Abstract
This chapter discusses anterior uveitis, acute retinal necrosis, progressive outer retinal necrosis, and non-necrotizing herpetic retinopathy associated with herpes simplex virus (HSV) and varicella-zoster virus (VZV). It also discusses anterior uveitis and cytomegalovirus (CMV) retinitis associated with cytomegalovirus.
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Keywords
- Uveitis
- Herpesviruses
- Acute retinal necrosis
- Progressive outer retinal necrosis
- Non-necrotizing herpetic retinopathy
- Herpes simplex virus (HSV)
- Varicella-zoster virus
- CMV retinitis
- Cytomegalovirus
Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV)
Anterior Uveitis
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Epidemiology
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Average age of onset
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40–50 years for HSV
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60–70 years for VZV
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M = F
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Immunocompetent
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Symptoms
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Redness
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Photophobia
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Pain
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Blurry vision
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Laterality
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Almost always unilateral
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Can be bilateral in patients with atopy and other immune dysfunctions
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Course
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Acute , but can become chronic if not treated promptly
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Chronic intraocular inflammation may be due to persistent viral replication or immune response against inactivated viral antigens or damaged self-tissue
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-
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Diagnosis
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Typically made by characteristic findings and history
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AC tap for viral PCR can confirm and speciate
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Exam
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Increased IOP , often as high as 50–60 mmHg (trabeculitis)
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Corneal edema (endotheliitis)
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Decreased corneal sensation
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Mild to severe AC inflammation (hypopyon possible)
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Diffuse stellate keratic precipitates (KPs) (also seen in toxoplasmosis and FHI), but can also have mutton-fat KPs
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Diffuse or sectoral iris atrophy (also seen in CMV anterior uveitis)
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Iris hyperemia
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Complications: hyphema , glaucoma, posterior synechiae, cataract, hypotony, and, rarely, phthisis bulbi
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HSV: Key points
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Uveitis and trabeculitis can appear with or without corneal lesions (dendritic epithelial keratitis or disciform stromal keratitis)
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Check for decreased corneal sensation
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Iris FA shows intact circulation in atrophic area (vs. no circulation in VZV)
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Given near-universal exposure and seroconversion by middle age, anti-HSV IgG is only helpful if negative, that is, rule out disease; IgM indicates acute infection
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Can be complicated by encephalitis in immunocompromised
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VZV: Key points
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Up to 40% of patients with VZV ophthalmicus may develop anterior uveitis; usually within the first week but may be delayed by weeks to months
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Uveitis can occur without previous zoster dermatitis (zoster sine herpete)
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Hutchinson’s sign: cutaneous vesicles at the side of the tip of the nose; greater likelihood of ocular involvement
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Treatment
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As it is not always possible distinguish HSV from VZV unless PCR is done on an AC tap, we recommend treating all herpetic anterior uveitis with VZV-specific dose for at least 4 weeks
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Acyclovir 800 mg 5×/day
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Valacyclovir 1 g TID
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Famciclovir 500 mg TID
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Maintenance therapy
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Acyclovir 800 mg QD-BID
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Valacyclovir 500 mg−1 g QD
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Famciclovir 250 mg BID or 500 mg QD
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Topical steroids are used aggressively once antiviral therapy is on board, as long as there is no concurrent epithelial keratitis (in the case of HSV); often tapered very slowly, and some patients may need low-dose therapy to remain quiescent even with antiviral prophylaxis, for example, 1 gtt QD-QoD
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Topical cycloplegic for symptomatic relief and prevention of posterior synechiae
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Caution with prostaglandin in HSV uveitis as it may lead to reactive keratitisAcute Retinal Necrosis (ARN)
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Epidemiology
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Age: bimodal with one peak at age 20 (HSV-2) and another at age 50 (HSV-1 and VZV)
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M = F
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Immunocompetent
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Symptoms
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+/− Pain
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Redness
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Photophobia
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Blurry vision
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Floaters
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Visual field defects
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Laterality
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Starts unilaterally , but becomes bilateral in 35–40% of cases within 6 weeks
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Diagnosis
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Usually made on clinical findings, but aqueous and vitreous samples for viral PCR and fungal/bacterial culture are appropriate in atypical presentation or if there is no response to anti-viral therapy
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Exam
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One or more foci of necrotic retina with discrete borders in the peripheral retina; may have macular lesions as well
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Circumferential spread of retinal necrosis
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Rapid progression without antiviral therapy
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Occlusive vasculopathy with arteriolar involvement
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Prominent vitritis and AC inflammation
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Optic neuropathy/atrophy (disc edema a common early finding)
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Scleritis
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RD is very common, occurring in three-fourths of untreated cases within 6–12 weeks; vitreous traction and PVR further complicate matters
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Differential diagnosis
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Progressive outer retinal necrosis
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CMV retinitis
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Atypical toxoplasmosis
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Syphilitic retinitis
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Intraocular lymphoma
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Leukemia
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Metastasis
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Autoimmune retinal vasculitis (sarcoid, Behcet’s, etc.)
