|Year : 1999 | Volume
| Issue : 3 | Page : 155-165
Herpes simplex keratitis
PS Suresh, AB Tullo
Manchester Royal Eye Hospital, UK,
P S Suresh
Manchester Royal Eye Hospital, UK
Chronic infection of the cornea by Herpes simplex virus (HSV) continues to be an important cause of unilateral blindness. Despite considerable progress in the understanding of the virus at cellular and molecular levels, the prospect of prevention still appears to be long way off. The development of non-toxic topical antiviral agents has been an important step forward in management. However, correct diagnosis and treatment, in particular, the avoidance of inappropriate use of topical steroid remains as important as ever. This article reviews the virological and clinical aspects of HSV keratitis including the current concepts of pathogenesis and management
Keywords: Herpes simplex keratitis, topical steroids, unilateral blindness, corneal stromal disease
|How to cite this article:|
Suresh P S, Tullo A B. Herpes simplex keratitis. Indian J Ophthalmol 1999;47:155-65
The human herpes viruses are an important source of ophthalmic morbidity worldwide including cytomegalovirus retinitis in AIDS. Herpes simplex virus (HSV), however, remains the most common cause of unilateral corneal blindness worldwide. A basic understanding of how the virus behaves is helpful in understanding why efforts must still be concentrated on making best use of new antiviral agents and avoiding inappropriate treatment.
| Virology|| |
Herpes simplex virus belongs to a family of viruses called Herpesviridae. They are composed of a central DNA core and a protein capsid with 162 hollow cylindrical capsomeres. This nucleocapsid is surrounded by an envelope forming a virus particle (virion) with an overall diameter of 130-180 nm.
There are two types of HSV, namely, type 1 and 2. In general, type 1 causes infection above, and type 2, below the waist. Thus the rare neonatal HSV infection including herpetic keratitis and conjunctivitis is due to HSV type 2 in a majority of cases.
The severity and frequency of ocular disease may be influenced by strain differences. Strains which produce large amounts of glycoproteins are capable of inducing more humoral and cell-mediated immune response. These strains may be associated with more severe forms of corneal stromal disease. The viral genome may also play a role in determining the clinical response to topical steroids.
Herpes simplex virus usually affects tissues of ectodermal origin, such as skin, mucous membrane, or the nervous system. After the attachment to specific receptors on the surface of human cells (adsorption) the virion loses its envelope to the cell membrane and enters the cells by pinocytosis (penetration). The DNA released into the cells travels to the nucleus. There follows an eclipse period during which no virus can be detected. In fact the viral DNA induces the production of both host and virus-specific enzymes, namely, thymidine kinase and DNA polymerase. Viral proteins synthesised in the cytoplasm are transferred to the nucleus where the nucleocapsid is assembled. The nucleocapsids gain an envelope as they bud through the nuclear membrane. The host cell becomes packed with such particles before it ultimately undergoes cell lysis and releases the infectious particles.
Latency and reactivation
Like other herpes viruses [Table - 1] HSV has the ability to induce latent infection. After primary infection, that is, the host's first exposure at the peripheral site, the virus enters sensory nerve endings which supply the site of peripheral epithelial infection, usually the oropharynx. Virus particles travel centripetally to the neuronal cell body by retrograde axoplasmic flow. Here they can survive for decades probably integrated into the host-cell nuclear DNA; yet they leave the cell morphologically, antigenically, and functionally normal. This latent infection can be demonstrated by removing the host tissue and culturing it in vitro for several days, after which the virus can once again be identified.
In 1973 Baringer and Swoveland5 first demonstrated the presence of latent infection by isolating HSV type 1 in a majority of trigeminal ganglia taken at routine post-mortem. The virus may have entered the ganglion via any of the 3 major divisions of the fifth nerve. The reactivated virus may travel down any division despite and independent of the original portal of entry to cause peripheral disease., The trigeminal ganglion is therefore the source of infection in recurrent herpes labialis when virus produced by reactivation of latent infection travels by centrifugal axoplasmic flow to the lip to produce a lesion.
More recently it has been suggested that the cornea itself may be an extra-neuronal site of latent infection., In 1985 Tullo et al using co-cultivation techniques cultured the virus from 6 out of 9 corneal discs of patients with herpetic keratitis who had undergone corneal transplantation. Further studies, carried out in the United Kingdom confirmed this finding. However none of the studies assessed an immediate homogenate of the cornea to determine the presence of infectious virus. This raises the possibility that these corneas had persistent infections which were reactivated during penetrating keratoplasty rather than true latent infection.
The exact molecular mechanisms involved in HSV latency and reactivation are unknown. Latency-associated transcripts (LAT) have been identified in human and animal experiments. But latency-associated proteins have yet to be identified during latency in vivo.
The cornea itself is a site of persistent infection; therefore injudicious use of topical steroids in chronic disease may promote proliferation and penetration of virus within the cornea. For the same reason considerable care must be taken while selecting patients with corneal opacification for treatment with phototherapeutic keratectomy.
| Clinical Features|| |
Infection with HSV for the first time can develop at any age although most cases occur within the first few years of life. Salivary contamination from a person with silent salivary shedding of herpes labialis is the most common source of infection. Aphthous stomatitis is the usual clinical picture, which can range from subclinical to very severe infection. However primary HSV infection can also occur in other mucous membranes, including the conjunctiva.
