratio = 2.3:1), and the 100 % of the cases had an identifiable cause of systemic immunosuppression. The most common factors contributing to a relative decline in immune function included an underlying malignancy (n = 3; 30.0 %), age over 60 years (n = 2; 20.0 %), an autoimmune disorder (n = 2; 20.0 %), organ (n = 3; 30.0 %) or bone marrow (n = 1; 10.0 %) transplantation requiring systemic immunosuppression, and diabetes mellitus (n = 1; 10.0 %). The three reported cancers included two patients with acute lymphoblastic leukemia and one patient with chronic lymphocytic leukemia. The use of systemic immunosuppressive medication was reported in 8 out of the 10 cases (80.0 %). All of these patients were on two or more immunosuppressive agents. Corticosteroids were the most common immunosuppressive agent used in four patients (50.0 %), followed by cyclophosphamide in three patients (37.5 %), and two patients each (25.0 %) treated with vincristine and mycophenolate mofetil. One patient each (12.5 %) was treated with rituximab, fludarabine, methotrexate, and tacrolimus. Clinically, the retinitis was bilateral in 6 (60.0 %) out of 10 cases. Most case reports provided limited clinical information, and the location was either reported or illustrated in only 1 out of the 10 patients (10.0 %). In this patient, the retinitis was found to involve zone II. Additional clinical features were noted in 5 out of 16 eyes (31.3 %). Among these five eyes, just two eyes (40.0 %) were noted to have moderate anterior chamber inflammation. All five eyes (100.0 %) were noted to have vitreous inflammation, among which inflammation was described moderate to severe in all cases. An occlusive vasculitis was not present in any reported case of CMVR associated with IRU. Visual acuity at initial CMVR diagnosis was reported in 15 out of 16 eyes (93.8 %). Among these 15 eyes, visual acuity at initial diagnosis was better than 20/40 in 40.0 %, between 20/40 and 20/200 in 53.3 %, and worse than 20/200 in 6.7 % of eyes. The method of diagnostic confirmation of CMVR was reported in 1 of the 10 cases (10.0 %), among which the diagnosis of CMVR was confirmed serum PCR testing. The retinitis responded to antiviral therapy in all cases. The therapeutic treatment administered was reported in 6 of the 10 cases (60.0 %). Of these 6 cases, treatment was administered systemically only in 33.3 % of patients and intravitreally alone in 66.7 % patients. Visual acuity at last follow-up visit was reported in 8 patients and 13 eyes (mean 22.2 months; median 19 months; range 1 to 43 months). Visual acuity at last follow-up was better than 20/40 in 38.5 %, between 20/40 and 20/200 in 46.1 %, and worse than 20/200 in 15.4 % of eyes.

Since the December, 2014, cutoff for our literature review, there have been several publications of CMVR in HIV-negative patients [108113]. While these publications are not incorporated into this review, the clinical context in which CMVR developed and the clinical characteristics of the retinitis and the treatment(s) given for the infection were not significantly different from those previously reported or from the conclusions drawn by our review [114].

Conclusions

Although uncommon, CMVR can occur in the absence of HIV infection. Over 95 %, of HIV-negative patients who developed CMVR were found, ultimately, to have one or more factors contributing to a relative decline in immune function, such as advanced age, an underlying malignancy, an autoimmune disease or organ/bone transplantation requiring systemic immunosuppression, administration of periocular or intraocular corticosteroids, diabetes mellitus, or, less commonly, an inherited or acquired immune disorder, such as Good syndrome. While the clinical features of CMVR were generally similar in HIV-negative and HIV-positive patients, accumulated data regarding the rate of moderate to severe intraocular inflammation and occlusive retinal vasculitis would seem to suggest that these more ARN-like features occur more often in HIV-negative patients.