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Treatment
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Intravenous (IV) acyclovir 10–15 mg/kg TID for 7–14 days, followed by prolonged oral therapy, is the classic approach
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PO valacyclovir 2 g TID may be equally effective as induction therapy
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IV foscarnet is effective in cases resistant to traditional antiviral
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Intravitreal antiviral is repeated twice weekly until retinitis resolve
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Foscarnet 2.4 mg
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Ganciclovir 2 mg
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Oral corticosteroids appropriate if vision loss is significant from optic nerve inflammation, but only after 24–48 h of systemic antiviral
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Topical corticosteroids safe for AC inflammation
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Prophylactic laser retinopexy if there is clear view
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Pars plana vitrectomy for RD
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Progressive Outer Retinal Necrosis (PORN)
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Epidemiology
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VZV most common: two-thirds of patients have previous or concurrent cutaneous zoster
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HIV/AIDS (CD4 ≤ 50) and profoundly immunocompromised patients
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Symptoms
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Painless loss of vision often out of proportion to exam findings
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May be NLP
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Constricted visual field
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Redness, irritation, photophobia if positive VZV ophthalmicus
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Laterality
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70% bilateral
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Diagnosis
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Based on clinical history and findings, but vitreous tap can confirm organism
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FA
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Late staining of active lesions; window defects in inactive lesions
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+/− focal vascular occlusion
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OCT
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Outer retinal disorganization
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Inner retinal hyper-reflectivity
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CME
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-
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Exam
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Characterized by minimal or no AC or vitreous inflammation (clear view)
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Multifocal patches of outer retinal whitening that coalesce quickly
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Affect both posterior pole and periphery
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50–70% complicated by RD (rhegmatogenous or exudative)
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Differential Diagnosis
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Similar to ARN
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Treatment
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HAART to increase CD4 count
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Treatment otherwise similar to ARN, though visual prognosis often poor
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Non-necrotizing Herpetic Retinopathy
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HSV/VZV can also cause panuveitis in the absence of retinal necrosis, with or without concurrent papillitis or retinal vasculitis
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More like ARN/PORN than anterior uveitis, these cases are often bilateral
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Consider this diagnosis when presumed autoimmune panuveitis or retinal vasculitis fail to respond to systemic IMT
Cytomegalovirus (CMV)
Anterior Uveitis
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Epidemiology
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Most common ocular manifestation of CMV in the immunocompetent
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M > F
-
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Symptoms
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Redness
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Photophobia
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Pain
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Blurry vision
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Laterality
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Unilateral
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Course
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Acute and hypertensive in younger patients (20–50 years)
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Implicated in Posner-Schlossman syndrome (along with HSV)
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Chronic in older patients (>50 years)
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Diagnosis
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Typically made by characteristic findings and history
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Consider CMV when what otherwise appears to be viral AU does not respond to acyclovir or valacyclovir
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AC tap for viral PCR
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Exam
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AC inflammation
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Little to none in acute form
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1–2+ in chronic form
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Increased IOP
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Much higher in acute form
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Diffuse stellate KPs
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Diffuse or sectoral iris atrophy (not always)
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Iris heterochromia
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In contrast to HSV/VZV anterior uveitis
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Normal corneal sensation is normal