Primary ocular HSV infection [Table - 2] most commonly manifests as blepharoconjunctivitis which is predominantly unilateral. The periorbital skin can develop intense blisters associated with conjunctivitis and blepharitis [Figure - 1]. Extensive spread on the facial skin can occur, particularly in eczematous individuals.
The conjunctivitis is usually follicular although severe cases may develop pseudo-membranous reaction. Preauricular lymphadenopathy often accompanies the conjunctivitis. Keratitis develops a few days after conjunctival involvement in 30-50% of cases. The morphology of the corneal lesions varies from superficial punctate keratitis, microdendrites or frank dendritic ulceration. Stromal involvement is rare. Interestingly, though subsequent recurrent disease is uncommon, it may occur as focal clusters of vesicles in the lids or as follicular conjunctivitis. In these cases corneal involvement is usually minimal or absent.
The clinical appearance is usually highly suggestive of HSV infection. Also, a history of exposure to a person with active herpes labialis infection may be obtained.
The major factors which dictate the severity of recurrent herpes are: immune response of the host, the viral strain, and treatment. Superficial corneal lesions (dendritic and geographic ulcers) are associated with the presence of replicating virus whilst deeper lesions (stromal, uveal) appear to be predominantly due to the immune response.
Corneal epithelial disease
The vast majority of cases of HSV keratitis are those which present with a corneal epithelial lesion, usually a dendritic ulcer. Such individuals may experience this first episode in adulthood. This is due to reactivation of a latent virus from a previously unrecognised primary ocular infection or from a virus which has reached ophthalmic neurons in the trigeminal ganglion during primary infection of the oropharynx. It usually occurs as isolated lesion(s) without involvement of conjunctiva and lids. The presenting symptoms include irritation, watering, photophobia, and occasionally, blurring of vision. Cold sores are common in such individuals but are rarely simultaneous.
The morphology of the lesions are quite varied. They can appear as superficial punctate keratitis, stellate epithelial lesions, dendritic or geographic ulcers [Figure - 2]. Ulcers are usually single but may be several. The infected epithelial cells appear as opaque lesions which form white plaques. Further enlargement results in dendritic ulceration. The mechanism for dendrite formation is not known, but is thought to be related to linear spread of virus from cell to cell in a contiguous manner.,  With further growth of the dendrite the central epithelium is sloughed off and the lesion stains with fluorescein. The marginal infected cells take up rose bengal stain [Figure - 3]. The linear branches characteristically end in expansions called "terminal bulbs". The stroma under the ulcer may show a faint haze and there may be evidence of mild iritis. Corneal sensation is lost in the areas where lesions are present. Repeated attacks may result in generalised corneal anaesthesia. In our clinical experience we have noted that recurrent lesions tend to occur at the same site.
Typical lesions involve the central cornea. Ulcers at the periphery of the cornea may behave differently, sometimes masquerading as ulceration due to staphylococcal infection. They appear to be more resistant to treatment and to have more stromal complications. They are also predisposed to chronic trophic ulceration. In a majority of patients healing occurs with minimal stromal scarring. Repeated attacks and severe infections may result in stromal scarring, thinning and vascularisation.
Sight-threatening problems associated with HSV type 1 infection appear to be largely due to an inflammatory response involving the corneal stroma. It is predominantly immune-mediated although in few cases direct invasion and active replication of the virus play a role. Secondary stromal inflammation can follow epithelial or endothelial involvement.
Immune-mediated stromal keratitis is the most common form of the stromal disease where an antibody response is mounted against the viral antigen present in the stroma expressed as a result of persistent infection. There is deposition of antigen-antibody-complement in the stroma. Animal studies show additional mechanisms involved in the stromal tissue destruction. It is proposed that CD4+ T cells play a significant role in the recognition of antigens presented by Langerhan's cells which migrate from limbus to central cornea after HSV type 1 infection. The activated CD4+ T cells release cytokines, in particular interleukin 2 and gamma interferon. Both factors attract large numbers of polymorphonuclear leucocytes which are responsible for corneal tissue destruction.
Clinically there is stromal infiltration without necrosis and ulceration. The size and the area involved may vary and include small infiltrates to large area of stromal haze. Some cases may be associated with dendritic lesions demonstrating the presence of the entire virus. The outcomes of these lesions vary. Progression or persistence of inflammation can occur. Neovascularisation, secondary lipid keratopathy, thinning of the cornea and recurrent inflammation are well recognised. Another distinct form of stromal infiltrate is the immune ring of Weseley. This represents a circular deposit of antigen-antibody complexes with polymorphonuclear leucocyte infiltrate as a result of complement activation.
Necrotising stromal keratitis is typically associated with ulceration. It can follow epithelial disease, superficial stromal disease or disciform keratitis, and is believed to be due to active viral replication and intense immune stromal inflammation. It may be generalised or localised. These cases may have to be differentiated from other forms of microbial keratitis and indeed secondary infection with bacteria and fungi can complicate HSV stromal keratitis. Secondary complications include hypopyon, uveitis, posterior synechiae, glaucoma, retrocorneal membrane, cataract, and rarely, perforation [Figure - 4].
