Figure 1. Diagram of herpes simplex virus. Image from http://www.herpesdiagnosis.com/herpes.html.
By Weon Jun, O.D., F.A.A.O.
You can use this outline to navigate through the course. Return to the top of this page by using your browser's back button.
Herpes simplex virus (HSV) is a relatively common virus that can infect humans. HSV infections are endemic worldwide, affecting nearly 75% of the general population at some time during the life span. (1) The herpes simplex virus can invade the body and infect the skin, mucous membranes, nervous system, and the eye. (The term "herpes" is derived from the Greek work meaning to creep, probably because of the way herpetic lesions progress along the surface of the body and the cornea of the eye.)
HSV is a double-stranded DNA virus (Fig. 1) that enters host cells and replicates in their nuclei (i.e., the virus uses the cell's metabolic machinery to produce more virus particles). This ultimately leads to cell death, which releases viral particles to invade surrounding cells. HSV replicates rapidly in many different cell types, but replication is especially rapid in stratified squamous epithelium (e.g., the cornea and skin).
Figure 1. Diagram of herpes simplex virus. Image from http://www.herpesdiagnosis.com/herpes.html.
Approximately 20,000 new cases of ocular HSV and more than 28,000 reactivations occur in the United States annually. (2) Males and females are affected equally often. Ocular infections can present as primary, neonatal, and recurrent HSV infections.
Recurrence of ocular HSV infection typically affects the eyelids, conjunctiva, and cornea. The most common form of recurrent infection is keratitis, which affects up to 10 million people worldwide. (3) HSV infection is a common cause of unilateral corneal disease and is one of the leading causes of blindness from corneal opacification.
Ocular manifestations of HSV infection include blepharitis, conjunctivitis, infectious epithelial keratitis, neurotrophic keratopathy, immune stromal keratitis, necrotizing stromal keratitis (uncommon), endotheliitis, anterior uveitis, and, rarely, retinitis.
The diagnosis of ocular HSV infection is usually based on clinical signs and symptoms; laboratory testing is seldom necessary for confirmation. If a laboratory test is required, a swab for virus culture can be obtained from the presumed herpetic lesions and immunofluoresence or nucleic acid amplification by polymerase chain reaction testing can be performed.
When managing a disease such as herpes, it is important to understand as much as possible about the infecting organism. The family of herpes viruses is very large, and its members infect most animal species. There are eight recognized herpes viruses that affect humans. These viruses are divided into three groups: alpha, beta and gamma. Herpes viruses within these groups are listed in Table 1.
Table 1. Classification of Human Herpes Viruses. Table modified from http://www.ihmf.org/general/HerpesVir.asp
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Alpha-herpes viruses
|
Herpes simplex virus type 1 (HSV-1)
Herpes simplex virus type 2 (HSV-2) Varicella-zoster virus (VZV) |
|
Beta herpes viruses
|
Cytomegalovirus (CMV)
Human herpes virus type 6 (HHV-6) Human herpes virus type 7 (HHV-7) |
|
Gamma-herpes viruses
|
Epstein-Barr virus (EBV)
Human herpes virus type 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpes virus |
Worldwide, more than 90 percent of humans have been exposed to HSV-1 and are seropositive for this virus by the fourth decade of life. Probability of exposure is especially high for those in lower socioeconomic groups. (4) Viral transmission is by direct contact of infectious secretions with the epidermis or mucous membranes of the recipient.
Primary or initial (as opposed to recurrent) herpetic infection occurs most commonly along the mucocutaneous distribution of the trigeminal nerve. It is typically a mild or sub-clinical infection that often does not include significant signs or symptoms. Children have the greatest risk for contracting primary herpes simplex infection between ages 6 months and 5 years.
When symptomatic, primary herpes can produce a mild fever, malaise, and upper respiratory infection. Sometimes oro-facial lesions such as stomatitis or gingivostomatitis are also present. The infection is generally self-limiting and will typically resolve without any medical intervention or treatment.
Primary herpetic infections involving the eyes are rare but may present as ulcerative blepharitis, follicular conjunctivitis, or keratitis. The infection is often associated with localized eyelid vesicles (viral eczema), which can aid in making the diagnosis.
After a primary infection, the herpes simplex virus spreads from the infected epithelial cells to the axons of the sensory nerves and onward to cell bodies in the neural ganglia. These include the trigeminal dorsal root ganglion (from which reactivation can cause oro-facial and ophthalmic lesions), and the sacral ganglion (from which reactivation can cause genital lesions).
When the virus enters the nucleus of a neuron, it can persist in a latent state. Inside cells, the virus is well protected from the body's immune system and can exist for a lifetime causing occasional outbreaks (i.e., reactivations or recurrences) when triggered by unknown factors. (Figure 2)
It was previously thought that virus reactivation could be triggered by emotional or physical stress, sunlight exposure, hormonal changes, and/or immune-compromise. However, these causes of reactivation are now questionable. The Herpetic Eye Disease Study found no association between increased risk of recurrence and stress, systemic infection, sunlight exposure, menstrual cycle, contact lens wear, or eye injury. (5)
Figure 2. The herpes simplex virus life cycle. Image from http://www-ermm.cbcu.cam.ac.uk/03006987h.htm.
There are three main herpes viruses that cause ocular infection and inflammation. They are the herpes simplex virus, varicella-zoster virus, and cytomegalovirus. This course will consider only infections caused by herpes simplex virus.