Declarations

Acknowledgements

This study is supported in part by The Pacific Vision Foundation and The San Francisco Retina Foundation (ETC.).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

(1)
The Department of Ophthalmology, California Pacific Medical Center
(2)
The Department of Ophthalmology, Kaiser Permanente Medical Center
(3)
The Department of Hematology/Oncology, Kaiser Permanente South San Francisco Medical Center
(4)
The Department of Ophthalmology, Stanford University School of Medicine
(5)
The Francis I. Proctor Foundation, UCSF School of Medicine
(6)
West Coast Retina Medical Group

References

  1. Liang X, Lovell MA, Capocelli KE et al (2010) Thymoma in children: report of 2 cases and review of the literature. Pediatr Dev Pathol 13(3):202–208PubMedView ArticleGoogle Scholar
  2. Cucchiara BL, Forman MS, McGarvey ML et al (2003) Fatal Subacute Cytomegalovirus Encephalitis Associated with Hypogammaglobulinemia and Thymoma. Mayo Clin Proc 78(2):223–227PubMedView ArticleGoogle Scholar
  3. Kelleher P, Misbah SA (2003) Review: What is Good's syndrome? Immunological abnormalities in patients with thymoma. J Clin Pathol 56(1):12–16PubMed CentralPubMedView ArticleGoogle Scholar
  4. Kitamura A, Takiguchi Y, Tochigi N et al (2009) Durable Hypogammaglobulinemia Associated with Thymoma (Good syndrome). Inter Med 48(19):1749–1752View ArticleGoogle Scholar
  5. Leibovitz I, Zamir D, Polychuck I et al (2003) Brief report. Recurrent Pneumonia Post-Thymectomy as a Manifestation of Good Syndrome. Eur J of Intern Med 14(1):60–62View ArticleGoogle Scholar
  6. Robinson MR et al (2000) Immune-Recovery Uveitis in Patients With Cytomegalovirus Retinitis Taking Highly Active Antiretroviral Therapy. Am J Ophthalmol 130(1):49–56PubMedView ArticleGoogle Scholar
  7. Good RA et al (1956) Thymic Tumor and Acquired Agammaglobulinemia: A Clinical and Experimental Study of the Immune Response. Surgery 40(6):1010–7PubMedGoogle Scholar
  8. Kelesidis T et al (2010) Good's Syndrome Remains a Mystery After 55 years: A Systematic Review of the Scientific Evidence. Clinical Immunology 135:347–363PubMedView ArticleGoogle Scholar
  9. Miao H, Tao Y, Jiang YR, Li XX (2013) Multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation. Graefes Arch Clin Exp Ophthalmol 251(7):1829–33. doi:10.1007/s00417-013-2368-6 PubMedView ArticleGoogle Scholar
  10. Ho JK et al (2010) A rare combination of recurrent pneumonia, diarrhoea, and visual loss in a patient after thymectomy: Good syndrome. Hong Kong Med J 16(6):493–6PubMedGoogle Scholar
  11. Mateo-Montoya A et al (2010) Cytomegalovirus retinitis associated with Good’s Syndrome. Eur J Ophthalmol 20(2):479–480PubMedGoogle Scholar
  12. Park D et al (2010) Bilateral Cytomegalovirus Retinitis with Unilateral Optic Neuritis in Good Syndrome. Jpn J Ophthalmol 54(3):246–8PubMedView ArticleGoogle Scholar
  13. Sen H et al (2005) CMV Retinitis in a Patient with Good Syndrome. Ocul Immunol Inflamm 13:475–478PubMedView ArticleGoogle Scholar
  14. Wan C et al (2013) Autoimmune Retinopathy in Benign Thymoma after Good Syndrome-associated Cytomegalovirus Retinitis. Ocul Immunol Inflamm 21(1):64–66View ArticleGoogle Scholar
  15. Yong D et al (2008) Good’s syndrome in a patient with cytomegalovirus retinitis. Hong Kong Med J 14:142–4PubMedGoogle Scholar
  16. Assi A et al (2002) Cytomeagalovirus retinitis in Patients with Good Syndrome. Arch Ophthalmol 120(4):510–2PubMedGoogle Scholar
  17. Bessho K, Schrier RD, Freeman WR (2007) Immune Recovery Uveitis in a CMV Retinitis Patient Without HIV Infection. Retin Cases Brief Rep I:52–53View ArticleGoogle Scholar