Traditionally disciform keratitis (vide infra) has been described under stromal keratitis. However the recent trend is to describe it under endotheliitis as the actual mechanism involved is thought to be endothelial cell infection by HSV and associated inflammation.
Development of persistent epithelial defects or recurrent epithelial erosions can be seen with HSV epithelial infection.These are generally round or ovoid ulcers with a grey and thickened margin which is due to piled up epithelial cells [Figure - 5].
The mechanism appears to be due to damage to underlying basement membrane at the time of epithelial infection and denervation. Consequently the epithelium fails to adhere the basement membrane resulting in persistent defect or recurrent erosion. Additional factors like lack of trophic innervation, drug toxicity and stromal inflammation may play a role. Viral cultures are negative and the base of the ulcer stains with both rose bengal and fluorescein. Persistent ulcers have the potential to progress to corneal melt, perforation, and superinfection.
Indolent ulcers (sometimes referred to as "metaherpetic") have to be differentiated from geographic ulcers which are characteristically caused by inappropriate steroid use. The latter have flat edges and stain with rose bengal stain. They also change shape due to continued viral progression. Viral cultures will be positive.
Progressive or nonprogressive forms of endothelial inflammation can occur with type 1 HSV infection. Dendritic ulceration can precede these lesions in some patients. Disciform keratitis is the most common form in which a disc-shaped area of stromal oedema occurs without infiltration or vascularisation [Figure - 6]. The area of involvement may be diffuse and central or eccentric. The presenting symptoms include watering, photophobia, discomfort or blurred vision. A history of herpetic eye disease is usually present. The involved cornea shows appreciable thickening of all layers sometimes with epithelial oedema and often with folds in Descemet's membrane. Careful examination usually reveals keratic precipitates (KPs) in the affected area associated with mild anterior chamber activity. Spontaneous clearing can follow although progression to necrotising keratitis, vascularisation, scarring and thinning are also possible. Delayed hypersensitivity mediated by T lymphocytes is probably important in the pathogenesis of disciform keratitis. [21,22] The distribution of KPs strictly confined to the endothelium behind the swollen area suggests cell-mediated reaction directed at HSV determinants on the surface of endothelial cells.
Rarely linear involvement of the endothelium can occur.[24-26] In these cases stromal oedema is seen associated with KPs separating the involved and uninvolved cornea similar to the Khodhadoust line of corneal graft rejection. Slitlamp examination may show dark areas in the endothelium which appear as nonreflective black endothelial areas under a specular microscope. There may be progression of the endothelial line and the associated stromal oedema. Immunological studies on the aqueous aspirates have revealed HSV antigen in several of these cases.
Occasionally diffuse involvement of the endothelium can occur resulting in generalised corneal edema associated with scattered KPs.
All deeper forms of HSK can be associated with uveitis. However recurrent nongranulomatous anterior uveitis may be an isolated manifestation of HSV ocular involvement which can occur without a prior history of ocular HSV infection. Immunological reaction was thought to be the cause in most of the cases although in some cases live viruses have been demonstrated in the anterior chamber, and in iris tissue.
Clinically the severity can vary from mild to severe inflammation which may result in fibrin formation, hypopyon, hyphema, posterior synechiae, segmental iris necrosis similar to the picture seen in zoster keratouveitis, and inflammatory membrane in the angle of the anterior chamber with secondary glaucoma. The recent tendency to treat severe forms of anterior segment involvement with oral acyclovir is best reserved for those cases confirmed by laboratory diagnosis, as dosages and duration of treatment have not yet been defined.
Herpetic peripheral corneal involvement may extend to the trabecular meshwork resulting in trabeculitis. The resultant secondary glaucoma may be transient or lead to permanent damage.
AIDS and HSK
The experience of HSK in post-transplant immuno-suppressed patients suggests that the condition may be more common and more serious than in immunocompetent individuals. An initial report suggested that HSK may be similarly influenced in patients with AIDS. However, the number of cases were limited and no control group was used. More recently Hodge and Margolis undertook a larger carefully constructed and controlled retrospective study and concluded that HSK in patients with AIDS and AIDS-related complex was no different in incidence or response to treatment than in a nonimmuno-compromised control group of hospital-based patients. Nevertheless, overall recurrence rates were significantly higher amongst the HIV-positive group. If it is assumed that after a first episode a site of chronic latent infection is established in the cornea this suggests the immunosuppression by HIV infection may impair those mechanisms which are normally responsible for containing such an infection in the cornea.
Laboratory tests are not an absolute requisite for the diagnosis of HSV infection as clinical features are often highly characteristic. However, we believe whenever possible culture should be undertaken to establish a firm diagnosis. The chronic nature of the condition is such that a positive diagnosis once established, is invaluable in guiding management over what may be many years.
The available methods include virus culture, immunological tests, and histopathological examination of keratoplasty specimens.
The definitive method of diagnostic testing is isolating virus in tissue culture. The lesion is swabbed and placed in viral transport medium and sent to the laboratory. It is then inoculated onto cell monolayers and incubated at 37° C. A typical cytopathic effect is generally noticed in 2-4 days.
