There are eight distinct DNA viruses that infect humans, and five of them cause significant ocular disease. These include: HSV-1, HSV-2, varicella-zoster, cytomegalovirus and Epstein-Barr virus.1 
HSV-1, which most commonly affects the eyes, is almost universally acquired. In fact, by age 60, more than 90% of individuals have HSV-1 in their trigeminal ganglia.2 To date, more than 500,000 Americans have been diagnosed with HSV ocular infections, with about 20,000 new cases and 28,000 recurrences reported each year.3 
The breakdown is interesting, with 72% of HSV-1 cases involving the epithelium, 41% involving the lids and conjunctiva, 12% the corneal stroma and 9% involving the uveal tract. It’s interesting to note that humans are the only natural reservoir of HSV and that the virus can remain viable for up to two hours on a dry tonometer head or more than eight hours on a wet tonometer tip.4
Here, we review the ophthalmic ramifications of HSV infection as well as discuss some of the latest treatment options.  
Primary HSV 
  • Overview. Typically, HSV-1 infection occurs relatively early in life; however, recent research suggests that primary acquisition of HSV-1 is becoming progressively delayed in industrial countries.2 In most cases, patients with primary HSV exhibit mild flu-like symptoms that may be associated with a low-grade fever. A small percentage of individuals also experience viral skin eruptions, which generally manifest as a vesicular rash found around the eyelids, conjunctiva or facial skin. Often, pre-auricular node swelling and pain also accompany these skin eruptions. After the primary infection runs its course, the HSV becomes latent in the trigeminal ganglion. Recurrent HSV typically occurs in the oral or nasal mucosa because of certain reactivation triggers, such as local trauma from ocular surgery, UV light exposure, hormonal changes, stress and systemic illnesses that compromise the immune system.5
  • Treatment. Children who manifest primary HSV usually are less responsive to medications, although they still should be treated with anti-viral medications, such as oral acyclovir or topical antivirals (if a conjunctivitis is present). Topical corticosteroids should be avoided because of the risks associated with further immune system suppression. It is also important to note that laser surgery procedures, such as LASIK and PRK, can reactivate a latent HSV virus.6,7 Additionally, corticosteroids have not been shown to be a trigger for HSV reactivation. Nevertheless, if a reactivation occurs in the presence of steroids, the disease can progress aggressively.8
A Look at Ocular HSV 
Corneal involvement of HSV can include epithelial keratitis, neurotrophic keratopathy, stromal keratitis and endotheliitis. The infectious epithelial keratitis presentation includes corneal vesicles, dendritic keratitis and geographic ulcers. Corneal vesicles are the corollary to the vesicular lesions found on the skin or eyelids. They are cystic or small, raised, clear lesions that contain the active virus. Corneal dyes are an important diagnostic tool in HSV identification (although epithelial defects will not be apparent at this stage, you will note inverse or negative staining or pooling of the fluoresceine around the raised vesicles). This is a rare clinical presentation because patients typically are not very symptomatic, but as the vesicles coalesce, they form the classic dendritic ulcer presentation. 
New treatments for ocular herpes could potentially benefit this patient who presented with significant iritis secondary to HSV. 
The dendritic ulcer is the most common presentation of ocular HSV. The features include a branching lesion with swollen epithelial borders. It is sometimes difficult to differentiate a pseudodendrite (i.e., as seen in herpes zoster) from HSV. The key is to realize that HSV dendrites are true ulcers, so they accrue stain within the lesion as well as along the borders and terminal end bulbs. This can often be enhanced with the addition of lissamine or rose bengal dye. 
The geographic ulcer is essentially an enlarged or expanding dendritic ulcer that often presents with scalloped borders. The geographic ulcer can occur if a patient with a dendritic ulcer is placed on a corticosteroid. Other forms of HSV keratitis include the marginal ulcer. This lesion mimics a Staphylococcal hypersensitivity or sterile infiltrative keratitis as a lesion near the limbus. Because the location is in close proximity to the blood vessels, it causes rapid infiltration of white blood cells under the ulcered area. Patients with HSV marginal ulcers are more symptomatic than patients with sterile limbal infiltrates. Additionally, HSV marginal ulcers do not exhibit a clear zone between the infiltrate and the limbus, and they show the presence of deep stromal vessels. 
Research shows that 10% of patients with epithelial keratitis go on to experience stromal disease within one year.9 Stromal forms of keratitis include neurotrophic keratopathy, immune stromal keratitis (ISK) or interstitial keratitis and endotheliitis. Stromal haze and neovascularization (also known as ghost vessels) with an intact epithelium are the hallmark signs of ISK. Occasionally, it can present as an immune ring. This presentation is most common in recurrent HSV disease and may often be accompanied by cell and flare in the anterior chamber. 
Finally, disciform endotheliitis presents with a deep disc-shaped area of edema and keratic precipitates on the endothelium but no stromal infiltrate or neovascularization. Typically, endotheliitis has a corresponding mild to moderate iritis and is often associated with elevated IOP.      
New Treatment Options 
During the last decade, there has been a trend toward the use of oral antivirals for the treatment of all forms of HSV. This shift was due, in part, to higher rates of corneal toxicity that were associated with the topical antiviral medications that were available 10 years ago. It is interesting to note that trifluridine was approved in the U.S. more than 30 years ago, and only last year did we see the introduction of a new topical antiviral––Zirgan (0.15% ganciclovir gel, Bausch + Lomb).
  • Zirgan. This prodrug is only activated by the viral enzyme thymidine kinase to inhibit synthesis of viral DNA. Because of this, Zirgan is more selective than other antiviral agents and does not target healthy corneal cells. Zirgan should be dosed five times a day until the dendritic ulcer is healed, and then three times a day for an additional seven days. It does not require refrigeration and unlike Viroptic (trifluridine, Monarch Pharmaceuticals), Zirgan is preserved with 0.075mg of BAK. It also has a comparable pH and osmolarity to natural tears. 
  • Valtrex. Another development in the improved management of HSV is the increased availability of oral Valtrex (valacyclovir, GlaxoSmithKline), which became available as a generic medication in November 2009. Although all oral antivirals demonstrate low toxicity and are very effective, valacyclovir has five times the bioavailability of acyclovir.10
Still, with the approval of Zirgan and its selective antiviral properties and lessening of epithelial toxicity, we may again see clinicians switching back to topical medications for managing HSV keratitis and limiting systemic drug exposure.
New developments in HSV keratitis treatments have prompted clinicians to stay abreast of the most effective management strategies of this multi-presentation virus. Understanding the various forms of HSV keratitis can aid in accurate diagnosis and successful treatment, thus reducing the risk for associated corneal morbidity. 