  18. Chawla HB, Ford MJ, Munro JF, Scorgie RE, Watson AR (1976) Ocular involvement in cytomegalovirus infection in a previously healthy adult. Br Med J 2(6030):281–2PubMed CentralPubMedView ArticleGoogle Scholar
  19. England AC 3rd, Miller SA, Maki DG (1982) Ocular Findings of Acute Cytomegalovirus Infection in an Immunologically Competent Adult. N Engl J Med 307:94–95PubMedView ArticleGoogle Scholar
  20. Kuo IC, Kempen JH, Dunn JP, Vogelsang G, Jabs DA (2004) Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 138(3):338–46PubMedView ArticleGoogle Scholar
  21. Maguire AM, Nichols CW, Crooks GW (1996) Visual loss in cytomegalovirus retinitis caused by cystoid macular edema in patients without the acquired immune deficiency syndrome. Ophthalmology 103(4):601–5PubMedView ArticleGoogle Scholar
  22. Pathanapitoon K, Tesavibul N, Choopong P, Boonsopon S, Kongyai N, Ausayakhun S, Kunavisarut P, Rothova A (2013) Clinical manifestations of cytomegalovirus-associated posterior uveitis and panuveitis in patients without human immunodeficiency virus infection. JAMA Ophthalmol 131(5):638–45PubMedView ArticleGoogle Scholar
  23. Silverstein BE, Conrad D, Margolis TP, Wong IG (1997) Cytomegalovirus-associated acute retinal necrosis syndrome. Am J Ophthalmol 123(2):257–8PubMedView ArticleGoogle Scholar
  24. Stewart MW, Bolling JP, Mendez JC (2005) Cytomegalovirus retinitis in an immunocompetent patient. Arch Ophthalmol 123(4):572–4PubMedView ArticleGoogle Scholar
  25. Tajunisah I, Reddy SC, Tan LH (2009) Acute retinal necrosis by cytomegalovirus in an immunocompetent adult: case report and review of the literature. Int Ophthalmol 29(2):85–90PubMedView ArticleGoogle Scholar
  26. López-Contreras J, Ris J, Domingo P, Puig M, Rabella N, Nolla J (1995) Disseminated cytomegalovirus infection in an immunocompetent adult successfully treated with ganciclovir. Scand J Infect Dis 27(5):523–5PubMedView ArticleGoogle Scholar
  27. Voros GM, Pandit R, Snow M, Griffiths PG (2006) Unilateral recurrent acute retinal necrosis syndrome caused by cytomegalovirus in an immune-competent adult. Eur J Ophthalmol 16(3):484–6PubMedGoogle Scholar
  28. Tran TH, Rozenberg F, Cassoux N, Rao NA, LeHoang P, Bodaghi B (2003) Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol 87(1):79–83PubMed CentralPubMedView ArticleGoogle Scholar
  29. Radwan A, Metzinger JL, Hinkle DM, Foster CS (2013) Cytomegalovirus retinitis in immunocompetent patients: case reports and literature review. Ocul Immunol Inflamm 21(4):324–8PubMedView ArticleGoogle Scholar
  30. Aghamohammadi A, Abolhassani H, Hirbod-Mobarakeh A, Ghassemi F, Shahinpour S, Behniafard N, Naghibzadeh G, Imanzadeh A, Rezaei N (2012) The uncommon combination of common variable immunodeficiency, macrophage activation syndrome, and cytomegalovirus retinitis. Viral Immunol 25(2):161–5PubMedView ArticleGoogle Scholar
  31. Coors LE, Spencer R (2010) Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection. Retina 30(4 Suppl):S59–62PubMedView ArticleGoogle Scholar
  32. Gupta S, Vemulakonda GA, Suhler EB, Yeh S, Albini TA, Mandelcorn E, Flaxel CJ (2013) Cytomegalovirus retinitis in the absence of AIDS. Can J Ophthalmol 48(2):126–9PubMedView ArticleGoogle Scholar
  33. Moritake H, Kamimura S, Kojima H, Shimonodan H, Harada M, Sugimoto T, Nao-I N, Nunoi H (2013) Cytomegalovirus retinitis as an adverse immunological effect of pulses of vincristine and dexamethasone in maintenance therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 60(2):329–31PubMedView ArticleGoogle Scholar
  34. Mota A, Breda J, Silva R, Magalhães A, Falcão-Reis F (2011) Cytomegalovirus retinitis in an immunocompromised infant: a case report and review of the literature. Case Rep Ophthalmol 2(2):238–42PubMed CentralPubMedView ArticleGoogle Scholar