A variety of immunological tests are available to detect HSV antigens in specimens, namely, enzyme linked immunoadsorbent assay (ELISA), immunofiltration test, latex agglutination and immunoperoxidase methods. In addition, an immunoaffinity membrane test has also been described. In this test a protein-binding affinity membrane used as a blotter is gently touched to the corneal lesion and processed with peroxidase-conjugated HSV antibody. In few centres fluorescent antibody-staining technique is available for rapid detection of herpetic antigen in cytoplasm or the nucleus of the cell.
Histopathological examination of keratectomy specimens may show granulomatous reaction in deep stroma and around Descemet's membrane. Immunocytochemistry may demonstrate HSV antigens in stromal keratocyctes, endothelial cells, and epitheloid cells. These are more often seen with the necrotising type of herpetic stromal keratitis.
The optimal approach to laboratory diagnosis is:
- - to establish firm links with laboratories who can provide the necessary expertise and dialogue;
- - to use test(s) which are sensitive, specific and affordable; and
- - to use any test selectively, that is, when it is likely to be influential in diagnosis and in management.
| Medical Management|| |
The following topical agents are currently available for use in HSK.
Idoxyuridine (IDU), a thymidine analogue was the first agent found to be effective in the treatment of HSV keratitis. It is incorporated into the viral DNA, produces faulty DNA chain and also inhibits viral enzymes. It also incorporates into normal host cells which accounts for its toxicity., Though IDU is useful in treating epithelial infection,[38-40] the problems of toxicity allergic reaction, clinical viral resistance, poor solubility and penetration, and rapid inactivation have led to the use of other antiviral drugs. Notable ocular side effects include contact dermatitis, punctate keratitis, epithelial opacification, chronic epithelial defects, lacrimal punctal stenosis, follicular conjunctivitis, corneal pannus and teratogenicity in rabbits.
Vidarabine, the second agent developed for human use, inhibits viral DNA polymerase and gets incorporated into both viral and host DNA. It is equally effective as IDU in treating epithelial disease., and being highly soluble, is available only as ointment. Although it is much less toxic, punctate keratopathy (similar to IDU toxicity) can be a problem with topical use. Its use is generally restricted to viral strains resistant to other antiviral agents.
Trifluridine (Triflurothymidine-TFT) is a halogenated pyrimidine inhibiting thymidylate synthetase incorporated into viral DNA impairing transcription and translation. It is more potent than IDU and AraA in healing dendritic ulcers. Also TFT is superior to IDU in the management of steroid-treated corneal ulcers. Although therapeutic levels of the drug can be achieved in the anterior chamber, its role in treating deep stromal diseases and uveitis is yet to be determined. Adverse effects include superficial punctate keratitis, follicular conjunctivitis, lacrimal punctal stenosis, corneal filaments, and contact dermatitis. Viral resistance to TFT is rare.
Acyclovir (ACV) is a purine analogue. It its specifically activated by virus induced thymidine kinase which initiates phosphorylation. Subsequently two additional phosphates are added by host-cell kinases to produce an active triphosphate form which is more inhibitory to viral DNA polymerase than host-cell polymerase. Thus ACV is specific to viral-infected cells with low toxicity. After topical application it achieves therapeutic concentration in the anterior chamber. ACV is as equally effective as TFT and AraA in the treatment of herpes simplex keratitis. [46,50] ACV is less toxic to ocular surface than earlier generation antiviral agents and as such represents a major therapeutic advance. However, mutant virus strains with deficient thymidine kinase continue to replicate; therefore the development of drug-resistant strain may post a problem.
Brovinyl Deoxyuridine acts by a mechanism similar to ACV. It appears to be effective in the treatment of epithelial herpetic disease. Recently Gancyclovir ophthalmic gel has been shown to be equally effective as ACV ointment with the added advantage of increased local tolerance. It acts by competitive inhibition of viral DNA polymerase and by direct incorporation into viral DNA.
It is likely that antiviral therapy will advance rapidly in the next few years with 3-Hydroxy-2-phosphonyl-methoxypropyl cytosine, a nucletide analogue (Cidofovir) showing promise as a broad-spectrum antiviral agent.
Judicious use of steroids is recommended in certain types of HSV infection of the cornea. Corticosteroids suppress inflammation by interfering with the normal immunologic response to various stimuli and are an important management tool. Clinically they reduce infiltration, oedema, inflamation, and neovascularisation. Generally their treatment is restricted to the management of stromal keratitis and herpetic uveitis. Steroids do not appear to increase the risk of aquiring HSV infection, but certainly promote severity of the disease when present. Disadvantages include delayed epithelial and stromal healing, increased collagenolytic enzyme production, stimulation of viral replication, risk of secondary infection, glaucoma, and cataract. Infectious crystalline keratopathy is a recognised complication of steroid treatment for HSK. The major problem with steroids is inappropriate use at the epithelial stage, particularly as it may improve the symptoms initially. Widespread over-the-counter treatment is undoubtedly responsible for converting what may have been relatively benign disease into irreversible corneal damage.
