Pearls in the diagnosis and management of herpetic keratitis
Authors:
Juan Carlos Ochoa-Tabares MD Narlly del Carmen Ruiz-Quintero MD Manuel Alejandro Garza-León MD María del Carmen Preciado Delgadillo MD PhD
Manuel M Dieguez #118 Colonia Manuel Ladrón de Guevara CP 44600 Guadalajara Jalisco México
Phone: 52-33-36301372
Email:
Declaration of interests:
The author declare that does not have or has had any relationship with the companies that directly or indirectly could associate with the manuscript information. There is no influence on the process of selection of information, wording or content, so it does not exist any kind of interests or influence; in the expression of the scientific approach.
Summary
Viral keratitis caused by the family of Herpes viruses including Herpes simplex virus, Varicella Zoster, Epstein-Barr and Cytomegalovirus; they can cause a wide variety of clinical appearance, representing a diagnostic challenge. It is a pathology often, almost always unilateral and recurrent; whose triggers are stress exposure to the sun, trauma, and hormonal changes.
The Herpes simplex virus keratitis represents the leading infectious cause of unilateral blindness. The understanding of its pathophysiology of inflammatory and infectious nature; It is necessary to establish the appropriate treatment.
Advances in medical therapy and surgical techniques make it possible to improve the quality of life of these patients. The total cure for herpes does not exist, there are already efforts even to eliminate its latent state.
Key words
Herpes keratitis Dendritic, Neutrophilic, acyclovir.
Introduction
The human herpesvirus family is large and heterogeneous, very prevalent and able to cause asymptomatic infections or very diverse clinical syndromes. 1-14 From a point of view diagnosis and therapeutic, herpetic keratitis, is one of the most challenging facing clinical ophthalmologist.
The infectious and immunological effects that affect all levels of the cornea. It can affect people of any age or gender, the immune competence and the stress of the host are directly related to the intensity of the disease and recurrence rates.15
Epidemiology
Affects half a million people in the United States and have 48 thousand episodes of the disease, of whom 20,000 were new cases. 60% of the population has herpes virus simplex or virus varicella zoster in a latent state in the trigeminal ganglion. 16 New cases per 100,000 population estimated a rate of 32 affected persons per 100,000 population and 13.2.15
Men are affected more than women, including relapses. Bilateral disease, either at the same time or at different times occurs in 3–11% of cases and is most common in young 17 40% Of bilateral cases have atopy. 18;19 Recurrence rates of 9.6% in the first year and 22.9% in the second year.20
The most common clinical forms are: dendritic keratitis (56.3%), stromal keratitis (29.8%) and geographic keratitis (9.9%). 21 Herpetic keratitis is a problem of public health, with a high rate of morbidity; it is the infectious cause of unilateral blindness more common in developed countries.6;22-24
Pathophysiology
The morphology of both viruses herpes simplex (HSV-1 and HSV-2) is similar to other herpes viruses including varicella zoster, Epstein-Barr and Cytomegalovirus. 25 Until recently herpetic eye disease awareness was very limited, and its pathophysiology is barely understood partially. The correct identification of the disease allows to avoid relapse, its sequels or the development of a terminal or leucoma vascularized corneal pannus injury. Medical and surgical advances now provide us with a more encouraging Outlook for these patients.10;25-27
Man is the only natural reservoir of HSV. The virus is very unstable to the environment. HVS primary infection commonly affects the orofacial region and occurs almost always inadvertently during childhood. This is only symptomatic in 1 to 6% of the
cases. The passive transfer of maternal antibodies explains high levels of these in children less than 6 months. 3;22;28;29
The time between the contact with the virus and the manifestation of the disease is 3 to 9 days. The infection of the trigeminal ganglion is homolateral, the affected trigeminal ganglion is on the same side that manifest the disease. The activation of the virus is latent in the trigeminal ganglion and its centripetal migration promote the replication of the virus in the cornea.30
Systemic antibodies do not have a recognized role in the development of recurrences, despite the role played in the host response to activate the primary infection and the appellant, this has been demonstrated by observing that antibody levels remain unchanged between the episodes of recurrence; These titles can likewise increase without evidence of active infection.31
Response to viral herpes infection is humoral and cellular, produces changes in the viral cytolysis and cell destruction by immune reactions create together the tissue alteration. 32-34 Secondary to HSV, ulcerative keratitis and stromal keratitis are inflammatory lesions with cell infiltration, edema, fibrosis, neovascularization, corneal and tissue destruction scar. 7 This process is not understood completely, partly a reacción de retard hiper sensibility a viral replication in the corneal stroma.35
There is a degree of inflammation clinical sub in 74% of patients; which can affect the survival of grafts wrest them, encourage recurrences and the installation of the neutrophilic lesion.36
The neutrophilic injury occurs by decrease of trophic as acetylcholine and substance P mediators, as well as the decrease in the production of the watery component of the tear.
