Herpes Simplex Ophthalmicus

Etiology

Herpes simplex ophthalmicus is caused by a neurotrophic double-stranded DNA virus with an icosahedral capsid surrounded by a poorly defined tegument (covering). Two types of herpes simplex virus (HSV) affect humans, HSV type 1 (HSV-1) and HSV type 2 (HSV-2). HSV-1 causes orofacial and eye infections by contact from an infected individual, while HSV-2 causes genital disease transmitted sexually. HSV-2 can be transmitted to neonates during birth through HSV-2 infected genitalia of the mothers and to children through orofacial contact by infected adults.

Primary infection occurs in neonates as ophthalmia neonatorum or children less than five years of age as blepharoconjunctivitis. The virus ascends through the cutaneous nerves to stay latent in the trigeminal ganglion. Viral replication is triggered by conditions like fever, menstruation, irradiation, stress, steroid treatment, immunocompromised conditions, etc. to cause secondary infection in adults. Secondary herpes simplex ophthalmicus manifests most commonly as epithelial dendritic keratitis and its recurrences as stromal keratitis.[2]

Epidemiology

Herpes simplex ophthalmicus is a ubiquitous infection and is universal by late adulthood. HSV keratitis is the most common corneal blindness in developing nations. Worldwide, HSV affects between 60-95% of adults. HSV-1 is more commonly affects 70-80% of low socioeconomic groups and 40-60% of improved socioeconomic status.[3] In the United States of America (USA), neonatal HSV infection occurs at a rate of 1 in 3200 deliveries, and 1500 cases are seen every year.[4][5] The USA has a total prevalence of 400,000 cases of HSV keratitis and a total number of episodes at 58,000/year with an incidence of new cases of about 24,000/year. Recurrent disease, estimated to occur in 27% of patients at one year and over 60% at 20 years, commonly causes keratitis, though it can affect all parts of the eye.[6][7]

Pathophysiology

HSV-1 virus commonly causes Herpes simplex ophthalmicus. Rarely HSV-2 infection can occur in neonates from maternal infected genitalia during birth. Primary infection generally occurs through the oropharyngeal mucosa on exposure to secretions of an individual shedding HSV. At the primary site, the virus enters the epithelial cell, replicates, and transports retrogradely through neurons to the dorsal root ganglia of the Trigeminal nerve where it stays latent.[8][9] Recurrent infection due to viral replication in the sensory ganglia is induced by various stimuli like trauma (physical/surgical/laser), ultraviolet radiation, immunosuppression, stress, hormonal changes (menstruation), etc. During the primary infection, CD8+ T cells are primed by the upregulation of chemokine receptors, CXXR3, and CCR10. HSV-specific CD8+ T cells play an important role in recurrent infections.[10][11][12] 

HSV infections incite an inconsistent antibody production, which offers only partial protection to recurrences or reinfections. Recurrent viral replication destroys sensory ganglion cells leading to corneal hypesthesia. Corneal hypesthesia or decreased corneal sensation is a hallmark of HSV keratitis. Rong et al. have shown that the cornea is capable of extraneuronal viral latency and later reactivation.[13]

Classification of Herpes Implex Ophthalmicus

• Primary infection:
  • Ophthalmia neonatorum
  • Blepharoconjunctivitis (children, adults)
• Recurrent infection:
  • Blepharoconjunctivitis (adults)
  • Herpetic keratitis
  • Marginal keratitis
  • Necrotizing stromal keratitis
  • Metaherpetic keratitis
  • Immune-mediated: endotheliitis and keratouveitis.
  • Acute retinal necrosis
• Miscellaneous associations: episcleritis, scleritis, epidemic keratoconjunctivitis, ocular cicatricial pemphigoid, erythema multiforme major, ICE syndrome, Possner-Schlossman syndrome, Fuch heterochromic iridocyclitis.[14]

History and Physical

Primary herpes simplex ophthalmicus is an acute infection occurring in a nonimmune host. It can occur in neonates through intrauterine or birth canal transmission or can occur in children through oro-labial transmission from an infected individual. Primary infection can also occur in an adult as a sexually transmitted disease. 

