© Springer Nature Switzerland AG 2021
C. S. Foster et al. (eds.)Uveitishttps://doi.org/10.1007/978-3-030-52974-1_35

35. Herpesviruses

Andrew Phillips Stephenson1  
(1)
University of Cincinnati College of Medicine, Cincinnati, OH, USA
 
 
Andrew Phillips Stephenson
Email: stepha5@mail.uc.edu
Keywords
UveitisHerpesvirusesAcute retinal necrosisProgressive outer retinal necrosisNon-necrotizing herpetic retinopathyHerpes simplex virus (HSV)Varicella-zoster virusCMV retinitisCytomegalovirus

Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV)

Anterior Uveitis

  • Epidemiology
    • Average age of onset

      • 40–50 years for HSV

      • 60–70 years for VZV

    • M = F

    • Immunocompetent

  • Symptoms

    • Redness

    • Photophobia

    • Pain

    • Blurry vision

  • Laterality

    • Almost always unilateral

    • Can be bilateral in patients with atopy and other immune dysfunctions

  • Course
    • Acute , but can become chronic if not treated promptly

      • Chronic intraocular inflammation may be due to persistent viral replication or immune response against inactivated viral antigens or damaged self-tissue

  • Diagnosis

    • Typically made by characteristic findings and history

    • AC tap for viral PCR can confirm and speciate

  • Exam

    • Increased IOP , often as high as 50–60 mmHg (trabeculitis)

    • Corneal edema (endotheliitis)

    • Decreased corneal sensation

    • Mild to severe AC inflammation (hypopyon possible)

    • Diffuse stellate keratic precipitates (KPs) (also seen in toxoplasmosis and FHI), but can also have mutton-fat KPs

    • Diffuse or sectoral iris atrophy (also seen in CMV anterior uveitis)

    • Iris hyperemia

    • Complications: hyphema , glaucoma, posterior synechiae, cataract, hypotony, and, rarely, phthisis bulbi

  • HSV: Key points

    • Uveitis and trabeculitis can appear with or without corneal lesions (dendritic epithelial keratitis or disciform stromal keratitis)

    • Check for decreased corneal sensation

    • Iris FA shows intact circulation in atrophic area (vs. no circulation in VZV)

    • 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

    • Can be complicated by encephalitis in immunocompromised

  • VZV: Key points

    • 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

    • Uveitis can occur without previous zoster dermatitis (zoster sine herpete)

    • Hutchinson’s sign: cutaneous vesicles at the side of the tip of the nose; greater likelihood of ocular involvement

  • Treatment
    • 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

      • Acyclovir 800 mg 5×/day

      • Valacyclovir 1 g TID

      • Famciclovir 500 mg TID

    • Maintenance therapy

      • Acyclovir 800 mg QD-BID

      • Valacyclovir 500 mg−1 g QD

      • Famciclovir 250 mg BID or 500 mg QD

    • 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

    • Topical cycloplegic for symptomatic relief and prevention of posterior synechiae

    • Caution with prostaglandin in HSV uveitis as it may lead to reactive keratitisAcute Retinal Necrosis (ARN)

  • Epidemiology

    • Age: bimodal with one peak at age 20 (HSV-2) and another at age 50 (HSV-1 and VZV)

    • M = F

    • Immunocompetent

  • Symptoms

    • +/− Pain

    • Redness

    • Photophobia

    • Blurry vision

    • Floaters

    • Visual field defects

  • Laterality

    • Starts unilaterally , but becomes bilateral in 35–40% of cases within 6 weeks

  • Diagnosis

    • 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

  • Exam

    • One or more foci of necrotic retina with discrete borders in the peripheral retina; may have macular lesions as well

    • Circumferential spread of retinal necrosis

    • Rapid progression without antiviral therapy

    • Occlusive vasculopathy with arteriolar involvement

    • Prominent vitritis and AC inflammation

    • Optic neuropathy/atrophy (disc edema a common early finding)

    • Scleritis

    • RD is very common, occurring in three-fourths of untreated cases within 6–12 weeks; vitreous traction and PVR further complicate matters

  • Differential diagnosis

    • Progressive outer retinal necrosis

    • CMV retinitis

    • Atypical toxoplasmosis

    • Syphilitic retinitis

    • Intraocular lymphoma

    • Leukemia

    • Metastasis

    • Autoimmune retinal vasculitis (sarcoid, Behcet’s, etc.)

  • Treatment
    • Intravenous (IV) acyclovir 10–15 mg/kg TID for 7–14 days, followed by prolonged oral therapy, is the classic approach

      • PO valacyclovir 2 g TID may be equally effective as induction therapy

      • IV foscarnet is effective in cases resistant to traditional antiviral

    • Intravitreal antiviral is repeated twice weekly until retinitis resolve

      • Foscarnet 2.4 mg

      • Ganciclovir 2 mg

    • Oral corticosteroids appropriate if vision loss is significant from optic nerve inflammation, but only after 24–48 h of systemic antiviral

      • Topical corticosteroids safe for AC inflammation

    • Prophylactic laser retinopexy if there is clear view

    • Pars plana vitrectomy for RD

Progressive Outer Retinal Necrosis (PORN)

  • Epidemiology

    • VZV most common: two-thirds of patients have previous or concurrent cutaneous zoster

    • HIV/AIDS (CD4 ≤ 50) and profoundly immunocompromised patients

  • Symptoms
    • Painless loss of vision often out of proportion to exam findings