  35. Samia L, Hamam R, Dbaibo G, Saab R, El-Solh H, Abboud M (2013) Muwakkit S. Cytomegalovirus retinitis in children and young adults with acute lymphoblastic leukemia in Lebanon, Leuk LymphomaGoogle Scholar
  36. Schneider EW, Elner SG, van Kuijk FJ, Goldberg N, Lieberman RM, Eliott D, Johnson MWCHRONICRETINALNECROSIS (2013) Cytomegalovirus Necrotizing Retinitis Associated With Panretinal Vasculopathy in Non-HIV Patients. Retina 33(9):1791–9PubMedView ArticleGoogle Scholar
  37. Singh R, Singh R, Trehan A, Jain R, Bhalekar S (2013) Cytomegalovirus Retinitis in an ALL child on exclusive chemotherapy treated successfully with intravitreal ganciclovir alone. J Pediatr Hematol Oncol 35(3):e118–9PubMedView ArticleGoogle Scholar
  38. Squires JE, Sisk RA, Balistreri WF, Kohli R (2013) Isolated unilateral cytomegalovirus retinitis: a rare long-term complication after pediatric liver transplantation. Pediatr Transplant 17(1):E16–9PubMed CentralPubMedView ArticleGoogle Scholar
  39. Svozílková P, Heissigerová J, Brichová M, Kalvodová B, Dvořák J, Ríhová E (2013) A possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin's lymphoma. Virol J 10:18PubMed CentralPubMedView ArticleGoogle Scholar
  40. Wakai K, Sano H, Shimada A, Shiozawa Y, Park MJ, Sotomatsu M, Yanagisawa R, Koike K, Kozawa K, Ryo A, Tsukagoshi H, Kimura H, Hayashi Y (2013) Cytomegalovirus retinitis during maintenance therapy for T-cell acute lymphoblastic leukemia. J Pediatr Hematol Oncol 35(2):162–3PubMedView ArticleGoogle Scholar
  41. Squirrell DM (2013) Bhatta S. Mudhar HS, Rennie IG. Hypertensive iridocyclitis associated with delayed onset biopsy proven Cytomegalovirus retinitis. Indian J OphthalmolGoogle Scholar
  42. Takayama K, Ogawa M, Mochizuki M, Takeuchi M (2013) Cytomegalovirus retinitis in a patient with proliferative diabetes retinopathy. Ocul Immunol Inflamm 21(3):225–6PubMedView ArticleGoogle Scholar
  43. Yashiro S, Fujino Y, Tachikawa N, Inamochi K, Oka S (2013) Long-term control of CMV retinitis in a patient with idiopathic CD4+ T lymphocytopenia. J Infect Chemother 19(2):316–20PubMedView ArticleGoogle Scholar
  44. Moss HB, Chavala S, Say E, Miller MB (2012) Ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with wild-type CMV in her plasma. J Clin Microbiol 50(5):1796–9PubMed CentralPubMedView ArticleGoogle Scholar
  45. Agarwal A, et al. Outcome of cytomegalovirus retinitis in immunocompromised patients without Human Immunodeficiency Virus treated with intravitreal ganciclovir injection. Graefes Arch Clin Exp Ophthalmol. Feb 21, 2014Google Scholar
  46. Bertelmann E, Liekfeld A, Pleyer U, Hartmann C (2005) Cytomegalovirus retinitis in Wegener's granulomatosis: case report and review of the literature. Acta Ophthalmol Scand 83(2):258–61, ReviewPubMedView ArticleGoogle Scholar
  47. Chou PI, Lee H, Lee FY (1996) Cytomegalovirus retinitis after heart transplant: a case report. Zhonghua Yi Xue Za Zhi (Taipei) 57(4):310–3Google Scholar
  48. Church J, Goyal S, Tyagi AK, Scott RA, Stavrou P (2007) Cytomegalovirus retinitis in chronic lymphocytic leukaemia. Eye (Lond) 21(9):1230–3, 2006 Aug 18PubMedView ArticleGoogle Scholar
  49. Egli A, Bergamin O, Müllhaupt B, Seebach JD, Mueller NJ, Hirsch HH (2008) Cytomegalovirus-associated chorioretinitis after liver transplantation: case report and review of the literature. Transpl Infect Dis 10(1):27–43, 2007 Dec 17PubMedView ArticleGoogle Scholar
  50. Eid AJ, Bakri SJ, Kijpittayarit S, Razonable RR (2008) Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis 10(1):13–8, 2007 May 19PubMedView ArticleGoogle Scholar