Oral ACV appears to be as effective as topical ACV for HSV epithelial keratitis, but cannot be recommended as it is much more expensive. However, oral ACV may be beneficial in reducing the ocular recurrence and may gain a place in deep corneal disease, keratouveitis, and post-transplant management in proven cases.
| Specific Treatment|| |
Antiviral treatment is generally advisable even though it is not absolutely indicated as primary blepharo-conjunctivitis can resolve spontaneously. Acyclovir ointment is applied over the skin lesions and in the conjunctival sac up to five times a day. Keratitis can be treated with antiviral alone or debridement and antiviral treatment. A shield to the eye may be necessary to prevent a child from rubbing the eye.
Careful epithelial debridement is equally effective or even better than antiviral treatment alone. Epithelial keratitis is therefore treated with debridement, antiviral agent or a combination of both. Debridement involves removing the infected epithelial cells using a sterile cotton-tipped applicator after instillation of local anesthetic. The antiviral treatment is then initiated to improve viral clearance.
Acyclovir is the agent of choice (3% ointment, × 5 times a day). Treatment duration is usually for 10-14 days. It is to be noted that the epithelium often looks abnormal at the site of initial dendritic ulcer even resembling the original lesion but without fluorescent staining. This may take several weeks to heal and treatment is not indicated. However, persistent epithelial lesions with areas of fluorescent staining may indicate continued viral replication due to resistant strain or development of metaherpetic disease. Presence of scalloped edges with progression indicates persistent infection and warrants a change of antiviral agent.
Epithelial indolent ulceration
Antiviral agents are not always needed as the underlying problem is damaged basement membrane and denervation. Generous use of lubricants, preferably unpreserved agents, often results in epithelial healing. Use of patch, bandage contact lens and occasionally a conjunctival flap, helps in resistant cases.
A combination of an antiviral agent and topical steroids is the preferred treatment. Topical steroids result in significantly reducing stromal inflammation and decrease the duration of stromal keratitis. The starting dose of topical steroids is adjusted to the level of inflammation, but it should always be a weak steroid. Once the inflammation is brought under control, gradually steroid drops are tapered and every attempt should be made to discontinue them. An individualized maintenance dose may be indicated for some patients who show frequent disease flare-up without steroid treatment. The use of oral acyclovir in addition to topical treatment does not appear to show any additional beneficial effect.
Necrotising stromal keratitis
After culturing samples to exclude microbial secondary infection, antiviral treatment is started in suspected HSV stromal keratitis. Topical steroids may be added cautiously if the overlying epithelium is intact. Continued stromal necrosis calls for surgical interventions such as cyanoacrylate glue, or penetrating keratoplasty.
A combination of topical steroids and antiviral agents is indicated to treat this form of HSV infection. Additional treatment with oral acyclovir has also been found to be effective in cases of linear endotheliitis.
Steroids are the treatment of choice. It is advisable to add topical antiviral treatment as some cases have been shown to be associated with live virus in the anterior chamber. Similarly oral acyclovir may be added if the response is not good or if live virus is isolated from the anterior chamber.
Antiglaucoma treatment should be initiated in addition to steroid and antiviral agents.
| Surgical Management|| |
Surgical procedures may sometimes be necessary to treat acute and or chronic complications of HSK.
Penetrating keratoplasty (PK)
Penetrating keratoplasty is the procedure of choice to restore vision in those with significant corneal scarring due to recurrent HSV keratitis. However, serious consideration must be given to the possibility of recurrence and rejection especially when the fellow eye may be normal. In parts of the world where donor corneas are in short supply penetrating keratoplasty for HSK cannot be seen as a priority. PK is also performed to re-establish the integrity of the globe after ulceration and perforation. This procedure also reduces the viral load in the cornea responsible for repeated episodes of immune-mediated keratitis. The prognostic factors for corneal grafting in HSK are the presence of an inflamed eye and corneal vascularisation., Patients with active disease, an inflamed eye and vascularisation have poor graft survival. Other factors such as use of 10/0 or finer nylon sutures and high doses of postoperative steroids appear to improve clear graft success rate. Approximately 70-80% of the corneal grafts performed in quiet eyes are clear at 2 years and 50-60% at 5 years.
The major complications following penetrating keratoplasty are HSV infection [Figure - 7] and allograft rejection. There are three possible ways a post-PK patient can get HSV infection, namely, recurrence of the disease process, transmission through donor corneal buttons, or development of HSV infection for the first time in patients who had PK for reasons unrelated to HSV infection.
The incidence of recurrence depends on the duration of the follow up. Dendritic keratitis recurs in 6-47% of patients. Although there is no consensus on the efficacy of prophylactic topical antiviral treatment,,, long-term use following PK is rarely practised. However, topical antiviral agents may prevent HSV recurrence in periods of graft rejection where high dose steroids are used., Long-term use of oral acyclovir has been proven to be effective in reducing the recurrence of oral and genital herpes infection., It also now appears to significantly reduce recurrence in stromal keratitis for the duration of treatment. One study has shown longterm oral acyclovir significantly reduced recurrence and graft failure in patients with history of HSV keratitis. In patients with a vascularised cornea, HLA A and B matched grafts have been shown to improve clear graft survival rate.
In patients with graft rejection, it is particularly difficult to differentiate it from recurrence of herpetic uveitis. This is especially true in cases of linear endotheliitis occurring in the grafted eye which closely resembles a rejection episode with migrating line of KPs and stromal oedema. However linear endotheliitis crosses the graft host junction and responds well to oral acyclovir. It is therefore safe to treat any graft rejection with antiviral cover in such circumstances.