For Herpes Zoster or Shingles:
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If you had chickenpox as a kid, it is not over yet! 1 million American adults each year get chicken pox like rash all over again, but this time it returns and can be very painful: it is called shingles. And if not treated properly it can cause a lifetime of pain called Post Herpetic Neuralgia.

The great news is we have better ways to prevent PHN in most patients. 

The pain of shingles can be excruciating, but the condition goes away in a few weeks — for most people. Postherpetic neuralgia (PHN), a form of neuropathic pain that can last for months or years, even after the virus is no longer active.
Postherpetic neuralgia can make you feel truly miserable.
Chickenpox, shingles, and postherpetic neuralgia all result from infection with a single virus called varicella zoster virus (VZV). Most people catch the varicella zoster virus as children, itch and shiver through the rash and fever of chickenpox, and get better.
But that’s not necessarily the end of the story of varicella infection. After a bout of chickenpox, our immune systems never completely eradicate the VZV virus. They just chase it into hiding. Varicella retreats into nerve cells deep under the skin, near the spine.
For most of us, VZV lies dormant inside our bodies throughout our lives, never causing further problems. In about one-third of people, however, VZV infection has a second act. The virus emerges from hiding, travels along a nerve to the skin, and erupts in a bumpy, painful rash on one side of the body. This sneak attack is called herpes zoster, or shingles. (Varicella zoster virus belongs to the family of herpes viruses, but does not cause cold sores or genital herpes.)

Shingles Symptoms: What Should You Look For?

Unlike the whole-body rash of chickenpox, the shingles rash is limited to the area of skin assigned to the infected nerve. The rash usually consists of small bumps that may turn into blisters before bursting and crusting over. If shingles appears on the face, the eye can be affected, posing a threat to sight.
Also unlike chickenpox, this rash hurts, sometimes intensely. People typically describe shingles pain as burning, stabbing, or electrical.
“Shingles can be almost unbearably painful,” says Jeffrey Ralph, MD, assistant professor of neurology at the University of California in San Francisco and a fellow of the Neuropathy Association. “The nerve itself is inflamed. The pain can sometimes come even weeks before a rash appears.”