The herpes simplex virus has two forms: HSV-1 and HSV-2. HSV-1 is usually associated with oro-facial and ophthalmic lesions as illustrated in Figure 3. HSV-2 infection is usually associated with genital lesions. (Figure 4) Ocular herpes simplex virus infections are primarily caused by HSV-1 and are only rarely the result of HSV-2 infection.
Figure 3. Ocular and facial lesions produced by herpes simplex virus type 1 infections. Image from http://www.iceh.org.uk/files/tsno4/slides/s11.htm.
Figure 4. Illustration of herpes simplex virus type 2 infections, which commonly produce genital lesions. Image from http://yalenewhavenhealth.org/library/healthguide/.
HSV-1 ocular infections are occasionally asymptomatic but can produce a variety of signs and symptoms that affect several different ocular structures. (6) Manifestations of HSV-1 infection can include:
These manifestations will be discussed individually.
Herpes simplex virus blepharitis can present as a primary ocular HSV infection or as a recurrent condition. It is most often encountered in children, but it is also observed in adults.
The classic presentation includes an accumulation of small, seropurulent vesicles along the lid margin and/or on the periocular skin. Within the first week of infection, the seropurulent vesicles may ulcerate or harden into crusts as shown in Figure 5. The lesions then usually resolve without scarring.
The seropurulent vesicles of HSV blepharitis can appear similar to those produced by herpes zoster ophthalmicus. However, herpes simplex virus vescicles do not follow a cranial nerve V1 distribution and there is a lack of antecedent pain or paresthesia, both of which would be expected if the infection were caused by varicella-zoster virus.
HSV blepharitis can also be accompanied by HSV keratitis and by seropurulent vesicles present elsewhere on the body (e.g., cold sores).
Figure 5. Herpes simplex virus blepharitis with clustered vesicles and ulcerated lesions on the lower lid.
Signs and symptoms of HSV blepharitis can include all or some of the following:
The differential diagnosis of HSV blepharitis should include ruling out the following conditions, all of which can produce similar signs or symptoms:
Herpes simplex virus conjunctivitis is another form of HSV ocular infection. The patient usually presents with a unilateral follicular conjunctivitis and positive (i.e., palpable or tender) preauricular lymphadenopathy. He or she can also have seropurulent vesicles along the lid margin and/or periocular skin and may have coarse superficial punctate keratitis.
Figure 6. HSV Conjunctivitis. Image from http://www.vigamox.com/pedoph_conjunctivitis.html.
Signs and symptoms of HSV conjunctivitis can include all or some of the following unilateral findings:
The differential diagnosis of HSV conjunctivitis should include ruling out the following conditions, which can produce similar signs or symptoms:
The clinical manifestations HSV keratitis can present diagnostic and therapeutic challenges. In this course, the HSV keratitis classification system proposed by Holland and Schwartz will be followed. (6)
HSV Infectious Epithelial Keratitis
The most common ocular herpes simplex virus disease is epithelial keratitis that results from an active infection of the corneal epithelium. This condition usually presents as a unilateral, painful, red eye with excessive tearing and photophobia.
HSV epithelial keratitis can resolve without treatment, but it can also produce devastating ocular consequences and may lead to blindness.
Infectious epithelial keratitis can take the form of corneal vesicles, or it can present as dendritic, geographic, or marginal ulcers. Rose bengal, lissamine green, and fluorescein can be used to help diagnose this type of HSV keratitis.
The earliest lesions of reactivated HSV appear as small vesicles in the epithelium. These tiny, raised, clear vesicles correspond to similar vesicles elsewhere on the skin and mucous membranes, and quickly coalesce to from a dendritic ulcer.
A dendritic ulcer is pathognomonic of HSV corneal infection. Features of a dendritic ulcer include a branching, linear, epithelial defect with swollen borders. The center of the lesion ulcerates with a depth beyond the basement membrane, and the lesion has bulb-like enlargements at the end of each linear branch (terminal end bulbs), which makes it relatively easy to diagnose. The dendritic ulcer stains brightly with fluorescein, and the edges stain with rose bengal or lissamine green. (Figure 7)
Figure 7. Dendritic ulcer produced by HSV infection. Image from www.emedicine.com.
Dendritic ulcers can produce abnormal-appearing epithelium with a remnant of the dendriform-shaped lesion for several weeks after the ulcer heals. In contrast to the positive fluorescein staining of an active dendritic ulcer, the dendriform-shaped healing epithelium is slightly raised and shows negative fluorescein staining (i.e., the fluorescein is not taken up by the lesion but forms a border around it).
An HSV geographic ulcer is basically an enlarged HSV dendrite, but the dendritic pattern is lost as the viral infection progresses. The scalloped or geographic border of a HSV geographic ulcer differentiates this lesion from the smooth border of a neurotrophic ulcer.
Figure 8. HSV geographic ulcer. Image from http://www.emedicine.com.
A marginal ulcer is an uncommon manifestation of HSV epithelium infection. Similar to a staphylococcal marginal infiltrate/ulcer, a marginal HSV lesion has an epithelial defect with an anterior stromal infiltrate and adjacent limbal infection. Careful inspection may reveal that the epithelial defect is actually a dendritic ulcer.
Symptoms of HSV infectious epithelial keratitis can include all or some of the following typically unilateral findings:
The differential diagnosis of HSV infectious epithelial keratitis should include ruling out the following conditions, all of which can produce similar signs or symptoms:
HSV neurotrophic keratopathy usually occurs as a result of recurrent HSV infectious epithelial keratitis and/or HSV disciform endotheliitis. Each recurrence causes greater damage to the corneal nerves and leads to hypoesthesia, which can be detected by use of the cotton-wisp test.