Other treatment modalities include use of cyanoacrylate glue in small perforations as a temporary measure. Conjunctival flap, tarsorraphy and botilinum-induced ptosis may have a role in selected cases of nonhealing ulcers, particularly where access to corneal donor tissue and expert postoperative management is not available.
| Conclusion|| |
Despite many years of shared clinical experience and a vastly improved knolwedge of HSV, it could be argued that we have made limited progress in managing HSV infection. We still rely heavily on clinical signs for the diagnoses described in this article. We recognise several influential host factors including the fact that HSK is more common in men than women. We do not know if the epidemiology of HSK is changing significantly. We understand the ability of HSV to establish latent infection in sensory neurons and possibly cornea, but have as yet been unable to use this knowledge to prevent the disease. Topical steroids have been, and still are used inappropriately, and antiviral agents have their limitations. Acknowledging our limitations may further stimulate application of laboratory knowledge in coping with HSK which continues to present a major challenge in terms of management.
| References|| |
|1.||Kaufman H, Centifanto-Fitzgerald Y, Varnell E. Herpes simplex keratitis. Ophthalmology 1983;90:700-6. |
|2.||Centifanto-Fitzgerald Y, Fenger T, Kaufman HE. Virus protein in herpetic keratitis. Exp Eye Res 1982;35:425-41. |
|3.||Smeraglia R, Hochadel J, Varnell ED, Kaufman HE, Centifanto-Fitzgerald Y. The role of herpes simplex virus secreted glycoproteins in herpetic keratitis. Exp Eye Res 1982;35:443-59. |
|4.||Kaufman HE, Varnell ED, Centifanto-Fitzgerald Y, Kissling GE. Effect of the herpes simplex virus genome on the response of infection to corticosteroids. Am J Ophthalmol 1985;100:114-18. |
|5.||Baringer JR, Swoveland P. Recovery of herpes simplex virus from human trigeminal ganglion. N Engl J Med 1973;288:648-50. [PUBMED] |
|6.||Tullo AB, Shimeld C, Blyth WA, Hill T, Easty DL. Spread of virus and distribution of latent infection following ocular herpes simplex in the non immune and immune mouse. J Gen Virol 1982;63:95-101. |
|7.||Hill TJ. Ocular pathogenicity of herpes simplex virus. Curr Eye Res 1987;6:l-7. |
|8.||Tullo AB, Easty D, Scimeld C, Stirling PE, Darville JM. Isolation of herpes simplex virus from corneal discs of patients with chronic stromal keratitis. Trans Ophthalmol Soc UK 1985;104:159-65. |
|9.||Pavan Langston D, Rong B, Dinkel E. Extraneural herpetic latency. Animal and human corneal studies. Acta Ophthalmol (Copenh) 1989;67 (Suppl):135-41. |
|10.||Coupe D, Klapper PE, Cleator GM, Bailey AS, Tullo AB. Herpes simplex in chronic human stromal keratitis. Curr Eye Res 1986;5:735-38. |
|11.||Cook SD. In vitro and in vivo ocular studies using HSV type 1 & 2. [PhD thesis]. Glasgow, UK:University of Glasgow. 1988. |
|12.||Cook SD, Hill JH. Herpes Simplex Virus: Molecular biology and the possibility of corneal latency. Surv Ophthalmol 1991;36:141-48. [PUBMED] |
|13.||Van Home DL, Edelhauser HF,. Schultz RO. Experimental herpes simplex keratitis. Early alteration of corneal epithelium and stroma. Arch Ophthalmol 1970;84:67-75. |
|14.||Baum J. Morphogenesis of the dendritic figure in herpes simplex keratitis. Am J Ophthalmol 1972;70:722-24. |
|15.||Thygeson P. Marginal herpes simplex keratitis simulating catarrahal ulcer. Invest Ophthalmol 1971;10:1006. |
|16.||Pavan Langston D. Viral Diseases of the cornea and external eye. In: Albert D, Jacobiec F, editors. Principles and Practice of Ophthalmology. Philadelphia, USA: WB Saunders Company; 1994. Vol 1, p126. |
|17.||Hendricks RL. An immunologist's view of the herpes simplex keratitis. Cornea 1997;16:503-6. [PUBMED] |
|18.||Mayers-Elliot R, Pettit T, Maxwell W. Viral antigens in the immune ring of herpes simplex stromal keratitis. Arch Ophthalmol 1980;98:897-904. |
|19.||Kaufman H. Epithelial erosion syndrome: metaherpetic keratitis. Am J Ophthalmol 1964;57:983-87. |
|20.||Boisjoly HM, Pavan Langston D, Kenyon KR, Baker AS. Superinfection in Herpes simplex keratitis. Am J Ophthalmol 1983;96:354-61. |
