CMV Retinitis
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Disease Entity
Cytomegalovirus (CMV) Retinitis
Disease
Cytomegalovirus (CMV) retinitis is the most important ocular AIDS associated illness. It is a full thickness retinal infection that can lead to necrosis and retinal breaks and detachments.
Etiology
CMV retinitis is caused by cytomegalovirus, a double stranded DNA virus in the herpesviridae family. It is almost exclusively associated with HIV/AIDS and was extrememly rare prior to the AIDS epidemic. It is also associated with severe immunosuppression from chemotherapy and autoimmune conditions requiring immunomodulators.
Risk Factors
Risk factors include HIV, CD4 count less than 50, severe immunosuppression.
General Pathology
CMV reaches the retina hematogenously and infects the vascular endothelium which then spreads to the retinal cells. Infected cells show pathognomonic cytomegalic inclusions with large eosinophilic intracellular bodies. Electron microscopy can show the typical virus particles within infected cells. Histopathology shows full thickness retinal necrosis, coagulative vasculitis, and choroiditis.
Pathophysiology
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Primary prevention
CMV retinitis has dropped in incidence and prevalence since the advent of HAART. The incidence has declined 55-99% and the odds of progression has reduced by 50% with HAART. Survivial has improved from 0.65 years to greater than 1 year.
Diagnosis
Diagnosis is largely clinical based upon the classic retinal findings and an immunosuppressive condition such as HIV; however, polymerase chain reaction (PCR) analysis of the vitreous or aqueous can further support the diagnosis.
History
Patients present with decreased visual acuity and floaters. Some may present with flashing lights (photopsias) or blind spots (scotomata). One study showed 54% were asymptomatic.
Physical examination
Physical exam shows yellow white retinal lesions that often start in the periphery and follow the vasculature centripetally. However, it can start in the posterior segment. The classic findings are retinal hemorrhages with a whitish, granular appearance to the retina. Each lesion has the most activity in the borders. Vitreous signs of inflammation may be minimal as most patients are severely immunosuppressed. Very early CMV may resemble cotton wool spots, but with lesions larger than 750 µm, CMV must be considered. Fundoscopy may show a granular pattern, a fulminant/hemorrhagic appearance, or "frosted brach" angiitis.
Signs
CMV retinitis can present as: 1. Fulminant - hemorrhagic necrosis on white/yellow cloudy retinal lesions. They may be centered around vasculature. 2. Granular - Found more often in the retinal periphery with little to no necrosis and hemorrhage. 3. Perivascular - The classic "frosted branch" angiitis showing white lesions surrounding the retinal vessels.
Symptoms
Most patients are asymptomatic, but may have floaters, flashes (photopsias), blind spots (scotomata).
Clinical diagnosis
The clinical diagnosis is made on history and classic retinal findings.
Diagnostic procedures
Diagnostic procedures are not typically needed given the right history and classic findings.
Laboratory test
In cases of unknown retinitis, aqueous or vitreous tap and PCR analysis for CMV can be done. Patients should be followed in an appropriate HIV clinic with CD4 counts and viral load studies.
Differential diagnosis
Early CMV can resemble cotton wool spots. It may be confused with HIV retinopathy, which is actually more common the CMV retinitis. HIV retinopathy occurs in 50-70% of patients and is characterized by intraretinal hemorrhages, cotton wool spots, and microaneurysms.
Management
Management is largely medically based with intravenous (IV), oral, and intravitreal medications. Topical medications are not used. Management also hinges on HAART. If patients are on HAART, show no progression over months, and have CD4 counts > 100, they can be considered for discontinuation of CMV retinitis therapy.
Patients should be started on high dose induction therapy, which is followed by continuous maintenance therapy until CD4 counts increase, HAART is therapeutic, and CMV retinitis shows no progression.
General treatment
There are at least 5 options for long-term therapy of CMV retinitis.
1. Oral valganciclovir
2. IV ganciclovir
3. IV foscarnet
4. IV Cidofovir
5. Intraocular ganciclovir device
| Valganciclovir/Ganciclovir | Myelosuppression - Concommitant use of Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) can help reduce this risk. Thrombocytopenia occurs in 5-10% of patients. |
|---|---|
| Foscarnet | Renal dysfunction with electrolyte abnormalities. Increased risk of seizures. |
| Cidofovir | As high as 50% of patients taking cidofovir may experience ocular hypotony and anterior uveitis. |
Medical therapy
First line therapy is generally oral valganciclovir, which is a pro-drug of ganciclovir. The induction dose is 900 mg twice daily for 21 days followed by maintenance of 900 mg daily. Valganciclovir has increased bioavailability compared to oral ganciclovir and does not require IV administation, making it a favorite for patients and doctors alike.
IV ganciclovir is given at 5 mg/kg twice daily for two weeks as induction therapy then followed by daily 5 mg/kg infusions. This can be quite cumbersome to patients.
Foscarnet is given at 90 mg/kg twice daily for two weeks followed by maintenance therapy of 90-120 mg/kg daily through IV infusion.
Cidofovir has a longer half life and can be administered weekly during induction followed by bi-weekly maintenance therapy. The dose is 5 mg/kg weekly during induction, and 5 mg/kg every other week during maintenance.
Oral ganciclovir can be considered for maintenance therapy but regression and involvement of fellow eye is more frequent.
Intravitreal ganciclovir, foscarnet, or cidofovir can be considered for short-term management.
| Drug | Induction Dose | Maintenance Dose | Major Toxicity |
|---|---|---|---|
| Valganciclovir | 900 mg PO BID for 21 days | 900 mg daily | Myelosuppression |
| Ganciclovir | 5 mg/kg IV BID for 14 days | 5 mg/kg IV daily | Myelosuppression |
| Foscarnet | 90 mg/kg IV BID for 14 days | 90-120 mg/kg IV daily | Renal dysfunction, electrolyte abnormalities, seizures |
| Cidofovir | 5 mg/kg IV weekly for 14 days | 5 mg/kg IV every other week | Hypotony, anterior uveitis |
Medical follow up
Depending on the medication used, complete blood counts, chemistries, and introcular pressure checks will be needed. If patients are not on maintenance therapy, they should receive monthly to every 3 month follow up.
Surgery
The only surgical management involves intravitreal placement of intraocular ganciclovir devices. They have a relatively low risk profile and can last 6-8 months. They afford no protection to the fellow eye, however.
Surgical follow up
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Complications
The most serious complication of therapy for CMV retinitis, besides those listed above due to medications is immune recovery uveitis (IRU). As the CD4 counts rise with HAART, it is presumed that reactions to CMV antigens cause anterior or intermediate uveitis. Cystoid macular edema and epiretinal membranes are also potential complications of IRU. Posterior capsular cataracts, proliferative vitreoretinopathy, and optic nerve neovascularization are possible complications as well.
CMV retinitis can cause retinal tears from progressive necrosis which can lead to retinal detachments.
Prognosis
The prognosis was almost uniformly fatal prior to the advent of HAART. Now it carries a much better prognosis, but even with HAART, and anti-CMV therapy, mortality is still increased after diagnosis of CMV retinitis.
Additional Resources
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References
Basic and Clinical Science Course. Section 9: Intraocular Inflammation and Uveitis. Ocular Involvement in AIDS. 2010: AAO.
Basic and Clinical Science Course. Section 12: Retina and Vitreous. 2010: AAO.
Goldberg DE, et al. HIV-Associated Retinopathy in the HAART Era. Retina: THe Journal of Retinal and Vitreous Diseases. 2005: 25;5. 634-49.