Loss of sensory innervation causes diminished cornea epithelial regeneration and decreased tear formation. The resulting keratopathy can be exacerbated by chronic use of the topical antivirals.
The mildest from of neurotrophic keratopathy is a patch or patches of corneal surface irregularity. Punctate epithelial erosions then develop and may progress to form a persistent epithelial defect, which can ulcerate into the stroma and develop a gray-white opacification. (Figure 9)
These non-healing defects can become scarred, vascularized, necrotic, infected with bacteria, and perforated unless aggressive treatment is provided.
Figure 9. HSV neurotrophic keratopathy. Image from http://www.emedicine.com.
HSV immune stromal keratitis is a common manifestation of chronic, recurrent ocular HSV disease. As opposed to an actual HSV infection within the stroma, it is believed to be primarily an immune-mediated process (i.e., an antibody-complement cascade) that occurs as a reaction to viral antigens in the stroma. (7)
The main characteristic of immune stromal keratitis is stromal inflammation. The overlying epithelium is almost always intact except in situations of concomitant infectious epithelial keratitis or neurotrophic ulceration.
The inflammation can take a number of forms. A common, mild form is characterized by the subepithelial haze and scarring seen after a dendritic ulcer has resolved. Inflammation can present as punctate stromal opacities, focal, multifocal or diffuse cellular infiltrates, immune rings, neovascularization, or ghost vessels. An anterior chamber reaction may accompany this form of stromal inflammation.
Figure 10. HSV immune stromal keratitis. Image from www.emedicine.com.
HSV immune stromal keratitis is probably the most common cause of unilateral interstitial keratitis seen in the United States. (7) However, it is unusual to have HSV immune stromal keratitis as an initial manifestation of HSV keratitis. This condition most often appears as a sequela to prior HSV infectious epithelial keratitis, usually following it by days to years.
HSV immune stromal keratitis is often recurrent and can cause permanent dense stromal scars and lead to severe vision loss. These patients may need penetrating keratoplasty (PKP) to restore vision.
Patients with recurrent HSV immune stromal keratitis can also develop secondary glaucoma from anterior uveitis and trabeculitis and should be monitored for these complications.
If there is a suspicion that HSV might not be causing the stromal keratitis, TB-related or syphilis-related interstitial keratitis need to be ruled out. Also, a negative history of eye trauma and infection is needed to rule out these causes of the keratitis.
HSV Necrotizing Stromal Keratitis
HSV necrotizing stromal keratitis is relatively uncommon. It presents clinically as dense stromal inflammation, ulceration, and necrosis. (Figure 11) Significant anterior chamber inflammation with a hypopyon may also be present. This type of keratitis is believed to result from viral replication in stromal keratocytes and a severe host inflammatory response.
Figure 11. HSV necrotizing stromal keratitis. Image from http://www.nova.edu/~albert/phy_diag.html
HSV endotheliitis is thought to be caused by an immune reaction to viral antigens within the corneal endothelial cells. The inflammation causes endothelial decompensation that results in stromal and epithelial edema. This inflammation often triggers an iritis.
Clinical signs include keratic precipitates (KPs), overlying stromal and epithelial edema, and an absence of a stromal infiltrate or neovascularization.
Figure 12. Fine keratic precipitates in a patient with HSV endotheliitis. Image from http://www.emedicine.com.
Endotheliitis can present as disciform, diffuse, or linear forms based on the pattern of the keratic precipitates.
Disciform endotheliitis (also known as disciform edema and disciform keratitis) produces a central round area of KP deposition and corneal stromal edema with a clear demarcation between involved and non-involved cornea. Diffuse endotheliitis produces scattered KPs and diffuse edema. It may result from a previous disciform area of involvement. Linear endotheliitis produces a line of KPs progressing centrally from the limbus or progressing circumferentially with a trailing line of edema.
Figure 13. HSV Disciform endotheliitis. Image from www.emedicine.com.
Persistent or untreated HSV endotheliitis can lead to secondary corneal neovascularization and scarring.
A mild-to-moderate uveitis is frequently seen in conjunction with HSV endotheliitis. Patients may have an increased intraocular pressure due to trabeculitis or obstruction of aqueous outflow from inflammatory cells. These patients can develop chronic glaucoma from structural damage of the trabecular meshwork produced by the persistent trabeculitis or uveitis.
HSV anterior uveitis is an intraocular inflammation that can be accompanied by any form of HSV keratitis or it can occur independently without any previous history of ocular HSV infection. Clinical signs include anterior chamber reaction including cells and flare, keratic precipitates, and an increased intraocular pressure due to a concomitant trabeculitis. Iris atrophy and transillumination defects (which may be segmental) might be present from previous episodes of HSV anterior uveitis. (Figure 14)
Figure 14. Iris atrophy in a patient with herpes simplex virus–associated anterior uveitis. Image from http://www.emedicine.com.
HSV retinitis is a relatively rare condition that typically results from dissemination of an HSV epithelial infection. However, the retinitis usually occurs after the corneal involvement so it is rare to have HSV keratitis present at the same time as the retinitis.
HSV retinitis often presents bilaterally and is usually associated with a severe systemic HSV infection in neonates and immuno-compromised patients.