The progression of this alteration causes ulcer corneal, dissolution of the "melting" stroma and drilling. 37
Classification
Herpetic keratitis in particular be organized into four groups: 1) infectious epithelial keratitis: includes vesicles, dendritic ulcers, ulcers geographical and marginal ulcers. 2) Keratitis Neutrophilic: includes surface dotted erosive keratitis and neutrophilic ulcers them. 3) Stromal keratitis: includes the necrotizing stromal keratitis and stromal keratitis immune and 4) Endotelitis: includes three clinical presentations; Disciform, diffuse and linear.6
Clinical manifestations
Fortunately the congenital herpetic disease is rare and is generally acquired from genital herpes affecting the mother and that spread it through the birth canal. It is an important aspect, because untreated, 75% of the cases manifest involvement of the central nervous system.38
Primary HSV infection in the conjunctiva may occur as follicular conjunctivitis, is a auto limited disease, and occasionally may cause keratitis. 39 A manifestation of HSV is the recurring follicular conjunctivitis, and palpebral injury in 83% of cases this is accompanied.40
A primary form of eye HVS is the limbitis, which is suspected to the limbal conjunctival edema, the lesion must be stained by fluorescein, and if the swelling does not allow adequate observation of the staining in limbo (since this resembles only an accumulation of fluorescein due to adjacent limbal conjunctival edema), rose bengal should be used stained injury can be seen as a linear defect and shown in the edge of the limbo. 41;42
Should be considered a sign of herpetic disease the presence of a unilateral affectation. 43 The adequate capacity of B lymphocytes, is a protective factor of the healthy eye. 44. Also been exceptionally described bilateral tables of herpetic keratitis in patients immune suppressed.45
The most common form of herpetic keratitis is the dendritic. All types of epithelial herpetic keratitis, are caused by the reactivation of the live virus. Patients have pain, photophobia and tearing; If there are central injuries also suffer from decreased vision. The clinical signs are: 1. epithelial lesions in a branching pattern. 2. A central line of epithelial breakdown shown. 3 Branches are bordered by a mesh band of micro epithelial destruction. 4. The ramifications in bulbs end terminals, surrounded by the same aforementioned mesh band.
Only branches bordered by a mesh band of micro epithelial destruction and the ramifications that end in terminals bulbs are pathognomonic of herpetic epithelial keratitis.
The geographical lesions appear by the extension of the epithelial defect and the coalescence of new or persistent injury.
A manifestation of epithelial keratitis by less frequent HSV, is a marginal ulcer. This lesion is viral disease active, similar to the dendritic keratitis; but its proximity to the limbo promotes the rapid formation of a Subepithelial infiltrate with adjacent ciliary injection, careful examination may show a dendritic ulcer on the area of infiltration. This lesion is more symptomatic than the central and it is more difficult to treat. It responds well to antiviral. Some patients require topical steroids to suppress the inflammatory stage. But little frequent can be confused with marginal keratitis secondary to hypersensitivity by staphylococci. If it is treated with antibiotics and steroids without antiviral improperly, this lesion progresses with ulceration and Subepithelial infiltrates. 46
Only steroid use, can often result in the appearance of herpetic keratitis, dendritic. Therefore the combination of antiviral treatment with the use of steroids is necessary. 47 In the anterior chamber inflammation is much lower if compared to fungal or bacterial infections. The hypopyon is never itself only a sign of HSV keratitis; If present indicates a super infection by bacteria or fungi.