      • May be NLP

    • Constricted visual field

    • Redness, irritation, photophobia if positive VZV ophthalmicus

  • Laterality

    • 70% bilateral

  • Diagnosis

    • Based on clinical history and findings, but vitreous tap can confirm organism

    • FA

      • Late staining of active lesions; window defects in inactive lesions

      • +/− focal vascular occlusion

    • OCT

      • Outer retinal disorganization

      • Inner retinal hyper-reflectivity

      • CME

  • Exam

    • Characterized by minimal or no AC or vitreous inflammation (clear view)

    • Multifocal patches of outer retinal whitening that coalesce quickly

      • Affect both posterior pole and periphery

    • 50–70% complicated by RD (rhegmatogenous or exudative)

  • Differential Diagnosis

    • Similar to ARN

  • Treatment

    • HAART to increase CD4 count

    • Treatment otherwise similar to ARN, though visual prognosis often poor

Non-necrotizing Herpetic Retinopathy

  • HSV/VZV can also cause panuveitis in the absence of retinal necrosis, with or without concurrent papillitis or retinal vasculitis

  • More like ARN/PORN than anterior uveitis, these cases are often bilateral

  • Consider this diagnosis when presumed autoimmune panuveitis or retinal vasculitis fail to respond to systemic IMT

Cytomegalovirus (CMV)

Anterior Uveitis

  • Epidemiology

    • Most common ocular manifestation of CMV in the immunocompetent

    • M > F

  • Symptoms

    • Redness

    • Photophobia

    • Pain

    • Blurry vision

  • Laterality

    • Unilateral

  • Course
    • Acute and hypertensive in younger patients (20–50 years)

      • Implicated in Posner-Schlossman syndrome (along with HSV)

    • Chronic in older patients (>50 years)

  • Diagnosis
    • Typically made by characteristic findings and history

      • Consider CMV when what otherwise appears to be viral AU does not respond to acyclovir or valacyclovir

    • AC tap for viral PCR

  • Exam
    • AC inflammation

      • Little to none in acute form

      • 1–2+ in chronic form

    • Increased IOP

      • Much higher in acute form

    • Diffuse stellate KPs

    • Diffuse or sectoral iris atrophy (not always)

    • Iris heterochromia

    • In contrast to HSV/VZV anterior uveitis

      • Normal corneal sensation is normal

      • No posterior synechiae

    • Complications

      • Glaucomatous optic neuropathy (acute form)

      • Cataract (chronic form)

  • Treatment
    • Acute form

      • Valganciclovir 0.15% gel 5×/day

      • Topical corticosteroids or NSAIDs

      • Glaucoma drops for IOP control, but avoid prostaglandin

    • Chronic form
      • PO valganciclovir 900 mg BID for 4–6 weeks, then reduce to 450 mg BID for maintenance

        • Monitor for bone marrow and renal toxicities

      • May discontinue therapy after 1 year of disease quiescence (or if repeat AC tap is negative for CMV)

CMV Retinitis

  • Epidemiology

    • Often the initial presentation of systemic CMV infection in immunocompromised patients (CD4 typically <50 cells/mm3)

    • Occurred in 15–40% of AIDS patients in the pre-HAART era

    • ARN-like presentation has been rarely reported in immunocompetent

  • Ocular symptoms

    • May be minimal or absent initially

    • Vision loss

    • Floaters

    • Unspecific visual disturbances

  • Laterality

    • Unilateral or bilateral

  • Course

    • 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

  • Systemic association

    • Fever

    • Leukopenia

    • Arthralgia

    • Pneumonitis

    • Hepatitis

    • Colitis

    • +CMV in blood and urine

  • Diagnosis

    • Typically made by characteristic findings and history

    • Vitreous tap for unclear cases

    • DFE q3–4 months is recommended in patients with CD4 <50 cells/mm

  • Exam

    • Little or no AC inflammation

    • 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

    • Three clinical variants:

      • Classic, fulminant hemorrhagic necrotizing retinitis that extends along the major vascular arcades in the posterior pole

      • Granular, indolent form more often found in the periphery; little or no retinal edema, fewer hemorrhages, less vascular sheathing, and retinal atrophy

      • Perivascular form often described as a variant of frosted branch angiitis, with scattered retinal hemorrhages

    • While primary involvement is rare, optic nerve infiltration can occur if retinitis spread toward the posterior pole

    • Rhegmatogenous RD in one-fourth of patients

  • 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
    • Ganciclovir

      • Intravenous: 5 mg/kg BID × 2–3 weeks for induction, then QD for maintenance; AE: bone marrow suppression

      • Oral: 1 g TID for maintenance (not used for induction)

      • Intravitreal: 2 mg twice weekly x 3 weeks for induction, then 2 mg weekly for maintenance

      • 4.5 mg surgical implant: replaced every 6–8 months

    • Foscarnet

      • Intravenous: 60 mg/kg TID × 2–3 weeks for induction, then 90 mg/kg/day for maintenance; AE: nephrotoxicity

      • Intravitreal: 2.4 mg twice weekly × 3 weeks for induction, then 2.4 mg weekly for maintenance

    • Cidofovir

      • 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)

      • Intravitreal: 20 μg every 5–6 weeks

    • Valganciclovir

      • Oral: 900 mg BID × 2–3 weeks for induction, then 900 mg QD for maintenance; AE: bone marrow suppression