When Shingles Becomes Painful Postherpetic Neuralgia

In 10% to 20% of these people, however, the pain of shingles keeps hanging on after the rash is gone. “These folks go on to get postherpetic neuralgia, and we’re not exactly sure why,” Ralph tells WebMD. “Either the pain of shingles never leaves, or it resolves, comes back, and never goes away completely.”
PHN typically occurs in the area where the shingles occurred. The pain can be intermittent or constant, and it can take on any of the diverse qualities of shingles pain. Normal touching of the skin can set it off, Ralph adds. This is called allodynia.
The pain of postherpetic neuralgia can interfere with daily activities, exercise, sleep, and sexual desire. Irritability and depression often follow. “Generally, it makes people feel terrible if it can’t be controlled,” Rumbaugh says.
Why the pain of postherpetic neuralgia persists has mystified researchers. It’s not due to ongoing infection by VZV, but is thought to be due to residual damage or inflammation in the nerve after shingles resolves. It’s also impossible to predict who’ll get shingles or postherpetic neuralgia, although age, race, and health seem to have some impact.

Shingles and Postherpetic Neuralgia: What Are the Risk Factors?

You can’t control whether you’ll catch the chickenpox virus. Fully 99.5% of adults in the U.S. carry it, whether or not they remember having had chickenpox. But why do one-third of those people get shingles — and some of them go on to develop postherpetic neuralgia?
The risk of postherpetic neuralgia also goes up with age. More than 80% of cases of postherpetic neuralgia occur in people over 50 years old. “It’s likely that the natural decline of immunity with age is responsible,” says Ralph.
The results of one study showed that age had a huge effect on the risk for postherpetic neuralgia after shingles:
  • Among people under 60 years old who had shingles, less than one in 50 developed postherpetic neuralgia.
  • In people aged 60 to 69, about 7% of shingles sufferers developed postherpetic neuralgia.
  • In those age 70 and older, almost 20% developed postherpetic neuralgia after a bout of shingles.
Race seems to matter, too. For unknown reasons, white Americans get shingles and postherpetic neuralgia at more than twice the rate of African-Americans in their age group.
“People whose immune systems are impaired by drugs or diseases like AIDS are also more prone to zoster and PHN,” adds Ralph.
Exposure to someone with chickenpox or shingles does not increase your personal risk, however. In fact, experts believe that the slight immune stimulation may boost natural defenses, making you less likely to develop shingles or PHN.

Vaccine Prevention for Shingles and Postherpetic Neuralgia

In 2006, a vaccine to prevent shingles came onto the market. Called Zostavax, the vaccine cuts the likelihood of getting shingles after chickenpox by about half, dramatically reducing the number of people who might get nerve pain after shingles.
Based on these results, the CDC recommends Zostavax to all adults age 60 and older. Rumbaugh goes further: He suggests you get vaccinated at any age if you have had shingles. His clinical experience suggests the vaccine helps reduce postherpetic neuralgia even after infection with the varicella zoster virus.

Early Intervention Is the Key to Treatment

Antiviral medicines such as valacyclovir (Valtrex), famciclovir (Famvir) or acyclovir (Zovirax), taken orally, are usually used to treat shingles. When taken at the very beginning, Ralph says, they can improve symptoms and reduce the risk of postherpetic neuralgia.
Starting antiviral treatment for shingles more than three days after symptoms start is generally believed to be ineffective because the virus is no longer reproducing. Still, many doctors will try treating the condition with antiviral drugs after this time.
HSV-2 Genital Herpes:
Treatment Studies
 2016 Aug 30;(8):CD010684. doi: 10.1002/14651858.CD010684.pub2.

Interventions for men and women with their first episode of genital herpes.

Author information

  • 1Department of Obstetrics and Gynaecology, University of Auckland, Private Bag 92019, Auckland, New Zealand, 1023.



Genital herpes is incurable, and is caused by the herpes simplex virus (HSV). First-episode genital herpes is the first clinical presentation of herpes that a person experiences. Current treatment is based around viral suppression in order to decrease the length and severity of the episode.


To determine the effectiveness and safety of the different existing treatments for first-episode genital herpes on the duration of symptoms and time to recurrence.


We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (from inception to April 2016), MEDLINE (from inception to April 2016), the Specialised Register of the Cochrane Sexually Transmitted Infections Review Group (from inception to April 2016), EMBASE (from inception to April 2016), PsycINFO (from inception to April 2016), CINAHL (from inception to April 2016), LILACS (from inception to April 2016), AMED (from inception to April 2016), and the Alternative Medicines Specialised Register (from inception to April 2016). We handsearched a number of relevant journals, searched reference lists of all included studies, databases of ongoing trials, and other Internet databases.