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No posterior synechiae
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Complications
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Glaucomatous optic neuropathy (acute form)
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Cataract (chronic form)
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Treatment
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Acute form
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Valganciclovir 0.15% gel 5×/day
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Topical corticosteroids or NSAIDs
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Glaucoma drops for IOP control, but avoid prostaglandin
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Chronic form
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PO valganciclovir 900 mg BID for 4–6 weeks, then reduce to 450 mg BID for maintenance
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Monitor for bone marrow and renal toxicities
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May discontinue therapy after 1 year of disease quiescence (or if repeat AC tap is negative for CMV)
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CMV Retinitis
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Epidemiology
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Often the initial presentation of systemic CMV infection in immunocompromised patients (CD4 typically <50 cells/mm3)
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Occurred in 15–40% of AIDS patients in the pre-HAART era
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ARN-like presentation has been rarely reported in immunocompetent
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Ocular symptoms
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May be minimal or absent initially
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Vision loss
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Floaters
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Unspecific visual disturbances
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Laterality
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Unilateral or bilateral
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Course
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Slowly progressive retinal necrosis (0.2 mm/week) affecting the posterior pole, the periphery, or both; if untreated, destroy the entire fundus over 3–6 months
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Systemic association
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Fever
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Leukopenia
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Arthralgia
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Pneumonitis
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Hepatitis
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Colitis
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+CMV in blood and urine
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Diagnosis
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Typically made by characteristic findings and history
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Vitreous tap for unclear cases
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DFE q3–4 months is recommended in patients with CD4 <50 cells/mm
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Exam
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Little or no AC inflammation
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Early retinitis may disguise as cotton-wool spots, which is common in HIV retinopathy; however, lesion enlarges with irregular borders and is surrounded by satellite infiltrates
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Three clinical variants:
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Classic, fulminant hemorrhagic necrotizing retinitis that extends along the major vascular arcades in the posterior pole
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Granular, indolent form more often found in the periphery; little or no retinal edema, fewer hemorrhages, less vascular sheathing, and retinal atrophy
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Perivascular form often described as a variant of frosted branch angiitis, with scattered retinal hemorrhages
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While primary involvement is rare, optic nerve infiltration can occur if retinitis spread toward the posterior pole
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Rhegmatogenous RD in one-fourth of patients
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Treatment
Treatment should be tailored based on the location and severity of the retinitis, as well as host’s immune status. UL97 mutation confers treatment resistance in as many as one-third of patients; ensuring HAART compliance and employing combination therapy are crucial
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Ganciclovir
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Intravenous: 5 mg/kg BID × 2–3 weeks for induction, then QD for maintenance; AE: bone marrow suppression
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Oral: 1 g TID for maintenance (not used for induction)
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Intravitreal: 2 mg twice weekly x 3 weeks for induction, then 2 mg weekly for maintenance
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4.5 mg surgical implant: replaced every 6–8 months
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Foscarnet
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Intravenous: 60 mg/kg TID × 2–3 weeks for induction, then 90 mg/kg/day for maintenance; AE: nephrotoxicity
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Intravitreal: 2.4 mg twice weekly × 3 weeks for induction, then 2.4 mg weekly for maintenance
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Cidofovir
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Intravenous 5 mg/kg weekly × 2 weeks for induction, then 3–5 mg/kg q2 weeks for maintenance; AE: nephropathy and hypotony uveitis (co-administering probenecid reduces risk)
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Intravitreal: 20 μg every 5–6 weeks
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Valganciclovir
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Oral: 900 mg BID × 2–3 weeks for induction, then 900 mg QD for maintenance; AE: bone marrow suppression
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Stephenson, A.P. (2021). Herpesviruses. In: Foster, C.S., Anesi, S.D., Chang, P.Y. (eds) Uveitis. Springer, Cham. https://doi.org/10.1007/978-3-030-52974-1_35
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DOI: https://doi.org/10.1007/978-3-030-52974-1_35
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