The retinitis can take two forms: acute retinal necrosis and progressive outer retinal necrosis. Clinical signs include acute confluent peripheral retinitis, vitritis, papillitis, and anterior uveitis. Persistent retinal inflammation can lead to rhegmatogenous retinal detachments and resulting loss of vision.
Neonatal HSV infection is most commonly caused by HSV-2, which is transmitted during vaginal delivery. Some specialists recommend either suppressive therapy for pregnant women experiencing a genital HSV infection during the pregnancy or else planning for a cesarean section delivery. Oral acyclovir (400 mg tid) from 36 weeks until birth has been recommended if a vaginal delivery is planned. (8)
When selecting treatment regimens for the management of ocular HSV infections, it is important to consider mechanisms of action, relative effectiveness, safety profiles, and routes of administration for the available HSV medications. Drug interactions, toxicity, and the potential for allergic reactions are also important factors to consider.
The Herpetic Eye Disease Study (HEDS) has changed and refined treatment and management protocols for herpetic eye disease. (9, 10) HEDS was undertaken to:
HEDS results showed that long-term (12-month) suppressive therapy with an oral antiviral agent (acyclovir 400 mg bid) accomplished the following:
HEDS also showed that long-term acyclovir therapy was not effective in preventing HSV stromal keratitis or iritis in patients with HSV epithelial keratitis. (10)
Topical antiviral drugs are incorporated into viral and host cell DNA resulting in fraudulent DNA production. This results in fewer viral particles being produced to infect new cells and less host cell damage. Fewer viral particles being produced also reduces the immune system response and the subsequent cellular damage from this response.
Because topical drugs also cause fraudulent host cell DNA production, they cause cellular toxicity. This toxicity limits the systemic and topical usefulness of the drugs. Topical drugs that have proven effective for the management of ocular HSV infections are listed in Table 2.
Table 2. Topical HSV Ocular Infection Treatment Drugs.
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Generic Name
|
Trade Name
|
Forms
|
|
Trifluridine 1% ophthalmic solution
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Viroptic®
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Topical drops
|
|
Vidarabine 3% ophthalmic ointment
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Vira-A®
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Topical ointment
|
|
Idoxuridine 0.1% ophthalmic solution
|
Herplex®
|
Topical drops
|
|
Idoxuridine 0.5% ophthalmic ointment
|
Stoxil®
|
Topical ointment
|
Trifluridine 1% ophthalmic solution (Viroptic® and generic)
HSV epithelial keratitis (dendritic and geographic) is treated with topical antiviral medications. The drug of first choice is trifluridine 1% ophthalmic solution (Viroptic®), provided that the patient is not allergic to this medication. (Figure 15)
Figure 15. Trifluridine 1% ophthalmic solution (Viroptic® and generic) Images from www.kingpharm.com/Product_View.asp?id_product=12, and www.falconpharma.com/Pages/Trifluridine.html.
Trifluridine 1% ophthalmic solution is approved by the United States Food and Drug Administration for patients age 6 years and older. For children younger than 6 years of age, the safety and efficacy of the trifluridine has not been established.
Trifluridine is usually prescribed one drop every 2 hours during waking hours up to a maximum of nine times per day in the infected eye. Once resolution is seen and there are no signs of rose bengal, lissamine green, or fluorescein staining, the dose can be tapered for a period not exceeding than 7 days. Continuing the medication after clinical resolution is to insure that any lingering virus replication is blocked. Trifluridine should not be administered for more than 21 days because of potential ocular toxicity.
If there is no sign of improvement after 7 days of trifluridine 1% ophthalmic solution therapy, other forms of antiviral therapy or a different diagnosis should be considered.
If complete re-epithelialization has not occurred after 14 days of therapy, ocular toxicity from trifluridine may be causing medicamentosa keratitis. Discontinue the trifluridine and prescribe lubricant therapy. Continue to monitor.
If an anterior uveitis is present with epithelial keratitis, it is typical to prescribe a cycloplegic agent, usually homatropine 5% ophthalmic solution bid or tid, or scopolamine 0.25% ophthalmic solution bid to tid. The cycloplegic agent will help relieve pain and photophobia, as well as prevent the formation of posterior synechiae.
It is important to note that topical steroid medications are contraindicated for the treatment of HSV epithelial keratitis, because steroids can promote viral replication and the spread of HSV not only in the epithelium but also into the stroma.
Viroptic® is a rather expensive drug with a 7.5 ml bottle costing over US$100. A generic trifluridine 1% ophthalmic solution is available, which is about 10% less expensive than non-generic Viroptic®.
Topical Drugs Not Currently Available in the United States
For various reasons several topical drugs (e.g., Vidarabine 3% ophthalmic ointment, acyclovir 3% ophthalmic ointment, and idoxuridine ophthalmic 0.1% solution and 0.5% ointment) that have the potential for treatment of HSV are no longer commercially available in the United States. These drugs were withdrawn because of problems with corneal toxicity or for other reasons best known to the manufacturers. The drugs are discussed below for informational purposes and no treatment recommendations are made for these drugs.
Vidarabine 3% Ophthalmic Ointment (Vira-A®)
Vidarabine 3% ophthalmic ointment (Vira-A®) generally works well for patients who are allergic to or intolerant of 1% trifluridine ophthalmic solution. It is as effective as 1% trifluridine for treating HSV epithelial keratitis but is less effective than trifluridine for treatment of HSV geographic ulcers.
When this drug was available, it was prescribed five times a day in the infected eye until the HSV epithelial keratitis resolved (i.e., there was no sign of both rose bengal, lissamine green, fluorescein staining). This was followed by a one-week period of tapering the medication.