• In-utero HSV infection: The fetus can be infected by an ascending genital infection or trans-placentally and is born with cataracts and chorioretinitis.
• Neonatal conjunctivitis: It is transmitted through the birth canal and caused by the HSV-2 virus. Seen between 3-15 days of postpartum life and is associated with lid vesicles. Keratitis or keratouveitis can follow conjunctivitis. Cataract, vitritis, retinitis, retinal detachment, and optic neuritis have all been reported to occur with conjunctivitis. 
• Blepharoconjunctivitis: Primary herpes simplex conjunctivitis usually occurs in children less than 5 years old. Features are watery discharge, follicular conjunctivitis, and preauricular lymphadenopathy with cutaneous vesicular eruption over the lids and margins. Most are caused by HSV-1virus. The lesions are diffuse and shed virus for ten days and resolve over 2-3 weeks. Keratitis in the form of punctate epithelial keratitis, marginal infiltrates, or a dendritic ulcer can occur.

Recurrent herpes simplex ophthalmicus occurs due to the reactivation of the latent virus in the trigeminal ganglion. Rong et al have shown that cornea is also capable of extraneuronal viral latency and later reactivation.[13]

• Blepharoconjunctivitis: Lid vesicles are focal along the lid margin or eyelid skin. The weeping ulcers shed virus for only 2-3 days and last for only a week. The nasolacrimal system also gets involved with scarring and leading to epiphora due to punctal stenosis. It is associated with watery discharge, follicular conjunctivitis, and preauricular lymphadenopathy. Conjunctival smears show mononuclear cell infiltrates. Keratitis in the form of punctate epithelial keratitis, marginal infiltrates, or a dendritic ulcer can occur.
• Epithelial Keratitis: It starts as punctate epithelial opacities caused by actively replicating virus. These opacities coalesce centrally and then break down to form central desquamation. The presentation includes mild irritation, redness, watering, photophobia, and corneal hypesthesia.[15]
• Dendritic ulcer: Central epithelial desquamation develops into a dendritic ulcer with mild subepithelial haze, dichotomous branching, and terminal buds. The bed with dead epithelial cells stains with fluorescein, while the margins with virus-laden cells stain with rose bengal. Inadvertent use of topical corticosteroid drops would cause a dendrite to enlarge into a “Geographic ulcer” with amoeboid configuration.[16] Geographic ulcer also develops in immunocompromised patients and untreated longstanding ulcers. 
• Endotheliitis (Disciform keratitis): This is an immune-mediated condition that occurs as an immune reaction to a viral antigen or non-replicating viral particles and manifests as localized, diffuse, and linear forms. The localized form is called Disciform keratitis and manifests as central disc-shaped stroma edema with focal keratic precipitates. The diffuse form is accompanied by trabeculitis with elevated intraocular pressure. The linear form may mimic allograft rejection in a corneal graft.
• Metaherpetic keratitis: This neuropathic ulcer presents as a persistent epithelial defect with greyish elevated borders showing epithelial hyperplasia surrounding the ulcer with a subepithelial haze. Reverse staining is seen with rose bengal staining the unhealthy epithelial cells migrating the base of the ulcer while fluorescein leaks between these cells to stain the margins. Decreased corneal sensation, drug toxicity, poor tear film, chronic low-grade inflammation, and deficient neural growth factors contribute to form the Metaherpetic ulcer.
• Marginal Keratitis: Presents as marginal infiltrates similar to staphylococcal immune infiltrates but epithelial ulceration, and diminished corneal sensation helps in the diagnosis of herpes simplex marginal keratitis.
• Necrotizing stromal keratitis: This results from a severe inflammatory response to viral replication in the cornea. Presents as dense stromal infiltration, ulceration, necrosis, and eventually perforation due to corneal melting. Commonly seen in multiple recurrences and mimics microbial keratitis. 
• Keratouveitis: Herpes simplex keratouveitis is immune-mediated and presents as unilateral sectoral iritis with mutton fat keratic precipitates and elevated intraocular pressure, often complicated by posterior synechiae and complicated cataract.
• Acute retinal necrosis (ARN): usually caused by the Herpes zoster virus, Herpes simplex virus, Cytomegalovirus, and Epstein-Barr virus. The classic triad of ARN consists of occlusive vasculitis, rapidly progressing peripheral retinal necrosis and vitritis.