We included randomised controlled trials (RCTs) on participants with first-episode genital herpes. We excluded vaccination trials, and trials in which the primary objective assessed a complication of HSV infection.


All studies written in English were independently assessed by at least two review authors for inclusion, risk of bias for each trial, and to extract data. Studies requiring translation were assessed for inclusion, trial quality, and data extraction by external translators.


We included 26 trials with 2084 participants analysed. Most of the studies were conducted in the United Kingdom (UK) and United States (US), and involved men and women experiencing their first episode of genital herpes, with the exception of three studies which included only women. We rated the majority of these studies as having an unclear risk of bias; largely due to lack of information supplied in the publications, and due to the age of the trials. This review found low quality evidence from two studies of oral acyclovir, when compared to placebo, reduced the duration of symptoms in individuals undergoing their first episode of genital herpes (mean difference (MD) -3.22, 95% confidence interval (CI) -5.91 to -0.54; I(2) = 52%). In two studies (112 participants), intravenous acyclovir decreased the median number of days that patients with first-episode herpes suffered symptoms. Oral valaciclovir (converted to acyclovir) also showed a similar length of symptom duration when compared to acyclovir in two studies.There is currently no evidence that topical acyclovir reduces symptoms (MD -0.61 days, 95% CI -2.16 to 0.95; 3 RCTs, 195 participants, I(2) statistic = 56%). There is also no current evidence that the topical treatments of cicloxolone cream, carbenoxolone sodium cream, adenosine arabinoside, idoxuridine in dimethyl sulfoxide, when compared to placebo reduced the duration of symptoms in people undergoing their first episode of herpes.Two studies reported no evidence of a reduction in the number of median days to recurrence following treatment with oral acyclovir versus placebo. Adverse events were generally poorly reported by all of the included studies and we were unable to quantitatively analyse this outcome. For those taking acyclovir, there were no serious adverse events; the most common adverse events reported for oral acyclovir were coryza, dizziness, tiredness, diarrhoea and renal colic. For intravenous acyclovir these were phlebitis, nausea and abnormal liver function tests and for topical acyclovir there was pain with the topical application.Those undergoing interferon treatment had significantly more adverse events compared to those taking placebo.


There is low quality evidence from this review that oral acyclovir reduced the duration of symptoms for genital herpes. However, there is low quality evidence which did not show that topical antivirals reduced symptom duration for patients undergoing their first episode of genital herpes. This review was limited by the inclusion of skewed data, resulting in few trials that we were able to meta-analyse.


Treatment of genital herpes in males with imiquimod 1% cream: a randomised, double-blind, placebo-controlled study.

Author information

  • 1Department of Dermatology, University of California San Francisco, San Francisco, California, USA.



The aim of this randomised, double-blind, placebo-controlled study was to examine the clinical significance, efficacy and tolerability of imiquimod 1% cream to manage patients exposed to first episodes of genital herpes.


Male patients (n = 60), ranging in age between 18 and 50 years (mean 25.7 years), presenting for <6 days (mean 4.4 days) with culture-confirmed diagnosis of genital herpes, and bearing a total of 696 lesions (mean 11.6 lesions/ patient), entered the study and were randomised to receive a precoded 40g tube and instructions on how to apply the trial medication to their lesions twice for 5 consecutive days per week.


A marked clinical benefit from self-application of imiquimod 1% cream was demonstrated, resulting in both significantly shorter mean duration of healing than with the placebo (5.2 vs 14 days; p < 0.001) and more healed patients [23 of 30 (76.7%) vs 2 of 30 (6.7%); p < 0.0001]. Of the 60 patients, 54 (90%) reported no drug-related adverse effects. Two patients in the imiquimod group reported non-objective mild burning sensation and four experienced a transitory increase in their body temperature (>38 degrees C) accompanied by mild headache and malaise; however, such indications were not severe enough to cause discontinuation of the treatment, and resolved within 24 hours. Treatment was well tolerated by all the patients, with no dropouts. Among 25 healed patients, four had a relapse after 9 months.


Although the analogue of imiquimod 1% cream demonstrated mild to moderate subjective adverse effects, it was significantly more effective than placebo in treating patients with a first episode of genital herpes. Further clinical studies appear warranted.

 2006 Feb 15;42(4):575.

Imiquimod 5% cream for the treatment of recurrent, acyclovir-resistant genital herpes.

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3.  2006 Feb 15;42(4):575.

Imiquimod 5% cream for the treatment of recurrent, acyclovir-resistant genital herpes.

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