Acyclovir 3% Ophthalmic Ointment
Acyclovir 3% ointment in ophthalmic preparation is not commercially available in the United States, but a pharmacist can prepare a 3% ophthalmic ointment in petrolatum base. This is not usually recommended because the medication is unstable in this form.
Idoxuridine Ophthalmic 0.1% Solution and 0.5% Ointment
Idoxuridine (IDU) is no longer available in the United States market due to toxicity and a decreasing spectrum of effectiveness. All topical antiviral medications were toxic to the eye, but idoxuridine was the most toxic of the commonly used drugs.
When it was used, the IDU ophthalmic solution dosage for adults and children was one-drop qh during the day and one-drop q2h at night. After improvement, the dosage was decreased to one-drop q2h during the day and one-drop q4h at night. The ophthalmic ointment dosage for adults and children was every four hours during the day (up to five times a day).
Topical Steroids For HSV Stromal and Endothelial Disease
A topical steroid is contraindicated for HSV infectious epithelial keratitis because it encourages the development of more devastating HSV keratitis. In contrast, if HSV stromal keratitis or endotheliitis have already developed, a topical steroid is needed for treatment to reduce the inflammation and immune response.
There are many topical ophthalmic steroids available, however prednisolone acetate is usually the first choice for treatment of HSV disease because it depresses inflammation effectively and it has high corneal penetrating ability.
Prednisolone can cause an intraocular pressure rise in steroid responders; if this occurs, an anti-glaucoma drug can be added to the treatment regimen.
When a steroid is used for treatment of stromal keratitis or endotheliitis, trifluridine should be used for treatment of a concurrent infectious epithelial keratitis or to prevent a recurrence of infection.
Three systemic antiviral medications can be used to treat ocular HSV infections: acyclovir, valacyclovir, and famciclovir. (Table 3) These medications differ somewhat in their chemical structure, dosage, and price.
Table 3. Summary of Oral Antiviral Agents for Ocular HSV infection
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Generic Name
|
Trade Name
|
Preparation
|
Dose Forms/Concentration
|
|
Acyclovir
|
Zovirax®
|
Capsules, tablets, suspension, powder for intravenous use
|
200 mg capsules,
400 and 800 mg tablets, 5% ointment, 200 mg/5 mL suspension, 500 mg/vial and1000 mg/vial powder |
|
Valacyclovir
|
Valtrex®
|
Tablets
|
500 mg and1000 mg tablets
|
|
Famciclovir
|
Famvir®
|
Film-coated tablets
|
125, 250, and 500 mg tablets
|
All three oral antiviral medications are very effective and reasonably safe. Each drug inhibits viral DNA polymerase and this results in fewer virus particles being produced. Unlike topical antiviral agents, the oral medications do not disrupt DNA synthesis nor do they interfere with replication of normal cells. This means that they are less toxic than topical agents such as trifluridine.
For maximum reduction of symptoms and complications, it is best if treatment with any of these three drugs is initiated within 72 hours of disease onset.
Acyclovir (Zovirax® and generic)
In the early 1980s, acyclovir became the first systemic drug to successfully treat herpes virus infections.
Figure 16. Acyclovir (Zovirax®) tablets and oral suspension. Images from www.walgreens.com/library/finddrug/picture1.jhtml.
Acyclovir is available commercially as Zovirax® and in a much less expensive generic form. (Thirty 800 mg tablets of Zovirax® cost over US$175, whereas the same tablets in generic form cost less than US$25).
Oral acyclovir 400 mg given five times per day for 10 days is as effective as topical ophthalmic 1% trifluridine for treatment of HSV infectious epithelial keratitis. Oral acyclovir should be considered when treating patients with preexisting ocular surface disease who might be at high risk for topical trifluridine toxicity.
Oral acyclovir, 400 mg given five times per day, achieves therapeutic concentrations in the aqueous humor and may be more effective than topical agents for treatment of HSV endotheliitis.
Sometimes acyclovir suspension is prescribed for children with a primary herpes simplex virus infection or ocular HSV disease. Children less than 12 years of age are prescribed 20 mg/kg of body weight q6h.
Some studies have shown that oral acyclovir given after a corneal graft for treatment of ocular herpes simplex disease can reduce the rate of recurrent dendritic ulceration and improve graft survival. (11)
If an HSV infection is severe or if the patient is immunocompromised, hospitalization should be considered and acyclovir should be prescribed for 7 days at a dose of 5 mg/kg q8h.
The Herpetic Eye Disease Study has also shown that low dose acyclovir (400 mg bid) can also be used to suppress recurrences of infectious epithelial keratitis and stromal keratitis. (10)
For treatment of herpes labialis (cold sores), patients can be prescribed acyclovir 5% aqueous cream to be used four times a day. Penciclovir is also available in a cream form to treat recurrent herpes labialis. This cream is applied every 2 hours during the day.
Valacyclovir (Valtrex®) is another oral antiviral medication available for treatment of ocular HSV infections and can be used as a substitute for acyclovir for any of the applications described above. (12)
Figure 17. Valacyclovir (Valtrex®). Image from www.buy-adderall.com/valtrex-buy-valtrex.htm,
Valacyclovir is a pro-drug of acyclovir, and it is rapidly converted to acyclovir in the body. This drug is available in 500 mg and 1000 mg tablets.
