Ocular disease pattern induced by herpes simplex virus is genetically determined by a specific region of viral DNA.

The pattern of ocular disease produced in the rabbit eye by HSV-1 (F) and HSV-1(MP) strains and recombinants F(MP)A, F(MP)B, F(MP)C, F(MP)D, F(MP)E, and F(MP)F was studied. The characteristics of ocular herpetic disease such as morphology of dendritic ulcers, severity of epithelial disease and incidence and duration of stromal disease produced in the rabbit eye are genetically determined by the virus strain. Our studies show that transfer of a defined part of the genome of the stromal disease-producing virus, HSV-1(MP), to the genome of an epithelial disease-producing virus, HSV-1(F), yielded recombinants with one or more of the disease characteristics of the donor strain. Specifically, recombinant F(MP)D produced lesions characteristic of the donor HSV-1(MP) strain; recombinants F(MP)C and F(MP)E produced stromal disease approaching the severity of the disease produced by the donor HSV-1(MP) strain, and only recombinants F(MP)A and F(MP)B retained the typically elongate lesions of the recipient HSV-1(F), whereas the recombinant strain F(MP)F produced no disease. The viral functions pertaining to the ocular disease pattern map between 0.70 and 0.83 map units in HSV-1 DNA within the BglII F DNA fragment. The pattern of stromal disease is independent of the production of glycoprotein C and fusion of HEp-2-infected cells. The functions relating to these aspects of ocular disease segregate but are closely linked.

Recurrent herpes in the rabbit and man.

Herpesvirus was present in secretory glands and frequently in tears of rabbits with recurrent herpetic keratitis even in the absence of corneal lesions. In normal people, herpesvirus could be cultured from saliva and tears. Chronic virus multiplication in structures such as the lacrimal and salivary glands, rather than latency, may cause recurrent herpetic disease.

Herpes simplex keratitis after cataract surgery.

PURPOSE: Herpetic keratitis is a rare complication of cataract surgery. We describe 3 cases of herpes simplex keratitis after cataract surgery in eyes with no clinical history of this disease. METHODS: Three patients underwent uneventful phacoemulsification of cataract with intraocular lens implantation. All were treated postoperatively with topical steroids. On subsequent development of corneal dendritic epithelial lesions in the operated eyes, the corticosteroids were replaced by treatment with topical acyclovir. RESULTS: The first postoperative day was uneventful. Corneal dendritic epithelial lesions were observed 1-5 weeks postoperatively and healed without sequelae after topical acyclovir treatment. CONCLUSIONS: In view of the surgical trauma along with the topical corticosteroid treatment commonly prescribed after cataract surgery, physicians should be aware of the possible development of herpetic epithelial keratitis even in patients with no clinical history of this disease.

Unusual dendritic keratitis.

Bilateral pseudo-dendritic keratitis in infancy can be due to tyrosinemia, a rare metabolic disorder. Ocular involvement may be the earliest presenting manifestation of this disease. Early diagnosis is essential because dietary modifications can result in complete reversal of the manifestations of this disorder. This disease must be suspected in all cases of non-responsive dendritic keratitis in the pediatric age group, especially if it is associated with cutaneous lesions such as patmoplantar keratosis. Serum tyrosine levels must be done in these cases.

Role of virus-infected mononuclear leukocytes in herpetic chorioretinitis of newborn rabbits.

The role of virus-infected mononuclear leukocytes (MNLs) in the pathogenesis of neonatal herpetic chorioretinitis in newborn rabbits was investigated. As early as 2 days after inoculating the animals' skins with type 2 herpes simplex virus (HSV-2), infectious MNLs in the infected animals' peripheral blood were found. The virus was associated, for the most part, with MNLs that belonged to phagocytic and adherent cell fractions. Observations by electron microscopy indicated that HSV-2 was actively replicating in the MNLs. It was also found that as few as 80 virus-infected MNLs injected via the right common carotoid artery were capable of inducing the chorioretinal lesions in 50% of the eyes, but that as many as 10(3) Pfu of free virus were required to produce the same lesions in the same percentage of eyes. This result clearly indicated that virus-infected MNLs were far more efficient in producing chorioretinitis than free virus, and may thus play a crucial role in the pathogenesis of herpetic chorioretinitis in newborn rabbits. When 111In-labeled virus-infected or uninfected MNLs were injected into normal rabbits via the right common carotid artery, the virus-infected MNLs localized more readily in the eye than the uninfected MNLs. The virus-infected MNLs also attached to the cultured vascular endothelial cells significantly more often than the uninfected MNLs. These results suggested that virus-infected MNLs might be easily trapped in the circulation of the eye and, in this way, produce the ocular lesions.