|21.||Jones BR, Falcon MG, William HP, Coster DJ. Symposium on herpes simplex eye disease. Trans Ophthalmol Soc UK 1977;97:305-13. |
|22.||Hendricks RL, Epstein RJ, Tumpey T. The effects of cellular immune tolerance to HSV-1 antigens on the immunopathology of HSV-1 keratitis. Invest Ophthalmol Vis Sci 1989;30:105-15. |
|23.||Holbach LM, Font RL, Naumann GOH. Herpes simplex stromal and endothelial keratitis. Ophthalmology 1990;97:722-28. |
|24.||Oslen TW, Hardten DR, Meiusi RS, Holland EJ. Linear endotheliitis. Am J Ophthalmol 1994;117:468-74. |
|25.||Robin JB, Steigner JB, Kaufman HE. Progressive herpetic corneal endotheliitis. Am J Ophthalmol 1985;100:336-37. |
|26.||Hawkin KN, Dart JK, Sherrad E. Sporodic diffuse corneal endotheliitis. Am J Ophthalmol 1989;108:509-15. |
|27.||Vannas A, Ahonen R. Herpetic endothelial keratitis. Acta Ophthalmol 1981;59:296-301. |
|28.||Robin JB, Steigner JB, Kaufman HE. Progressive herpetic corneal endotheliitis. Am J Ophthalmol 1985;100:336-37. |
|29.||Kaufman H, Kanai A, Ellison E. Herpetic iritis: Demonstration of virus in the anterior chamber by fluorescent antibody techniques and electron microscopy. Am J Ophthalmol 1971;71:465-69. |
|30.||Sundmacher R, Neumann-Haefelin D. HSV isolation from the aqueous of patients suffering from focal iritis, endotheliitis and prolonged disciform keratitis with glaucoma. Klin Monatsbl Augenheilkd 1979;175:488-501. |
|31.||Witmer R, Iwamoto T. Electron microscopic observation of herpetic particles in the iris. Arch Ophthalmol 1968;79:331-37. |
|32.||Young TK, Robin JB, Holland GN, Hendricks RL, Paschal JF, Engstrom RE. Herpes simplex keratitis in patients with acquired immuodeficiency syndrome. Ophthalmology 1989;96:1476-79. |
|33.||Hodge WG, Margolis TP Herpes simplex virus keratitis among patients who are positive or negative for human immunodeficiency virus. Ophthalmology 1997;104:120-24. |
|34.||Gebhardt BM, Reidy J, Kaufman HE. An affinity membrane test for superficial corneal herpes. Am J Ophthalmol 1988;105:686-87. |
|35.||Kaufman HE, Nesburn AB, Maloney ED. IDU therapy of herpes simplex. Arch Ophthalmol 1962;67:583-91. |
|36.||Gasset AR. Katzin D. Antiviral drugs and corneal wound healing. Invest Ophthalmol 1975;14:628-30. |
|37.||Longston RHS, Pavan-Langston D, Dohlman CH. Antiviral medication and corneal wound healing. Arch Ophthalmol 1974;92:509-13. |
|38.||Kaufman HE, Martola EL, Dohlman C. Use of 5 Iodo-2'-deoxyuridine in treating herpes simplex keratitis. Arch Ophthalmol 1962;68:235-39. |
|39.||Patterson A, Fox AD, Davies G, Maguire C, Ellers H, Wright P, et al. Controlled studies of IDU in the treatment of herpetic keratitis. Trans Ophthalmol Soc UK 1963;83:583-91. |
|40.||Hart DR, Brightman VJF, Readshaw GG, Porter GTJ, Tully MJ. Treatment of human herpes simplex keratitis with idoxuridine. Arch Ophthalmol 1965;73:623-34. |
|41.||Itoi M, Gefter JW, Keneko N, Ishii Y, Ramer RM, Gasset AR. Teratogenecity of Ophthalmic drugs. Arch Ophthalmol 1975;93:46-51. |
|42.||Laibson PR. Current therapy of Herpes simplex virus infection of the cornea. Invest Ophthalmol 1973;13:39-52. |
|43.||Markham RHC, Carter C, Scobie MA, Metcalf C, Easty DL. Double blind clinical trail of adenine arabinoside and idoxuridine in herpetic corneal ulcers. Trans Ophthalmol Soc UK 1977;97:333. |
|44.||Pavan Langston D, Buchanan RA. Vidarabine therapy of Herpetic keratitis. Trans Am Acad Ophthalmol Otolaryngol 1976;81:813-25. |
|45.||Wellings PC, Awdry PN, Bors F, Jones BR. Clinical evaluation of triflurothymidine in the treatment of herpes simplex corneal ulcers. Am J Ophthalmol 1972;73:932-42. |
|46.||Collum L. Randomised double blind trail of acyclovir and idoxuridine in dendritic corneal ulceration. Br J Ophthalmol 1980;64:766-69. |
|47.||Pavan Langston D, Foster CS. Triflurothymidine and IDU therapy of ocular Herpes. Am J Ophthalmol 1977;84:818-25. |
|48.||McGill J, Holt Wilson D, Mckinnon JR, Williams HP, Jones BR. Clinical use of Trifluothymidine in the treatment of herpetic ulceration of cornea. Trans Ophthalmol Soc UK 1974;94:342-52. |
|49.||Polrier R H, Kingham JD, Paulo de Mirande, Annel M. Intraocular antiviral penetration. Arch Ophthalmol 1982;100:1964-67. |