Valacyclovir is well absorbed systemically and achieves high blood levels of acyclovir. For this reason, it is sometimes has referred to as “intravenous acyclovir” in pill form. However, valacyclovir is more expensive than acyclovir. (Thirty 1000 mg valacyclovir tablets cost over US$225.)
Because valacyclovir has a longer half-like in the body, it is prescribed at lower doses and less frequently than acyclovir. For herpes simplex virus infection, patients are typically given 500 mg tid for 7 days.
The main route of valacyclovir elimination is renal so dose modification is recommended for patients with a creatinine clearance below 30-mL/min/1.73 m2. (12)
Famciclovir (Famvir®) is a pro-drug of the antiviral drug penciclovir. (Figure 18). After absorption, famciclovir is rapidly converted to penciclovir by intestinal and liver tissues.
Figure 18. Famciclovir (Famvir®). Image from www.walgreens.com/library/finddrug/picture1.jhtml.
Famciclovir is available as 125 mg, 250 mg, and 500 mg film-coated tablets, which can be taken without food.
Like valacyclovir, famciclovir is given at less frequent intervals than acyclovir, but it is more expensive than acyclovir. (Thirty 500 mg tablets of famciclovir cost over US$225.) For herpes simplex infection, patients are typically given 250 mg tid for 7 days.
Foscarnet (24 mg/ml) is available in solution form for intravenous use. It is mainly used for management of CMV retinitis as a United States Food and Drug Administration approved treatment, but it can also be prescribed for treatment of other HSV infections that are resistant to other antiviral medications.
Foscarnet is also moderately effective in treating acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients, but its side-effect profile limits its use. Gastrointestinal problems and renal impairment (nephrotoxicity) are common major toxic side-effects of this drug and occur in more than 25% of patients.
Concurrent hydration therapy is recommended to reduce renal toxicity. Saline loading, meticulous dose adjustment, and avoidance of other nephrotoxic agents may help reduce side-effects.
Foscarnet is prescribed 40 mg/kg intravenously at a dosage of 1 mg/kg/min bid or tid for treatment of HSV infections.
Additional Drugs and Procedures That Can Be Used for Management of HSV Epithelial Infections
Topical Alpha or Beta Interferons
These drugs are alternatives to 1% trifluridine for treating HSV epithelial keratitis. Some studies have shown that they are as effective as 1% trifluridine after 7 days, and possibly more effective after 14 days. (13) Interferons can also be combined with 1% trifluridine for treating HSV epithelial keratitis.
Some practitioners recommend debriding the cornea as part of the treatment for HSV epithelial keratitis. Debridement is performed using a cotton tip applicator rolled (rather than rubbed) over the affected corneal area. A strip of filter paper or Schirmer Test paper can also be dabbed over the affected corneal area for debridement.
It has been difficult to show a significant difference in HSV infection healing between corneas that have undergone corneal debridement and those that have not.
HSV Infectious Epithelial Keratitis
HSV Stromal Keratitis, Endotheliitis, Anterior Uveitis
Case One: Herpes Simplex Virus Dendritic Keratitis
The following case demonstrates the management of a herpes simplex virus dendritic ulcer. It also illustrates the importance of proper patient education and compliance. As stated in the course, trifluridine 1% ophthalmic solution is very effective for treating HSV dendritic keratitis if the patient is compliant with instructions regarding use of this medication.
It is important to initiate treatment with trifluridine 1% ophthalmic solution aggressively by prescribing one-drop q2h during waking hours (up to a maximum of nine times per day) for 10 to 14 days. After resolution of the lesion, the medication should be tapered for another week. Continued use of trifluridine is not recommended because of possible corneal toxicity.
Prescribing a cyloplegic agent such as homatropine 5% ophthalmic solution can be helpful for reducing ocular pain associated with HSV dendritic keratitis. Medication specifically for pain relief might also be required in some cases.
History and Initial Examination
A 65 year-old Caucasian male presented with complaints of pain, redness, watery discharge (no mucus), and a foreign body sensation in the right eye for one week. He was also photophobic OU, but more so OD. The patient had rinsed out his eyes with water but found no relief from this procedure. He did not recall anything getting into his eyes and had no recent history of eye trauma. His personal medical history was positive for hypertension, seizures, and arthritis. He had no history of eye surgery or trauma, and there was no family ocular history of glaucoma or blindness.
The patient was taking hydrocodone/acetaminophen, hydroxychloroquine sulfate, amoxicillin, clonidine, paroxetine, verapamil, aspirin, hydrochlorothiazide, and nitroglycerin. Allergies to Motrin®, toradol, and lithium were reported.
Unaided entering acuities were 20/25 (6/7.5) OD and 20/20 (6/6) OS. Pinhole testing improved his vision to 20/20 (6/6) OD. Pupils were equal, round, and reactive to light with no afferent pupillary defects (APDs). Extraocular motilities were full and smooth without pain. External exam showed squinting with the right eye but no periocular/lid lesions.
Slit lamp examination of the anterior segment revealed trace upper lid erythema with grade 1 conjunctival injection OD. The left eyelid and conjunctiva were clear. A 2.5 mm stellate corneal dendritic ulcer was found OD as shown in Figure 20. The lesion stained positively with sodium fluorescein and rose bengal.
The anterior chambers were deep and quiet, the irises were flat and clear, and there was a grade 1 nuclear sclerotic cataract in both eyes. The cotton wisp test revealed reduced corneal sensitivity for the right eye as compare to the left.
A non-dilated fundus exam with a 90 D lens revealed healthy and distinct optic nerves with a cup to disc ratio of 0.25/0.3 OD and 0.25/0.25 OS. Both maculae were flat and dry.