  51. Gooi P, Farmer J, Hurley B, Brodbaker E (2008) Cytomegalovirus retinitis mimicking intraocular lymphoma. Clin Ophthalmol 2(4):969–71PubMed CentralPubMedView ArticleGoogle Scholar
  52. Haerter G, Manfras BJ, de Jong-Hesse Y, Wilts H, Mertens T, Kern P, Schmitt M (2004) Cytomegalovirus retinitis in a patient treated with anti-tumor necrosis factor alpha antibody therapy for rheumatoid arthritis. Clin Infect Dis 39(9):e88–94, 2004 Oct 11PubMedView ArticleGoogle Scholar
  53. Hoang QV, Simon DM, Kumar GN, Oh F, Goldstein DA (2010) Recurrent CMV retinitis in a non-HIV patient with drug-resistant CMV. Graefes Arch Clin Exp Ophthalmol 248(5):737–40. doi:10.1007/s00417-009-1283-3, 2010 Jan 22PubMedView ArticleGoogle Scholar
  54. Ishikawa K, Ando Y, Narita M, Shinjoh M, Iwasaki T (2002) Cytomegalovirus retinitis during immunotherapy for common variable immunodeficiency. J Infect 44(1):55–6PubMedView ArticleGoogle Scholar
  55. Kaulfersch W, Urban C, Hauer C, Lackner H, Gamillscheg A, Slavc I, Langmann G (1989) Successful treatment of CMV retinitis with ganciclovir after allogeneic marrow transplantation. Bone Marrow Transplant 4(5):587–9PubMedGoogle Scholar
  56. Kim HR, Kim SD, Kim SH, Yoon CH, Lee SH, Park SH, Kim HY (2007) Cytomegalovirus retinitis in a patient with dermatomyositis. Clin Rheumatol 26(5):801–3, 2006 Mar 15PubMedView ArticleGoogle Scholar
  57. Kobayashi R, Takanashi K, Suzuki D, Nasu T, Uetake K, Matsumoto Y (2012) Retinitis from cytomegalovirus during maintenance treatment for acute lymphoblastic leukemia. Pediatr Int 54(2):288–90PubMedView ArticleGoogle Scholar
  58. Lafaut BA, Vianna RN, De Baets F, Meire F (1995) Unilateral cytomegalovirus retinitis in a patient with immunoglobulin G2 deficiency. Ophthalmologica 209(1):40–3PubMedView ArticleGoogle Scholar
  59. Larsson K, Lönnqvist B, Ringdén O, Hedquist B, Ljungman P (2002) CMV retinitis after allogeneic bone marrow transplantation: a report of five cases. Transpl Infect Dis 4(2):75–9PubMedView ArticleGoogle Scholar
  60. Lee JJ, Teoh SC, Chua JL, Tien MC, Lim TH (2006) Occurrence and reactivation of cytomegalovirus retinitis in systemic lupus erythematosus with normal CD4(+) counts. Eye (Lond) 20(5):618–21View ArticleGoogle Scholar
  61. Long HM, Dick A (2005) Presumed CMV associated necrotizing retinopathy in a non-HIV immunocompromised host. Clin Experiment Ophthalmol 33(3):330–2PubMedView ArticleGoogle Scholar
  62. Margo CE, Arango JL (1998) Cytomegalovirus retinitis and the lupus anticoagulant syndrome. Retina 18(6):568–70PubMedView ArticleGoogle Scholar
  63. Nasir MA, Jaffe GJ (1996) Cytomegalovirus retinitis associated with Hodgkin's disease. Retina 16(4):324–7PubMedView ArticleGoogle Scholar
  64. Raz J, Aker M, Engelhard D, Ramu N, Or R, Cohen E, Nagler A, Benezra D (1993) Cytomegalovirus retinitis in children following bone marrow transplantation. Ocul Immunol Inflamm 1(3):263–8PubMedView ArticleGoogle Scholar
  65. Scott WJ, Giangiacomo J, Hodges KE (1986) Accelerated cytomegalovirus retinitis secondary to immunosuppressive therapy. Arch Ophthalmol 104(8):1117–8, 1124PubMedView ArticleGoogle Scholar
  66. Shimakawa M, Kono C, Nagai T, Hori S, Tanabe K, Toma H (2002) CMV retinitis after renal transplantation. Transplant Proc 34(5):1790–2PubMedView ArticleGoogle Scholar
  67. Song WK, Min YH, Kim YR, Lee SC (2008) Cytomegalovirus retinitis after hematopoietic stem cell transplantation with alemtuzumab. Ophthalmology 115(10):1766–70PubMedView ArticleGoogle Scholar
  68. Tranos PG, Georgalas I, Founti P, Ladas I (2008) Cytomegalovirus retinitis presenting as vasculitis in a patient with Wegener's granulomatosis. Clin Ophthalmol 2(4):961–3PubMed CentralPubMedGoogle Scholar