Miscellaneous Syndromes

• Episcleritis and scleritis: Rarely associated.[17]
• Epidemic keratoconjunctivitis: HSV can cause a picture like epidemic keratoconjunctivitis and its nearly impossible to differentiate between adenoviral and HSV infection In a Japanese study, it was observed that 3% of cases of epidemic keratoconjunctivitis (EKC) diagnosed clinically were caused by herpes simplex virus.[18]
• Erythema multiforme major: Erythema multiforme major is an immune-mediated type 4 hypersensitivity reaction triggered by drugs and infections caused by Herpes simplex virus, Mycoplasma pneumonia, Epstein-Barr virus, Histoplasmosis, etc. This self-limiting condition presents as target lesions around eyelids with conjunctivitis. Antiviral therapy helps prevent the complication like symblepharon and shortening of fornices.
• Iridocorneal endothelial (ICE) syndromes: HSV DNA has been isolated by the Polymerase chain reaction (PCR) test from corneal endothelium in Iridocorneal endothelial (ICE) syndromes.[19][20]

HSV DNA has also been isolated by the PCR test from aqueous humor samples from patients affected with Posner Schlossman syndrome and Fuch heterochromic iridocyclitis.[21]

Evaluation

Most diagnoses are done clinically or with the slit lamp examination because of the distinct characteristics of the infection. Laboratory diagnosis is done in atypical cases where the clinical picture doesn’t yield a conclusive diagnosis because of drug toxicity, immunosuppression, and polytherapy. The following are the methods to confirm Herpes simplex infection.[22] 

• Culture: Virus tissue culture is confirmative and yields positive results in 48 hours of inoculation. Prior rose bengal staining interferes with the culture results as it is viricidal. Immunofluorescent staining of the cells can differentiate between types 1 and 2.[23][24][23]
• Direct Fluorescent Antibody (DFA) Testing: Rapid test but low in specificity and sensitivity. Smear over a slide could obtain results in minutes. Requires a skilled technician and ultraviolet microscope. Fluorescent antibody staining reveals herpetic antigen and is a rapid and reliable test. Fluorescein staining interferes with the test.
• Polymerase chain reaction (PCR) DNA Testing: Polymerase chain reaction test is the preferred test for ocular HSV infection to detect HSV DNA. It is more sensitive than virus culture in the diagnosis of epithelial keratitis. Real-time PCR can differentiate virus shedding from replication by viral quantification. Rapid and more sensitive than culture and can detect virus shedders. Used to identify strains for epidemiological purposes.[25]
• Tzanck Smear: Scrapings are obtained from the corneal epithelium from open cutaneous vesicles and then stained. Giemsa stains of corneal smears show multinucleated giant cells and the Papanicolaou stain shows intranuclear eosinophilic inclusion bodies of Lipschutz (Cowdry type A). Rapid and less expensive tests but low in specificity and sensitivity with the inability to differentiate between type 1 and 2 viruses.
• Cytology: Surface cells are obtained by a brush or impression. Low-cost less sensitive rapid test. 
• Enzyme-linked immunosorbent assay (ELISA): ELISA kits yield rapid results and use monoclonal antibodies against HSV antigens.[26]
• Serum Antibody Testing: Most adults show positive IgG for HSV thereby making this test of less use. Antibody testing in children and infants is rarely done as most of the cases can be diagnosed clinically. IgM antibodies are seen in primary infection with seroconversion to IgG in 2 to 4 weeks after the infection.[27]