Figure 19. Cornea of patient's right eye.
Diagnosis and Management
The diagnosis was herpes simplex virus dendritic keratitis OD, and the patient was prescribed trifluridine 1% ophthalmic solution to instill one-drop q2h OD while awake (up to a maximum of nine times a day). He was also prescribed homatropine 5% ophthalmic solution one-drop tid OD and was instructed to return to the clinic in 3 days for a follow-up visit.
Three-Day Follow-Up
At the 3-day follow-up visit, the patient reported an improvement in the scratchy feeling in the right eye. However, he was still photophobic OD and had a watery discharge - but no mucus.
Although he had been prescribed trifluridine 1% ophthalmic solution q2h (up to a maximum of nine times a day), he thought he needed to use the trifluridine for a total of nine times before returning to clinic, so he was actually instilling the drug tid.
No changes in acuities or other entrance test results were noted on this visit. The right eye pupil was dilated and un-reactive to light as a result of homatropine use, and there was no afferent pupillary defect on reverse Marcus Gunn testing. The left eye pupil was round and reactive to light with no afferent pupillary defect.
Slit lamp examination revealed no upper lid erythema, but trace conjunctival injection was present OD. The left eye was unremarkable. The 2.5 mm stellate corneal dendritic lesion was still present OD. It stained significantly with fluorescein and a trace with rose bengal.
Because the dendritic keratitis had improved somewhat (even with limited trifluridine use), the patient was again instructed to use the trifluridine 1% ophthalmic solution one drop q2h while awake (up to a maximum of nine times a day) OD along with the homatropine 5% ophthalmic solution one-drop tid OD. He was also dispensed Celluvisc® ophthalmic solution to use one-drop qid or as needed OD and was scheduled for another follow-up in three days (or sooner if moderate or severe symptoms returned).
Six-Day Follow-Up
At the 6-day follow-up visit, the patient reported mild scratchiness and continued photophobia OD. There was no sign of discharge, but he indicated that the right eye still teared when it was exposed to light.
The patient had been using the trifluridine and homatropine as prescribed but did not use the drops 2 days earlier because he was in the emergency room as a result of seizures.
His unaided entering acuity was down a line to 20/30 (6/9) OD but remained 20/20 (6/6) OS. Pinhole testing improved his vision to 20/25+ (6/7.5+) OD.
Slit lamp examination showed that the stellate lesion was reduced in size to 2.0 mm and it stained less deeply with fluorescein as compared to the last visit. There was still trace staining with rose bengal.
The herpes simplex virus dendritic keratitis was resolving, so the patient was instructed to continue using the trifluridine 1% ophthalmic solution one-drop q2h OD while awake (up to a maximum of nine times a day). He was also instructed to continue with the homatropine 5% ophthalmic solution one-drop bid OD for 2 days and then reduce the dose to one-drop qd. Celluvisc® ophthalmic solution was continued one-drop qid OD or as needed. The patient was scheduled for another follow-up in four days (or sooner if moderate or severe symptoms returned).
Ten-Day Follow-Up
At the 10-day follow-up visit, the patient reported no eye pain or scratchiness, but his right eye remained light sensitive.
He had been instilling trifluridine as directed OD but was still instilling homatropine 5% ophthalmic solution one-drop bid OD.
Unaided acuities were 20/20 (6/6) OD and 20/15 (6/4.5) OS. As a result of homatropine use, the right pupil was dilated and non-reactive to light with no APD on reverse APD test. The left eye was unremarkable.
A 1.5 mm dendritic corneal lesion OD stained minimally with fluorescein and did not stain with rose bengal. No other ocular anomalies were noted.
Because the herpes simplex virus dendritic keratitis continued to resolve OD, the patient was instructed to taper his trifluridine 1% ophthalmic solution to one-drop six times a day for 3 days, one-drop four times a day for the next three 3 days, and one-drop three times a day for the three days following that. He was instructed to continue with the Celluvisc® one-drop qid or as needed in the right eye and to discontinue the homatropine 5% ophthalmic solution. The patient was scheduled for his next follow-up in one week (or sooner if moderate or severe symptoms returned).
Seventeen-Day Follow-Up
At the 17-day follow-up visit, the patient reported no eye pain, scratchiness, or photophobia OD. He was completely asymptomatic.
He was instilling trifluridine 1% ophthalmic solution one-drop qid in the right eye and was no longer using the Celluvisc® or homatropine. Acuities were unchanged from the previous follow-up and pupils were equal, round and reactive to light with no APD.
Slit lamp examination of the anterior segment revealed clear lids and conjunctiva in both eyes. A faint 1.5 mm corneal scar was present OD and there was no rose bengal or sodium fluorescein staining.
The HSV dendritic keratitis had resolved OD, so the patient was instructed to continue tapering the trifluridine 1% ophthalmic solution to one-drop tid for 2 days, one-drop bid for 2 days, and one-drop qd for 1 day. At the end of this taper, he was instructed to discontinue trifluridine use. He was also instructed to continue with Celluvisc® ophthalmic solution one drop qid (or as needed) OD.
The patient was educated on the potential risk of herpes recurrence and instructed to return to clinic as soon possible if symptoms reappeared. He was also scheduled for a complete eye and vision examination in one week.
Case Two: Herpes Simplex Virus Stromal Keratitis
The following case demonstrates management of relatively complex HSV disease. It illustrates the importance of prescribing prednisolone acetate 1% ophthalmic suspension along with trifluridine 1% ophthalmic solution for treating herpes simplex virus stromal keratitis.