  69. Vote B, Russell M, Polkinghorne P (2005) Recurrent cytomegalovirus retinitis in a patient with a normal lymphocyte count who had undergone splenectomy for lymphoma. Retina 25(2):220–1PubMedView ArticleGoogle Scholar
  70. Wimmersberger Y, Balaskas K, Gander M, Pournaras JA, Guex-Crosier Y (2011) Immune recovery uveitis occurring after chemotherapy and ocular CMV infection in chronic lymphatic leukaemia. Klin Monbl Augenheilkd 228(4):358–9PubMedView ArticleGoogle Scholar
  71. Winkler A, Finan MJ, Pressly T, Roberts R (1987) Cytomegalovirus retinitis in rheumatic disease: a case report. Arthritis Rheum 30(1):106–8PubMedView ArticleGoogle Scholar
  72. Davis JL, Haft P, Hartley K (2013) Retinal arteriolar occlusions due to cytomegalovirus retinitis in elderly patients without HIV. J Ophthalmic Inflamm Infect 3(1):17. doi:10.1186/1869-5760-3-17 PubMed CentralPubMedView ArticleGoogle Scholar
  73. Goldhardt R, Gregori NZ, Albini T, Yalamanchi S, Emanuelli A (2012) Posterior subhyaloid precipitates in cytomegalovirus retinitis. J Ophthalmic Inflamm Infect 2(1):41–5. doi:10.1007/s12348-011-0032-z, 2011 Jul 29PubMed CentralPubMedView ArticleGoogle Scholar
  74. Iwanaga M, Zaitsu M, Ishii E, Nishimura Y, Inada S, Yoshiki H, Okinami S, Hamasaki Y (2004) Protein-losing gastroenteropathy and retinitis associated with cytomegalovirus infection in an immunocompetent infant: a case report. Eur J Pediatr 163(2):81–4, 2003 Dec 5PubMedView ArticleGoogle Scholar
  75. Kabata Y, Takahashi G, Tsuneoka H (2012) Cytomegalovirus retinitis treated with valganciclovir in Wegener's granulomatosis. Clin Ophthalmol 6:521–3. doi:10.2147/OPTH.S31130, 2012 Mar 27PubMed CentralPubMedView ArticleGoogle Scholar
  76. Kelkar A, Kelkar J, Kelkar S, Bhirud S, Biswas J (2011) Cytomegalovirus retinitis in a seronegative patient with systemic lupus erythematosus on immunosuppressive therapy. J Ophthalmic Inflamm Infect 1(3):129–32. doi:10.1007/s12348-010-0017-3, 2011 Apr 3PubMed CentralPubMedView ArticleGoogle Scholar
  77. Libby E, Movva S, Quintana D, Abdul-Jaleel M, Das A (2010) Cytomegalovirus retinitis during chemotherapy with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. J Clin Oncol 28(32):e661–2. doi:10.1200/JCO.2010.29.6467, 2010 Sep 20PubMedView ArticleGoogle Scholar
  78. Oschman A, Murthy V, Kollipara R, Kenneth Lord R, Oluola O (2013) Intravitreal ganciclovir for neonatal cytomegalovirus-associated retinitis: a case report. J Perinatol 33(4):329–31. doi:10.1038/jp.2012.139 PubMedView ArticleGoogle Scholar
  79. Patel MP, Kute VB, Gumber MR, Shah PR, Patel HV, Dhananjay KL, Jain SH, Trivedi HL, Vanikar AV (2013) Successful treatment of Nocardia pneumonia with cytomegalovirus retinitis coinfection in a renal transplant recipient. Int Urol Nephrol 45(2):581–5PubMedView ArticleGoogle Scholar
  80. Piersigilli F, Catena G, De Gasperis MR, Lozzi S, Auriti C (2012) Active retinitis in an infant with postnatally acquired cytomegalovirus infection. J Perinatol 32(7):559–62. doi:10.1038/jp.2011.142 PubMedView ArticleGoogle Scholar
  81. Teh BW, Khot AS, Harrison SJ, Prince HM, Slavin MA (2013) A messenger at the door: cytomegalovirus retinitis in myeloma patients with progressive disease. Transpl Infect Dis 15(4):E134–8. doi:10.1111/tid.12106, 2013 Jun 23PubMedView ArticleGoogle Scholar
  82. Toriyama K, Suzuki T, Hara Y, Ohashi Y (2012) Cytomegalovirus retinitis after multiple ocular surgeries in an immunocompetent patient. Case Rep Ophthalmol 3(3):356–9. doi:10.1159/000343705, 2012 Oct 23PubMed CentralPubMedView ArticleGoogle Scholar
  83. Tuncer S, Oray M, Yildirim Y, Camcioglu Y, Tugal-Tutkun I. Bilateral intraocular calcification in necrotizing cytomegalovirus retinitis. Int Ophthalmol. 2014.Google Scholar