Treatment / Management

Antiviral medication is the mainstay of treatment for the herpetic epithelial disease. They interfere with DNA synthesis by inhibiting viral DNA polymerase. Acyclovir and Ganciclovir specifically inhibit thymidine kinase and polymerase and are least toxic. Topical Acyclovir 3% ointment, Ganciclovir 3% gel, and Trifluridine 1% solutions are used regularly at five times/day. Oral preparations are Acyclovir 400 mg 5 times/day and Valacyclovir 500 mg thrice daily. Intravenously Acyclovir 10mg/kg thrice daily is the usual dosage. Corticosteroids are the mainstay of treatment for stromal keratitis and Keratouveitis. 1% prednisolone acetate or 0.1% dexamethasone are commonly used under antiviral cover to prevent recurrence and reactivation of HSV infection.[28][29](B2)

• Neonatal conjunctivitis: Intravenous Acyclovir 60 mg/kg/day every 8 hours for 14 days for SEM (Skin-Eye-Mouth) disease. Extend the treatment for 21 days for central nervous system involvement and the disseminated disease.[30] Oral suppressive acyclovir therapy (300 mg twice or thrice a day) to pregnant women with active, recurrent genital HSV infection from 36 weeks of gestation and elective Caesarean surgery before the breakage of membranes offer the best prevention for birth-related transmission of the virus.
• Blepharoconjunctivitis: Resolves spontaneously in a week or two. Some patients might need acyclovir eye ointment for keratitis or lid vesicles.
• Dendritic ulcer: Most cases resolve spontaneously. Topical antivirals provide faster resolution in marginal ulcers, ulcers larger than 4 mm, and ulcers with stromal inflammation. Topical antivirals provide faster resolution with less scarring. Topical acyclovir 3% ointment or Ganciclovir 0.15% gel applied five times a day for two weeks will heal most of the ulcers. Surface debridement of the ulcer helps in reducing the viral load and offers better penetration of the medication. Toxicity is uncommon but presents as diffuse punctate erosions or follicular conjunctivitis. Most of the time, adding preservative-free lubricating eyedrops would be enough. 
• Disciform keratitis: The mainstay of treatment is corticosteroid eyedrops under topical Acyclovir cover for ten weeks. The antiviral cover is essential as any reactivation of the infection under steroid drops would lead to devastating stromal necrosis. Disciform keratitis is prone to recurrence leading to dense corneal opacity impairing vision. Recurrent episodes need long term oral acyclovir prophylaxis (400 mg bid) as it is proven to be beneficial in preventing recurrent attacks as per the Herpetic eye disease study.[31]
• Metaherpetic keratitis: The mainstay of treatment is first to eliminate the main cause for the persistent epithelial defect. Drug toxicity should be detected and avoided. Dry eye being an aggravating factor for neuropathic keratitis, is treated with preservative-free lubricating drops, punctal occlusion, and cyclosporin eyedrops. Epithelial healing is promoted by autologous serum eyedrops and bandage contact lenses. Resistant cases are treated with an amniotic membrane graft, Gunderson conjunctival fap, or with a central tarsorrhaphy. Cautious use of low potent topical corticosteroids like Fluorometholone is used to treat the underlying inflammation. Non-steroidal anti-inflammatory eyedrops are avoided as they might induce corneal melting leading to perforation.
• Stromal keratouveitis: Topical steroids either 1% prednisolone acetate or 0.1% dexamethasone resolves the underlying immune-mediated inflammation and prevents scarring. The topical antiviral cover is essential as HSV reactivation causes severe epithelial disease or stromal necrosis. Oral Acyclovir 400 mg twice daily for six months to one year prevents recurrences.
• Acute retinal necrosis(ARN): ARN is an ophthalmic emergency and needs to be treated immediately. The goal is to protect the fellow eye from the infection. Intravenous Acyclovir 10 mg/kg 3 times daily for 5 to 10 days depending on the response followed by oral acyclovir 800 mg five times daily orally for six weeks to 3 months.[32] 
(A1)

Surgery is usually done for dense stromal scarring, non-healing ulcers, and impending perforations as in stromal necrosis. 

