Herpes simplex ophthalmicus (HSO) is caused by the neurotropic herpes simplex virus type 1 and type 2 and affects all the structures of the eye. Primary infection occurs in the form of blepharoconjunctivitis both in neonate through birth canal transmission and in children through orofacial mucus membrane transmission. Primary infection is often self-limiting, and the virus ascends through the cutaneous nerves and stays latent in the trigeminal nerve ganglion. Upon reactivation due to unfavorable immune conditions, a secondary infection happens involving eyelids, conjunctiva, cornea, uvea, and rarely retina. Antiviral agents, both topical and systemic antivirals, are the treatment of choice. Severe infections and its sequelae can often cause severe impairment to the vision. Once infected, it is impossible to eradicate the virus from the body.
Herpes simplex ophthalmicus is caused by a neurotrophic double-stranded DNA virus with an icosahedral capsid surrounded by a poorly defined tegument. 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.
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. 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. 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.
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. 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.
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 cornea is capable of extraneuronal viral latency and later reactivation.
Classification of Herpes simplex ophthalmicus
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.
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.
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.
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.
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.
Surgery is usually done for dense stromal scarring, non-healing ulcers, and impending perforations as in stromal necrosis.
HSV Stromal/Interstitial Keratitis
Ophthalmia neonatorum and primary blepharoconjunctivitis responds well with antiviral treatment and has 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 is due to HSV ophthalmicus. 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.
Educating patients and care providers about the visually devastating nature of the HSV keratitis and the need for adherence to treatment are very important. As herpes simplex virus is ubiquitous in nature and nearly impossible to avoid the infection, the following measures will help in the prevention of both acquiring and recurrence of the disease.
The primary care physician, pediatricians, and health care workers should be educated and made well aware of the signs and symptoms of ophthalmia neonatorum and primary HSV blepharoconjunctivitis. Prompt referral pathways to primary care physicians or an ophthalmologist should be established to treat HSV ophthalmia neonatorum without delay. Primary care physicians should be trained to stain the corneas with the fluorescein and examine under cobalt blue light for a possible dendrite. Every physician and healthcare worker should be trained to assess corneal sensations. A proper detailed history of previous episodes of HSV keratitis should be elicited before starting the patients on topical steroids or before corneal surgical procedures. As of now, there isn’t a successful vaccine to prevent herpes simplex ophthalmicus. The treatment guidelines are provided by the Herpetic eye disease study (HEDS).
Herpetic eye disease study (HEDS) consists of five randomized double-masked placebo-controlled multicentre trials designed to evaluate oral acyclovir (400 mg twice daily) for herpetic stromal keratitis. The conclusions of the HEDS trial are as follows:
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