  84. Tzialla C, Decembrino L, Di Comite A, Bollani L, Colombo R, Stronati M (2010) Colonic stricture and retinitis due to cytomegalovirus infection in an immunocompetent infant. Pediatr Int 52(4):659–60PubMedView ArticleGoogle Scholar
  85. Sloan DJ, Taegtmeyer M, Pearce IA, Hart IJ, Miller AR, Beeching NJ (2008) Cytomegalovirus retinitis in the absence of HIV or immunosuppression. Eur J Ophthalmol 18(5):813–5PubMedGoogle Scholar
  86. Welling JD, Tarabishy AB, Christoforidis JB (2012) Cytomegalovirus retinitis after central retinal vein occlusion in a patient on systemic immunosuppression: does venooclusive disease predispose to cytomegalovirus retinitis in patients already at risk? Clin Ophthalmol 6:601–3. doi:10.2147/OPTH.S28086 PubMed CentralPubMedView ArticleGoogle Scholar
  87. Takakura, et al. Viral Retinitis following Intraocular or Periocular Corticosteroid Administration: A Case Series and Comprehensive Review of the Literature. Ocular Immunology & Inflammation. 2014, 1–8.Google Scholar
  88. Saidel M, Berreen J, Margolis T (2005) Cytomegalovirus Retinitis After Intravitreous Triamcinolone in an Immunocompetent Patient. Am J Ophthalmol 140(6):1141–1143PubMedView ArticleGoogle Scholar
  89. Delyfer M-N, Rougier M-B, Hubschman J-P, Aouizérate F, Korobelnik J-F (2007) Cytomegalovirus retinitis following intravitreal injection of triamcinolone: report of two cases. Acta ophthalmologica Scandinavica 85(6):681–3PubMedView ArticleGoogle Scholar
  90. Furukawa M. Cytomegalovirus Retinitis After IVTA treatment of a Vitrecotmized Eye in an Immunocompetent Patient. Retinal Cases & Brief Reports. 2007;1(4).Google Scholar
  91. Hsu J (2007) Cytomegalovirus Retinitis After Treatment with Intravitreal Triamcinolone Acetonide in an Immunocompetent Patient. Retinal Cases & Brief Reports 1(4):208–210View ArticleGoogle Scholar
  92. Ufret-Vincenty RL, Singh RP, Kaiser PK (2007) Cytomegalovirus Retinitis after Fluocinolone Acetonide (Retisert) Implant. Am J Ophthalmol 143:334–335PubMedView ArticleGoogle Scholar
  93. Park YS, Byeon SH (2008) Cytomegalovirus retinitis after intravitreous triamcinolone injection in a patient with central retinal vein occlusion. Korean J Ophthalmol 22(2):143–4PubMed CentralPubMedView ArticleGoogle Scholar
  94. Sekiryu T, Iida T, Kaneko H, Saito M (2008) Cytomegalovirus retinitis after intravitreal triamcinolone acetonide in an immunocompetent patient. Jpn J Ophthalmol 52(5):414–6PubMedView ArticleGoogle Scholar
  95. Babiuch AS, Ravage ZB, Merrill PT (2010) Cytomegalovirus Acute Retinal Necrosis in an Immunocompetent Patient After Sub-Tenon Triamcinolone Injection. Retin Cases Brief Rep 4(4):364–365PubMedView ArticleGoogle Scholar
  96. Shah AM, Oster SF, Freeman WR (2010) Viral retinitis after intravitreal triamcinolone injection in patients with predisposing medical comorbidities. Am J Ophthalmol 149(3):433–40PubMed CentralPubMedView ArticleGoogle Scholar
  97. Toyokawa N, Kimura H, Kuroda S (2010) Cytomegalovirus Retinitis After Subtenon TA and Intravitreal Injection of Anti-Vascular Endothelial Growth Factor in an ImmunocompetentPatient with Age-Related Macular Degeneration and Diabetes Mellitus. Jpn J Ophthalmol 54(2):166–8PubMedView ArticleGoogle Scholar
  98. Tugal-Tutkun I, Araz B, Cagatay A (2010) CMV retinitis after intravitreal triamcinolone acetonide injection in a patient with Behçet’s uveitis. International Ophthalmology 30(5):591–3PubMedView ArticleGoogle Scholar
  99. Vertes D, Snyers B, De Potter P (2010) Cytomegalovirus retinitis after low-dose intravitreous triamcinolone acetonide in an immunocompetent patient: a warning for the widespread use of intravitreous corticosteroids. International Ophthalmology 30(5):595–7PubMedView ArticleGoogle Scholar
