On this episode of Evidence Based Retina, Rishi P. Singh, MD, is joined by Isaac Bleicher, MD, to review a case of retinal hemorrhage from a unique presentation of cytomegalovirus (CMV) retinitis.
Dr. Bleicher is a vitreoretinal surgery fellow at Massachusetts Eye and Ear in Boston, Massachusetts.
CMV retinitis case report
Clinical presentation
A 52-year-old man presented to the clinic with flashes and floaters in the left eye (OS) for several days. The patient reported mild blurred vision OS and denied eye pain or redness, transient visual obscuration, vision changes in the right eye (OD), and recent trauma or illness.
Table 1: Findings from the clinical examination.
| OD | OS | |
|---|---|---|
| Acuity (sc) | 6/6 | 6/4.8 |
| Pupils | No APD | No APD |
| Confrontation | Full | Full |
| Color plates | 8/8 | 8/8 |
| Intraocular pressure (IOP) | 8mmHg | 9mmHg |
| Motility | Full | Full |
Table 2: Anterior segment findings.
| OD | OS | |
|---|---|---|
| Lids/Lashes | Normal | Normal |
| Conjunctiva/Sclera | Melanosis | Melanosis |
| Cornea | Clear | Chronic stromal scar |
| Anterior chamber | No cell | No cell |
| Iris | No TIDs | Segmentary loss pupillary ruff |
| Lens | Trace NS | Trace NS |
| Vitreous | No cell | PVD, no cell |
Other history for the patient included:
- History: Fasting and taking exercise supplements prior to symptom onset
- Past ocular Hx: Myopia
- Past Med Hx: Asthma
- Medications: None
- Social history: Construction business (office), avid golfer, no illicit drug use
- Family history: Diabetes (sister)
Figures 1 and 2: Fundus photography at baseline OD and OS, respectively; OD image was normal, while OS had a cluster of hemorrhages in the inferotemporal macula that appeared to be in vascular distribution and a stromal scar.
Figure 1: Courtesy of Isaac Bleicher, MD.
Figure 2: Courtesy of Isaac Bleicher, MD.
Figures 3 and 4: Magnified images of the fundus photos, OD and OS, respectively; the cluster of hemorrhages roughly follows a vein coming off the inferior arcade OS and appears to be located intraretinally.
Figure 3: Courtesy of Isaac Bleicher, MD.
Figure 4: Courtesy of Isaac Bleicher, MD.
Figures 5 and 6: Near infrared (NIR) and OCT imaging OS, respectively, demonstrating disorganization of the inner retinal layers, hyperreflective debris scattered in the retina, and no edema in the area.
Figure 5: Courtesy of Isaac Bleicher, MD.
Figure 6: Courtesy of Isaac Bleicher, MD.
Dr. Bleicher explained that the patient’s imaging guided the diagnosis to potential retinal vein occlusion (RVO), wherein fluorescein angiography (FA) would be confirmatory, and was taken at presentation.
Figures 7, 8, and 9: FA at presentation from the following time points: 0:20 mottled hyperfluorescence (Figure 7), 0:59 increased mottling (Figure 8), and 11:10 perivascular leakage in the proximate blood vessels to the area of the hemorrhages (Figure 9).
Figure 7: Courtesy of Isaac Bleicher, MD.
Figure 8: Courtesy of Isaac Bleicher, MD.
Figure 9: Courtesy of Isaac Bleicher, MD.
Dr. Bleicher noted that in the late FA frames, there was a vasculitic staining pattern but no microaneurysms. The final staining was nonspecific, but could potentially be observed in the proposed vein occlusion diagnosis.
Treatment plan
Patient characteristics: A 52-year-old male patient with blurred vision, flashes and floaters OS, found to have PVD, small macular hemorrhage, and retinal thinning without anterior chamber or vitreous cell.
A differential diagnosis for this patient would be:
- Vascular etiologies, such as vein occlusions could fit the appearance
- Infections with an acute localized area of hemorrhage in the retina (though there was no inflammation to suggest any active inflammation or infection associated with that finding)
- Trauma choroidal rupture
- Choroidal neovascular membrane (CNVM) in that location
Dr. Bleicher decided to observe this patient because there was no evidence of inflammation or infection, and the initial diagnosis was a branch retinal vein occlusion (BRVO), potentially a retinal artery occlusion component, given the degree of thinning.
The patient subsequently received a hypercoagulability workup with his primary care physician (PCP), with the following results:
- Lipids: Normal
- A1c: 5.6%
- Inherited hypercoagulability panel: Negative
- Cardiolipin and b-2-glycoprotein antibodies: Negative
4-month follow-up
The patient returned 4 months later with a visual decline to 6/24 OS.
Figures 10 and 11: Comparison of fundus and OCT imaging OS at baseline (Figure 10) and 4 months later (Figure 11), where the foveal appearance on OCT demonstrates prominent central thinning with ILM draping.