• Stromal melting: Penetrating keratoplasty may be needed with antiviral medication coverage. Long term oral acyclovir prophylaxis needed to prevent the recurrence of herpes simplex infection in the graft
• Corneal perforation: There needs to be cyanoacrylate glue application or placement of a corneal patch graft
• Persistent epithelial defect: Amniotic membrane grafting or Gunderson conjunctival flap or central tarsorrhaphy is usually performed. The amniotic membrane acts by lowering the inflammatory cells and matrix metalloproteinase levels on the corneas enabling better healing of the epithelial defect. Amniotic membrane causes reduced expression and activity of MMP-8 and nine and increases expression of TIMP-1 and 2.[33]
• Dense stromal scarring: Penetrating keratoplasty (PKP) is done 6 months after the infection is fully controlled. It has a poor prognosis with high graft recurrence and rejection rates. Prophylactic acyclovir 400 mg twice daily should be started prior to the surgery and continued until a year after the surgery to prevent recurrences.[34][35][36]
(A1)

Differential Diagnosis

Ophthalmia Neonatorum

• Infective keratitis
• Dacryocystitis
• Congenital nasolacrimal duct obstruction
• Congenital glaucoma
• Orbital and pre-septal cellulitis

HSV Keratitis

• Herpes zoster keratitis
• Microbial keratitis
• Adenoviral keratitis
• Acanthamoeba keratitis
• Drug toxicity
• Epithelial regeneration line
• Chronic Contact lens wear

HSV Stromal/Interstitial Keratitis

• Varicella-zoster keratitis
• Epstein-Barr virus keratitis
• Measles keratitis
• Mumps keratitis
• Cogan’s syndrome
• Syphilis
• Lyme’s disease

Corneal Hypesthesia

• Herpes virus keratitis
• Chronic contact lens wear
• Lesions of Trigeminal nerve: acoustic neuroma/surgery/trauma
• Diabetes
• Topical medications: anesthetics, beta-blockers, and nonsteroidal anti-inflammatory agents
• Laser surgery: surface ablation and Lasik.[37]

Prognosis

Ophthalmia neonatorum and primary blepharoconjunctivitis respond well with antiviral treatment and have a very good prognosis with the least complications. HSV epithelial keratitis resolves within 1 to 2 weeks with topical antiviral therapy. Stromal keratitis and iritis occur in 25% of people affected with epithelial keratitis and often recurs and results in corneal scarring, glaucoma, neovascularization, and corneal melting leading to irreversible loss of vision. The Australian corneal graft registry has reported that 4% of their failed grafts are due to HSV ophthalmicus.[38] Acute retinal necrosis has a very poor visual prognosis, with 64% of affected eyes have a final vision of 20/200 or worse due to vision-threatening complications like retinal detachment, optic neuropathy, macular edema, and retinal ischemia.[39]

Complications

• Infectious keratitis
• Dense corneal stromal scarring
• Chronic dry eye
• Chronic uveitis
• Corneal melting
• Corneal neovascularization
• Persistent epithelial defect
• Secondary glaucoma
• Complicated cataract
• Posterior synechiae
• Peripheral anterior synechiae
• Chronic vitritis with vitreous condensation and floaters
• Retinal detachment, optic neuritis, cystoid macular edema, and retinal ischemia in patients with acute retinal necrosis[40]