The use of prednisolone acetate 1% ophthalmic suspension is essential for reducing ocular inflammation because HSV stromal keratitis is believed to be a primarily an immune-mediated disease rather than an actual infection. Trifluridine is prescribed for prophylaxis against reactivation of herpes simplex virus infectious epithelial keratitis.
In this case, oral acyclovir was also prescribed to manage the herpes simplex virus stromal keratitis. Acyclovir (Zovirax) 400 mg tid for 10 days was prescribed by his primary care physician.
History and Initial Examination
A 24 year-old Hispanic male presented with complaints of redness and blurriness OD for 3 months. He also reported tearing, photophobia, and itchiness OS, and he had a history of splashing chlorinated water in the left eye. His personal medical history was unremarkable with no report of syphilis, tuberculosis, surgery, or previous eye infection. There was no family ocular history of glaucoma or blindness. The patient was not taking any medications and reported no known allergies.
Unaided entering acuities were 20/80 (6/24) OD and 20/40 (6/12) OS. Pinhole testing improved his vision to 20/40 (6/12) OD and 20/25 (6/7.5) OS. Pupils were equal, round, and reactive to light with no APD. Extraocular motilities were full and smooth without pain.
Slit lamp examination of the anterior segment revealed blepharitis OU with grade 2 diffuse conjunctival hyperemia and circumlimbal injection OD. The conjunctiva of the left eye was clear. Scattered superficial punctate keratitis with a grade 2 diffuse corneal inflammation/edema and folds in Descemet's was found OD. (Figure 21)
The OD cornea stained with fluorescein but not with rose bengal. The anterior chamber was deep and quiet OU. The irides were flat and clear, and the lenses were clear OU. A corneal sensitivity test conducted with a cotton wisp showed reduced sensitivity OD as compared to OS. There was no apparent preauricular lymphadenopathy.
Figure 20. Scattered superficial punctate keratitis with a grade 2 diffuse corneal inflammation/edema and folds in Descemet’s OD.
Goldmann applanation tonometry was 7 mmHg at 2:30 PM OU, and a dilated fundus exam revealed healthy and distinct optic nerves with a cup to disc ratio of 0.4/0.4 OU. Both maculae were flat and dry, and the peripheral retina was clear in both eyes.
Diagnosis and Prescription
Based on signs and symptoms, a diagnosis of herpes simplex virus stromal keratitis OD was made, and the patient was prescribed prednisolone acetate 1% ophthalmic suspension one-drop qid OD (he was instructed to shake the suspension before use), and Viroptic® 1% (trifluridine) ophthalmic solution one-drop qid OD.
He was also prescribed scopolamine 0.25% ophthalmic solution to use one-drop bid OD and was dispensed Refresh Plus® ophthalmic solution to be used qid or prn OD. In addition, he was prescribed oral acyclovir (Zovirax) 400 mg three times a day for 10 days by his primary care physician. The patient was instructed to return to the clinic in five days for a follow-up visit.
Five-Day Follow-Up
At the 5-day follow-up visit, the patient reported improvement in redness and blurriness, and the HSV stromal keratitis had improved in the right eye. He was instructed to continue with the same topical and oral medications and scheduled for a follow-up in ten-days (or sooner if moderate or severe symptoms returned).
Fourteen-Day Follow-Up
At the 14-day follow-up visit, the patient was completely asymptomatic with no reported redness or blurriness OD. He was maintaining his prescribed prednisolone, trifluridine, scopolamine, and Refresh Plus® regimen, and he had completed the 10-day regimen of oral acyclovir.
Unaided acuities were 20/20 (6/6) OD and 20/40 (6/12) OS. Pinhole testing improved his vision to 20/25 (6/7.5) OS. Entrance testing results, pupil responses, and extra ocular motilities were all normal.
The lids and conjunctiva of both eyes were clear; there was minimal superficial punctate keratitis with minimal sodium fluorescein staining remaining OD. All other test results were normal OU.
At the time of this follow-up examination, the HSV stromal keratitis had resolved, and visual acuity had returned to normal OD. The patient was instructed discontinue the scopolamine 0.25% ophthalmic solution and to taper the Viroptic® 1% and prednisolone acetate dosages to one-drop tid for 3 days, one-drop bid for 2 days, one drop qd for one day, and then to discontinue use of these drops. He was also instructed to continue with Refresh Plus® ophthalmic solution one-drop qid or prn OD indefinitely and to return to the clinic at the first sign of a herpes recurrence.
If left untreated, recurrent herpes simplex ocular infections can lead to devastating visual outcomes. With each recurrence, there is increased risk of a future recurrence and more debilitating complications.
The Herpetic Eye Disease Study has become critical in guiding the treatment and management of ocular HSV infections. It showed that oral acyclovir can play an important role in the management of HSV infection and that this drug is highly effective in suppressing recurrences of ocular HSV infection.
Although herpes infections are not common, neither are they especially rare, so it is fortunate that early diagnosis and the use of medications such as Viroptic®, acyclovir, and steroids can usually prevent severe consequences of this disease process.
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Contact the author:
Weon Jun, OD Portland VA Medical Center, P-5 Eye PO Box 1034 Portland OR, 97207 USAPacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses. Questions or concerns about courses should be directed to the individual authors and/or the Continuing Education Department at the College of Optometry at kundart@pacificu.edu.
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