Figure 10: Courtesy of Isaac Bleicher, MD.
Figure 11: Courtesy of Isaac Bleicher, MD.
It is uncommon to see a pattern like the one above in a patient with BRVO, which may indicate that the diagnosis was arterial in nature, Dr. Bleicher remarked. Given that there was no active inflammation and no apparent vascular changes beyond the atrophy in the previously involved area, the patient was brought back for a close follow-up a few weeks later to monitor for progression or changes.
5-month follow-up
The patient returned 1 month later for follow-up and his vision had further declined to counting fingers at 3 meters.
Figures 12 and 13: Fundus and fundus autofluorescence (FAF) imaging of the patient 1 month later, demonstrating an area of hemorrhage in a vascular distribution that was located in a different part of the retina from the initial appearance at onset.
Figure 12: Courtesy of Isaac Bleicher, MD.
Figure 13: Courtesy of Isaac Bleicher, MD.
Figures 14 and 15: NIR and OCT imaging OS at the 5-month follow-up; the patient had progressive disorganization of the inner retinal layers and atrophy in the areas that had been previously involved.
Figures 14 and 15: NIR and OCT imaging OS at the 5-month follow-up; the patient had progressive disorganization of the inner retinal layers and atrophy in the areas that had been previously involved.
Figure 14: Courtesy of Isaac Bleicher, MD.
Figure 15: Courtesy of Isaac Bleicher, MD.
There was a significant degree of degradation that had occurred within 1 month, making it clear that it was time to reevaluate, as there was now a clinical finding that was inconsistent with the initial diagnosis, Dr. Bleicher explained.
If the patient had a vein occlusion, you may expect to see persistent or recurrent hemorrhages in the isolated area of the vein occlusion, but now there was spread of involvement to a new vascular distribution, he added.
Thus, an inflammatory or infectious etiology was now suspected, requiring an expanded laboratory workup, and aqueous sampling for viral testing would be warranted at this stage.
Figures 16, 17, 18, and 19: FA imaging OS 5 months after presentation with the following time stamps: 0:23 and 0:56 highlight staining and an atrophic pattern in the area that was previously involved (Figures 16 and 17), and 5:57 and 8:23 demonstrate new areas of perivascular leakage in the area surrounding the hemorrhage, mottled hyperfluorescence in areas that were previously involved, and perivascular leakage in the supernasal macula where there was new evidence of disease (Figures 16 and 17).
Figure 16: Courtesy of Isaac Bleicher, MD.
Figure 17: Courtesy of Isaac Bleicher, MD.
Figure 18: Courtesy of Isaac Bleicher, MD.
Figure 19: Courtesy of Isaac Bleicher, MD.
Re-evaluating the differential diagnoses
Dr. Bleicher explained that he was casting a wide net when considering potential differential diagnoses, such as:
- Vascular etiology:
- Diabetic retinopathy
- Hypertension
- Retinal vein occlusion
- Retinal microaneurysm
- Ocular ischemic syndrome
- Embolic
- Hematologic:
- Anemia
- Thrombocytopenia
- Leukemia/lymphoma
- Sickle cell disease
- Hyperviscosity syndrome
- Retinal:
- Choroidal neovascularization
- Coat’s disease
- Polypoidal choroidal vasculopathy
- Macular telangiectasia
- Retinal vasculitis
- External:
- Trauma
- Purtscher’s retinopathy
- Terson’s syndrome
- Radiation retinopathy
- Inflammatory/Infectious:
- Connective tissue disease
- HIV
- Herpetic: HSV/VZV/CMV
- Endocarditis
Additional patient history:
- Fasting and outdoor activity the day leading to visual decline
- Patchy skin itching over the past year
- Malaria several years prior and West Nile last year
- Received BCG vaccine, treated for positive TB skin test distantly
- Grew up in Somalia
- Cleans daughter’s rabbit cage
With this information, the plan was to perform an extensive laboratory workup, imaging for embolic causes, and start prednisone 60mg.
Identifying the final diagnosis
The results from the serum and imaging studies are listed below:
- Serum studies:
- HB: 12.1
- WBC: 2.7
- PLT: 193
- HCT: 36.3
- Abs neutrophil: 1.43 x 103/μl
- Abs lymphocyte: 0.76 x 103/μl
- TSH: 3.90 mIU/L
- ACE/lysozyme: Normal
- ANA: Negative
- ANCA: Negative
- B12: 166 pg/mL
- Folate: 14.7 ng/mL
- A1c: 5.6%
- HLA-B51: Negative
- Quant gold: Negative
- RPR/FTA-abs: Negative
- HIV: Negative
- Bartonella: Negative
- Toxoplasma IgG/M: Negative
- West Nile IgG: Positive
- West Nile IgM: Negative
- Malaria smear: Negative
- Imaging:
- Chest X-ray: Normal
- Carotid US: No significant stenosis
- Echocardiogram: No evidence of thrombus or vegetation
The lab workup revealed relative leukopenia, mild anemia, a slightly elevated platelet count, and notably low neutrophil and lymphocyte counts. The patient had tested positive for West Nile IgG, which was expected from his history, and much of the serologic testing was otherwise unremarkable. The patient was close to neutropenic, and there seemed to be a general suppression of all white cell lines.