  100. Zaborowski AG. Cytomegalovirus Retinitis Following Intravitreal Triamcinolone Acetonide in a Patient with Chronic Uveitis on Systemic Immunosuppression. Ocular immunology and inflammation. 2013;(October):1–2Google Scholar
  101. Jabs DA (1995) Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 93:623–83PubMed CentralPubMedGoogle Scholar
  102. Jabs DA et al (2007) Longitudinal Study of the Ocular Complications of AIDS 1. Ocular Diagnoses at Enrollment. Ophthalmology 114:4View ArticleGoogle Scholar
  103. Jabs DA et al (2007) Longitudinal Study of the Ocular Complications of AIDS 2. Ocular Examination Results at Enrollment. Ophthalmology 114:4View ArticleGoogle Scholar
  104. Jabs DA (2011) Cytomegalovirus Retinitis and the Acquired Immunodeficiency Syndrome—Bench to Bedside: LXVII Edward Jackson Memorial Lecture. American journal of ophthalmology 151:2View ArticleGoogle Scholar
  105. Jabs DA et al (2010) Course of Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy: Five-year Outcomes. Ophthalmology 117(11):2152–2161PubMed CentralPubMedView ArticleGoogle Scholar
  106. Urban, B. Et al. Immune Recovery Uveitis: Pathogenesis, Clinical Symptoms, and Treatment. Mediators of Inflammation Volume 2014, Article ID 971417.Google Scholar
  107. Ruiz Cruz, M, et al. Proposed Clinical Case Definition for Cytomegalovirus–Immune Recovery Retinitis. HIV/AIDS CID 2014:59 (15 July)Google Scholar
  108. Vishnevskia-Dai V, Shapira Y, Rahav G, Shimoni A, Somech R, Moisseiev J (2015) Cytomegalovirus retinitis in HIV-negative patients: a practical management approach. Ophthalmology 122(4):866–868PubMedView ArticleGoogle Scholar
  109. Miszewska-Szyszkowska D, Mikołajczyk N, Komuda-Leszek E, Wieczorek-Godlewska R, Świder R, Dęborska-Materkowska D, Szmidt J, Durlik M (2015) Severe cytomegalovirus infection in second kidney transplant recipient treated with ganciclovir, leflunomide, and immunoglobulins, with complications including seizures, acute HCV infection, drug-induced pancytopenia, diabetes, cholangitis, and multi organ failure with fatal outcome: a case report. Ann Transplant 20:169–74PubMedView ArticleGoogle Scholar
  110. Chan TS, Cheung CY, Yeung IY, Hwang YY, Gill H, Wong IY, Kwong YL (2015) Cytomegalovirus retinitis complicating combination therapy with rituximab and fludarabine. Ann Hematol 94(6):1043–7PubMedView ArticleGoogle Scholar
  111. Vannozzi L, Bacherini D, Sodi A, Beccastrini E, Emmi G, Giorni A (2015) Menchini U. Cytomegalovirus retinitis following intravitreal dexamethasone implant in a patient with central retinal vein occlusion, Acta OphthalmolGoogle Scholar
  112. Matsumoto A, Umeda K, Kawada K, Maeda S, Kinehara T, Saida S, Kato I, Hiramatsu H, Watanabe K, Yasumi T, Heike T, Tsujikawa A, Uji A, Usami I, Ito K, Adachi S (2015) Development of CMV retinitis in an antigenemia-negative infant after cord blood transplantation. Rinsho Ketsueki 56(5):506–10PubMedGoogle Scholar
  113. Jeon S, Lee WK (2015) Cytomegalovirus Retinitis in a Human Immunodeficiency Virus-negative Cohort: Long-term Management and Complications. Ocul Immunol Inflamm 11:1–8View ArticleGoogle Scholar
  114. Cunningham ET Jr, Downes KM, Chee S-P, Zierhut M. Cytomegalovirus retinitis and uveitis. Ocul Immunol Inflamm. 2015, In press.Google Scholar
  115. Cunningham ET Jr, Hubbard LD, Danis RP, Holland GN (2011) Proportionate topographic areas of retinal zones 1, 2, and 3 for use in describing infectious retinitis. Arch Ophthalmol 129(11):1507–8PubMedView ArticleGoogle Scholar

Copyright

© Downes et al. 2016