Epithelial herpes simplex keratitis

Enormous strides have been made in the diagnosis, treatment and management of epithelial herpes simplex keratitis over the past 50 years, giving some grounds for optimism that a cure will one day be found for this particular disease, according to Peter R Laibson MD. 'Hopefully someday we will be able to cure herpes and be able to talk about it in retrospective like we do today with smallpox. I think that the fact that there is only one paper out of 320 dealing with ocular herpes on the programme at this meeting indicates the extent to which the disease has now been controlled to some extent,' Dr Laibson said in his EuCornea Medal Lecture at the Opening Ceremony of the 2nd EuCornea Congress.

Dr Laibson, an attending surgeon and director emeritus of the Cornea Service at Wills Eye Institute and professor of ophthalmology at Jefferson Medical College, explained that herpes is manifested in a number of different ways on the cornea. In the very earliest phases, he said that individual cells are involved, followed by small dendrites and geographic herpetic ulcers as the disease progresses.

'We need to remember that the cornea is not the only epithelial area that may be affected by the herpes virus. It may grow on the conjunctiva, and onto the cornea and we may see conjunctival dendrites alone. Very few physicians look at conjunctiva for dendritic lesions. It is important before treating a patient with combination medication such as antibiotics and steroids because of a red eye, to put fluorescein or other dye into the eye to make sure that there are no dendritic changes in the conjunctiva,' he said.

Dendritic lesions are not so simple to deal with, noted Dr Laibson, and it is not always clear why some superficial dendritic ulcers respond well to anti-viral medication while others go deep into the stroma and eventually perforate.

Looking at the history of ocular herpes treatment, Dr Laibson cited the groundbreaking research of Trygve Gundersen who reported in 1936 that tincture of seven per cent iodine, followed by cocaine neutralisation, was able to denude the corneal epithelium and with it the dendritic or geographic lesions.

Another study of note came in 1961 when Sery and Furgieule investigated over 150 compounds to see if any besides iodine was effective in treating herpes simplex dendritic keratitis.

'They found that in vitro a number of agents were effective, but in vivo there was very little that was effective in the rabbit cornea. Chemical cautery, as advocated by Gundersen, was recommended and used for treatment even after that,' he said.

Dr Laibson said that Herbert E Kaufman was the first to utilise an antiviral drug, idoxuridine (IDU), to treat epithelial herpes in the rabbit in 1961.

'It was originally synthesised as an anti-cancer therapy and IDU blocked DNA synthesis of intracellular herpes simplex virus. In a study with Nesburn and Moloney, Kaufman showed for the first time ever that an antiviral drug was effective against treating a human virus disease. Unfortunately, it also proved toxic and with serious side effects if used too long,' he said.

In 1996 the French company Thea produced ganciclovir (Zirgan), which became the drug of choice for epithelial herpetic keratitis in Europe. It would take another 15 years before the same compound under a different name, Virgan (Bausch + Lomb), became available in the US and gave ophthalmologists an alternative to topical trifluridine, said Dr Laibson. Other oral medications, such as acyclovir, famciclovir and valacyclovir were also effective in treating topical dendritic keratitis, he added.

The preferred treatment today, said Dr Laibson, is probably ganciclovir gel (Zirgan or Virgan) 0.15 per cent administered five times a day, followed by trifluridine (Viroptic), which is still quite effective.

The Cochrane Collaboration, a landmark study of almost 6,000 herpetic eyes conducted by Kirk Wilhelmus MD, further advanced understanding of the optimal treatment for herpes simplex virus infection.

'The study concluded that the ophthalmic formulations of trifluridine, acyclovir ointment, and gancyclovir gel are effective and safe. However, antivirals and interferon may also speed healing in cases of recalcitrant HSV, and debridement along with antiviral was also shown to be an effective treatment for HSV,' he said.

Other advances in knowledge for treating more problematic forms of stromal HSV came with the Herpetic Eye Disease Study (HEDS), made up of five randomised double-masked placebo controlled trials conducted in nine centres around the US.

The studies cumulatively showed that while oral acyclovir showed no effect in arresting stromal herpetic disease, steroids were found to be highly effective in treating the disease when used appropriately, said Dr Laibson. In terms of treating herpetic kerato-uveitis, Dr Laibson said that the group felt confident enough with the findings to recommend 400mg of acyclovir five times a day, even though statistical significance had not been achieved in the trial due to limited patient numbers.

In cases of recurrent HSV, oral acyclovir was found to be highly statistically significantly better than placebo in treating patients and preventing recurrent herpes.

'If someone has had one episode of recurrent herpes there is about a 13 per cent recurrence rate on acyclovir and almost twice that with placebo. If someone has had more than four episodes of recurrent herpes the incidence of recurrence doubles even in the acyclovir treated group but it goes up to almost 50 per cent in the placebo group,' he said.

Looking to the future, Dr Laibson said that earlier diagnosis of HSV keratitis would be helpful and that the RPS detector currently under development may prove useful in this regard. However, he thought it unlikely that new antiviral medications will enable further progress in the treatment of HSV.

'It took 15 years for ganciclovir to become accepted in the United States so I don't think we are going to get another topical antiviral any more effective than ganciclovir in the near future – it is simply too expensive to test these drugs,' he concluded.