Anterior chamber paracentesis was performed, which demonstrated positive cytomegalovirus (CMV) PCR and serology:
- AC tap:
- CMV: 1,700 IU/mL
- HSV: Negative
- VZV: Negative
- CMV serology
- IgM: Negative
- IgG: Positive (4.9 IU/mL)
- CMV PCR (blood) 134,870 IU/mL
The diagnosis had now shifted to presumed CMV retinitis, so the prednisone was rapidly tapered, the patient received an injection of foscarnet (weekly for four doses), and received oral valganciclovir 950mg BID.
CMV retinitis in immunocompromised vs. immunocompetent patients
Overall, this case highlights a unique presentation of CMV retinitis because it was focal, located posteriorly, and lacked prominent retinitis, which initially obscured the diagnosis. Dr. Bleicher explained that CMV retinitis can have a dichotomy of phenotypes in immunocompromised and immunocompetent patients.
CMV retinitis in immunocompromised patients tends to present as:1
- Characteristically found in AIDS patients
- Posteriorly:
- Necrotizing perivascular retinitis
- White infiltrates following the arcades
- Hemorrhages are often at the leading edge of retinitis
- Peripherally:
- Granular retinitis
- Minimal hemorrhagic component
- Slowly progressive, often requiring serial imaging to evaluate change
- Vitritis absent to minimal
While CMV in immunocompetent individuals may present as:2
- More fulminant than classic CMV retinitis, but more subacute/chronic compared to ARN
- Individuals typically have relative immunosuppression
- Diabetes
- Steroid use
- Advanced age
- s/p transplant, solid or bone-marrow
The name CMV chronic retinal necrosis has been proposed for this phenomenon when it occurs in immunocompetent or minimally immunosuppressed patients. The features of chronic retinal necrosis unique to non-HIV-associated CMV retinitis include prominent vitritis, severe, panretinal occlusive arteritis, neovascular complications, and less commonly retinal detachment.2
Comparing outcomes in immunocompromised vs. immunocompetent patients with CMV retinitis
Visual outcomes in immunocompromised individuals, particularly with HIV, are poor, with almost half of patients having no light perception.3,4 As outlined below, studies have shown that even after regular prescription of antiretroviral therapy, a significant number of HIV-infected patients still experience significant visual loss.3,4
Patient outcomes in HIV-infected patients with CMV retinitis:3,4
- Visual outcome:
- Prior to HAART: 79% <6/19, 49% no light perception (NLP)
- After HAART: 33% <6/12, 16% <6/60
- Retinal detachment
- 33 to 50% of eyes
- With modern therapy, around 10%
- Other
- Immune recovery uveitis
- 13 to 33% of patients
- Iritis, vitritis, macular edema, epiretinal membrane formation, cataracts, PVR
- Immune recovery uveitis
Patient outcomes in non-HIV-infected patients with CMV retinitis:3,4
- Visual outcome
- Typically stabilizes after initiation of therapy
- 20% with acuity <6/15
- Retinal detachment
- 3.0 to 8.7%
- 21.7% in studies with delayed presentations
- Other
- Recurrence
- Very low, most studies without recurrence
- One study with 33% rate of recurrence, 6.4 weeks after therapy
- Recurrence
Final follow-up
Interestingly, this patient didn’t seem to have relative immunosuppression, as he underwent evaluation for immune status with the following results:
- HB: 12.1
- WBC: 2.7
- PLT: 19.3
- HCT: 36.3
- Abs neutrophil: 1.43 x 103/μl
- Abs lymphocyte: 0.76 x 103/μl
- B-12 deficiency can cause cytopenias
- No improvement with repletion
- Flow cytometry with severely reduced polyclonal B-cell population
- Immune activity assays with reduced NK and killer T cell activity
The patient is currently undergoing whole exome sequencing and evaluation with the Rare Diseases Clinic at the National Institutes of Health to determine the functional status of his immune system and the underlying mechanism driving his unusual presentation of CMV retinitis.
Figure 20: Fundus photographs OS from positive CMV diagnosis to 1-, 3-, and 5-week follow-ups, highlighting progression and a new area of extramacular retinitis 1 week after treatment with foscarnet and valganciclovir. However, the retinitis progressively resolved as he received further treatment.
Figure 20: Courtesy of Isaac Bleicher, MD.
The patient is now over a year past this episode and the fundus appearance has remained the same. His vision is 6/60 (20/200), and he has reported no new retinitis.