Corneal sensitivity decreases directly proportionally to the number of relapses by HSV. It is important to determine because reduced corneal sensitivity that makes this useful sign, for the evaluation of the HSV keratitis. Some details are then shared:
1 Corneal sensitivity is different in the periphery, media periphery and center of the cornea. The variation between different people corneal sensitivity is very broad. The most valuable way to evaluate the corneal sensitivity is comparing the same site of the cornea sick with the healthy side.
2. Only the area affected by the diseased neurons, is that manifests decreased corneal sensation, this can cause errors in the assessment, so be careful in evaluating the affected area, without omitting it, sometimes it is very small, and it may go unnoticed.
3 Preference you must used an aesthesiometer to assess quantitatively corneal sensitivity.
4. Within an acute episode of illness, the sensitivity is can recover, considerably, in fact; after the first attack, the sensitivity recovers in the majority of cases in its entirety.
5.-All inflammatory diseases wrest them not herpetic also may decrease sensitivity corneal, even the use of contact lenses and diabetes mellitus.
Stromal keratitis can be of any size and location, is almost always a single injury, it may be covered with healthy epithelium or constitute a ulcer with tissue destruction. 48-50 this box is confused as other diseases that cause activation of keratinocytes, corneal edema,
etc. When there is a direct invasion of the virus to the stroma is set the box of herpetic keratitis Necrotizing; ulceration necrosis and dense infiltrates included in an area of epithelial defect is observed.
The combination of replication of the virus and the severe inflammatory reaction of the host, originating from a destruction of tissue that it may be refractory to treatment with high doses of steroid and antiviral, causing thinning, corneal and drilling. Likewise, the role of the use of steroids without antiviral has been implicated. The clinical picture is similar to the infectious keratitis; so that bacteria and fungi should be regarded as probable causes.51
Interstitial keratitis is inflammatory in nature, is conditioned by the retention of antigens viral in the stroma, which promotes a reaction in the complement system cascade. 32 The role of live virus in this entity is not understood completely.
The degree of opacity of the scar is directly related to the intensity of the immune response of the host. A repair of corneal tissue response is neovascularization, which can revert partially with the use of steroids.
Another mechanism that produces opacities wrest them it is the lipidic keratitis, this happens in cornea with neovascularization, corresponding to the escape of lipids abnormal capillaries in the stroma, they can be seen as a whitish deposits surrounded by a stroma with inflammatory changes.
Neutrophilic keratitis is characterized by the inability of corneal tissue to repair due to damage in virus herpes Zoster or Simple. 52
A peculiar form of herpetic keratitis is featuring nummular subepithelial opacities, has been called archipelago keratitis characterized by marginal corneal ulceration, underlying inflammatory infiltrates and superficial keratitis bulbs arranged in a line with centripetal pattern resembling an archipelago. The nummular epithelial opacities are
gradually replaced by epithelial defects. It is postulated that during the evolution of a recurrence of a herpetic limbitis, the migration of epithelial cells to the center of it cornea, facilitate the viral spread in that pattern. Requires antiviral treatment topical and systemic; as well as anti-inflammatory treatment I steroid topical to prevent scarring. 2;53
Epstein Barr virus is spread through oral secretions, is cause of infectious mononucleosis and has been implicated in Sjögren's syndrome and Burkitt's lymphoma and nasopharyngeal carcinoma. The most common ocular manifestation is a monocular follicular conjunctivitis. Keratitis can occur in two forms: stromal Opacities previous ring shaped or pleomorphic multifocal infiltrated in the periphery of the cornea, similar to those caused by adenovirus. Other rarer manifestations are micro dendrites in the form of Star and keratitis Nummular. 54-56
HSV infection in endothelial cells causes endotelitis with circumscribed areas of inflammation with endothelial edema, marked by beaker endothelial inflammatory cells, with destruction of endothelial cells, which can cause significant corneal edema and decreased vision. 57;58 The precipitates of inflammatory cells in the decement are separate and different size. 12 In the study of specular microscopy can be seen pseudogutattas, thickened intercellular junctions, infiltration of inflammatory cells in the endothelium, loss of definition of the cell edge, endothelial denudation, increasing the polimegatism and pleomorphism. 7;12