|50.||Pavan Langston D, Lass J, Whetting M, Duel I: Acyclovir and vidarabine in therapy of ulcerative herpes simplex keratitis. Am J Ophthalmol 1981;92:829-35. |
|51.||Maudgal P, De Clercque E, Missotten L. Efficacy of bromovinl deoxyuridine in the treatment of herpes simplex virus and varicella zoster eye infection. Antiviral Res 1984;4:281-91. |
|52.||Colin J, Bing Hoh H, Easty DL, Herbort CP, Resnikoff S, Rigal D, Romdane K. Ganciclovir ophthalmic gel in the treatment of herpes simplex keratitis. Cornea 1997;16:393-99. |
|53.||Kibrick S, Takahashi GA, Leibowitz HM, Laibson PR. Local corticosteroid therapy and reactivation of herpetic keratitis. Arch Ophthalmol 1971;86:694-98. |
|54.||Meisler DM, Langston RHS, Naab TJ, Aaby AA, McMahon J, Tubbs RR. Infectious crystalline keratopathy. Am J Ophthalmol 1984;97:337-43. |
|55.||Hung SO, Patterson A, Rees PJ. Oral acyclovir in the management of dendritic herpetic corneal ulceration. Br J Ophthalmol 1984;68:398-400. |
|56.||Collum LMT, Akhtar J, McGettrick P. Oral acyclovir in herpetic keratitis. Trans Ophthalmol Soc UK 1985;104:629-32. |
|57.||Schwab I. Oral acyclovir in the management of herpes simplex ocular infections. Ophthalmology 1988;95:423-30. |
|58.||Costner DJ, Jones B, Falcon MG. Role of debridement in the treatment of herpetic keratitis. Trans Ophthalmol Soc UK 1977;97:314-17. |
|59.||Wilhelmus KR, Gee L, Hauck WH, Kurinij N, Dawson CR, Jones DB, et al. Herpetic eye disease study, a controlled trail of topical corticosteroids for herpes simplex stromal keratitis. Ophthalomology 1994;101:1883-96. |
|60.||Williams HP, Falcon MG, Jones BR. Corticosteroids in the management of herpetic eye disease. Trans Ophthalmol 1977;97:341-44. |
|61.||Barran BA, Gee L, Hauck WH, Kurinij N, Dawson CR, Jones DB. Herpetic eye disease study. A controlled trail of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994;101:1871-82. |
|62.||Foster MD, Duncan BA. Penetrating keratoplasty for herpes simplex keratitis. Am J Ophthalmol 1981;92:336-43. |
|63.||Cobo, Coster DJ, Rice NS, Jones BR. Prognosis and management of corneal transplantation for herpetic keratitis. Arch Ophthalmol 1980;98:1755-59. |
|64.||Fine M, Cignetti FE. Penetrating keratoplasty in herpes simplex keratitis. Arch Ophthalmol 1977;95:613-17. |
|65.||Langston R, Pavan Langston D, Dohlman CH. Penetrating keratoplasty for herpetic keratitis. Prognostic and therapeutic determinants. Trans Am Acad Ophthalmol 1975;79:577-83. |
|66.||Ficker LA, Kirkness CM, Rice NSC, McG Steele AD. Long term prognosis for corneal grafting in herpes simplex keratitis. Eye 1988;2:400-8. |
|67.||Cleator GM, Klapper PE, Dennett C, Sullivan AL, Bonshek RE, Marcynuk B, Tullo AB. Corneal donor infection by herpes simplex virus: HSV DNA in donor corneas. Cornea 1994;13:294-304. |
|68.||Mannis MJ, Plotnik RD, Schwab IR, Newton RD. Herpes simplex dendritic keratitis after keratoplasty. Am J Ophthalmol 1991;111:480-84. |
|69.||Beyer CF, Byrd TJ, Hill JM, Kaufman HE. Herpes simplex virus and persistent epithelial defects after penetrating keratoplasty. Am J Ophthalmol 1990;109:95-96. |
|70.||Remeijev L, Doornenbal P, Geerads AJM, Rijneveld WA, Beekhuis WH. Newly acquired herpes simplex keratitis after penetrating keratoplasty. Ophthalmology 1997;104:648-52. |
|71.||Moyes AL, Sugar A, Musch DC, Barns RD. Antiviral therapy after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol 1994;112:601-7. |
|72.||Spruance SL, Stewart J, Rowe N, Mc Keough MG, Wenerstrom G, Freeman DJ. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 1990;161:185-90. |
|73.||Kaplowitz LG, Baker D, Gelle L. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex infection. JAMA 1991;265:747-51. |
|74.||The Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Eng J Med 1998;339:300-6. |
|75.||Barney NP, Foster CS. A prospective randomised trail of acyclovir after penetrating keratoplasty for herpes simplex keratitis. Cornea 1994;13:232-36. |
|76.||Vail A, Gore SM, Bradley BA, Easty DL, Rogers CA, Armitage WJ. Influence of donor and histocompatibility factors on corneal graft outcome. Transplantation 1994;58:1210-16. |
|77.||Cheng C, Chang S, Hu F. Acyclovir treatment for linear endotheliitis on grafted corneas. Cornea 1995;14:311-15. |
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]