Corneal Cytomegalovirus infection causes bilateral endotelitis. Attarzadeh and Khodadoust59 were the first to report a number of cases with recurrent bilateral corneal associated with a line of retrocorneal beaker edema also appreciate injury with circular pattern coin or ring-shaped. Later it was observed that some patients respond poorly to the use of steroids, suggesting an infectious etiology for these changes.57
Chronic scleritis by herpes simplex entity recently described. The clinical picture is composed of eye pain, persistent sectoral conjunctival hyperemia, thickening scleral which can evolve to slimming, peripheral corneal edema. The condition is almost always unilateral. Treatment should be 800 acyclovir mg five times daily until remission of inflammation and continue with doses of 800 mg every twelve hours to a year. Steroids should be avoided in the stage of active infection. Recurrences may also occur.60
In rare cases, some patients with unilateral herpetic keratitis have developed acute retinal necrosis in the eye against lateral¸ this Association is similar to animal Von Szily model. This condition is diagnosed sub and is not completely understood. It requires treatment with intravenous foscarnet and recoveries of vision has been up to 20/40. 61
Not all people that they have taken an infection by HVS, they came to have a recurrent illness, it is estimated that stress is the main factor. Other triggering conditions are infections of respiratory tract, fever, exposure to sunlight, trauma, menstruation, elderly, etc. 62;63 Herpetic eye disease is more common in patients with diabetes mellitus. 16 Recurrence ranges seem to be determined in part by the genome of the virus. Including the site of the manifestation of herpetic infection is also determined by the viral genome.64
Diagnostic tests
The use of PCR to HSV in tear can be used to establish a diagnosis in atypical cases.15;65
Treatment
The mainstay of treatment is based on the viral etiology and non-viral eye different institutions caused by the herpes virus. Table 3 shows the basic therapy for ocular herpetic diseases divided into 4 groups.
Acyclovir is a potent and selective inhibitor of HSV replication. Therapeutic concentrations in the cornea can be obtained either by topical or systemic administration. This is particularly useful in children and patients with rheumatoid arthritis.35
Treatment with acyclovir 400 mg twice a day for one year, reduces the rate of graft failure and relapse of herpetic keratitis in patients with penetrating keratoplasty. 66 Also the herpetic keratitis (epithelial and stromal) recurrence rate decreases from 32% to 19%, with the same scheme of treatment. 67 These treatments are long and evidence must be established serological exposure to HSV to indicate them. 1 Idoxidurina, trifluorotimidina, viradabina, and valacyclovir has also been used. Despite the intensity and longevity of treatments, the eradication of the virus of the corneal tissue, an aspect which explains the high rates of recurrence has not been achieved.30
The treatment of relapses should be established for each case in particular, a prophylactic treatment is not recommended. 68 An exception to the above are the patients that are going to undergo transplant of cornea.49
Neutrophilic keratitis treatment is difficult. Therapeutic resources include lubricants, contact lenses, seal with Cyanoacrylate, conjunctival coating and amniotic membrane has a limited role.
Autologous serum contains several growth factors and neuropepticos like (EGF) epidermal growth factor, factor, transforming growth (TGF), fibronectin, substance P and other cytokines essential for proliferation, differentiation and maturation of the epithelium of the ocular surface. 52 In table 5 is given a guide for the elaboration and use of autologous serum. This has been used at different concentrations (from 10% to 100%); Concentrations between 20% and 40% are the most used.
The use of specific transfer factor anti HSV has been shown to provide benefits in the treatment with antiviral drugs to prevent recurrences.69
Perspective
The search for a vaccine against herpes continues, represents an effort to make more efficient the cell-mediated protection. The use of plasmids containing viral antigens and the synthesis of viral proteins; they are promising. So far its efficacy and safety not have been demonstrated and apparently may require multiple doses.54
Genetic treatments that be deleted safely being developed and specified the State of neural tissue HSV latency.70
Reference List
1 Yoganathan P, Udell i. Treatment of Presumed Herpes Simplex Keratitis With Long Term Antivirals; Can We Refine the Treatment Paradigm? Invest RES Vis Sci 2006; 47: 3043.
2 Hoang-Xuan T, Alfonsi N, L Racine, et to the. Archipelago Keratitis: to Herpes Mediated Epithelial Cell Activation Syndrome? Invest RES Vis Sci 2005; 46: 2619.