Bilateral alterations of the ERG and retinal histology following unilateral HSV-1 inoculation.

The physiological condition of the retinas of BALB/c mice inoculated unilaterally in the anterior chamber with the KOS strain of herpes simplex virus type 1 (HSV-1) was monitored by ERG recordings. After the ERG recordings, the retinas were examined for histopathological changes. In the inoculated eye, depressed ERGs were recorded on day 2 PI and abolished ERGs on day 4 PI. The changes in the ERGs were complete by day 5-6 PI. Of the 53 inoculated eyes followed for longer than day 6 PI, four (7.5%) remained normal, 30 (56.6%) had reduced ERGs and 19 (35.8%) had abolished ERGs. In the contralateral eyes, the first changes were noted on day 8 PI, and abolished ERGs were recorded on day 9 PI. Of the 55 contralateral eyes followed for longer than 10 days, 15 (27.3%) remained normal, four (7.2%) had reduced ERGs and 36 (65.4%) had abolished ERGs. The percentage of eyes with depressed ERGs was significantly higher in the inoculated than in the uninoculated eyes, and the percentage of eyes with abolished ERGs was significantly higher in the uninoculated eyes than in the inoculated eyes. The histopathological alterations were different for the two eyes. In the inoculated eyes, the changes were mainly in the outer retina, with characteristic folds in the photoreceptor and outer nuclear layer interspersed with normal appearing retina. The pigment epithelium was also abnormal. In the uninoculated eyes, the changes began in the inner retina but rapidly spread to all layers of the retina. This panretinal necrosis accounted for the higher percentage of abolished ERGs in the uninoculated eyes. The differences in the alterations of the ERG and the histopathological changes may be related to the underlying mechanism of action of the HSV-1 during the evolution of the experimental retinopathy.

Suppression of secondary herpes simplex uveitis by cyclosporine.

The authors studied the effect of an immunosuppressive agent, cyclosporine (CyA), on experimental secondary herpes simplex (HS) uveitis. Secondary HS uveitis was induced in a rabbit eye that had recovered from primary HS uveitis by challenging it with an intravitreal injection of herpes simplex virus (HSV) antigen. Daily intramuscular injections of CyA (25 mg/kg body weight) for 7 days prior to the intravitreal challenge with HSV antigen significantly suppressed the induction of secondary HS uveitis, but daily injections of CyA after the challenge with HSV antigen was ineffective. Intravitreal injections of CyA (5 mg) 7 days and 3 days prior to the HSV challenge were less effective, but the combined treatment with seven daily intramuscular CyA and two intravitreal CyA injections prior to the HSV challenge was most effective in the prevention of the uveitis. The daily intramuscular treatment with CyA resulted in a marked reduction of cell-mediated immunity while leaving the level of circulating HSV specific antibody high. No reactivation of latent HSV was detected in trigeminal and superior cervical ganglia of CyA-treated rabbits.

Ocular herpes simplex infection: pathogenesis and current therapy.

Ocular herpes simplex disease has a variable pattern of manifestations and recurrences as a result of the site and extent of the infection, the host immunologic events, the trophic damage within ocular tissues, and the toxic effects of antiviral medications. Laboratory research has established a clinical model and a working hypothesis about the complex pathophysiologic features of the disease and the interaction of the virus with its host tissue. Recent studies have further defined the viral genome and its role in virulence and pathogenicity. Antiviral therapy is effective in some but not all aspects of the ocular infection. A proposed clinical classification of ocular herpes simplex is based on the manifestations associated with viral disease and those associated with the host response and the subsequent structural damage. A plan for medical and surgical management of ocular herpes simplex, based on current knowledge of the disease process, relates to the integrity of the epithelium and the presence of active viral disease.

Recurrent herpes simplex virus type 1 corneal epithelial lesions after radial keratotomy in the rabbit.

The effects of radial keratotomy (RK) on herpes simplex virus type 1 ocular shedding and recurrent corneal epithelial lesions were assessed for 14 days after RK in rabbits latently infected with strain McKrae. Ten latently infected rabbits had RK performed on the right eye. The left eye was used as the control. Viral shedding was monitored by ocular tear-film swabs. The recurrent lesions were monitored by slit-lamp examination. In the RK-treated eyes, 15 (11%) of 140 swabs were positive, compared with six (4%) of 140 swabs in control eyes. Slit-lamp examination disclosed recurrent lesions on 18 (33%) of 55 days on which it was performed in the RK group vs three (5%) of 55 days for the control group. The results suggest that patients who have a history of ocular herpes simplex virus type 1 disease are at risk for recurrences after RK.

Herpes simplex virus types 1 and 2 in ocular disease.

In a continuous series of 457 patients with presumed herpetic eye disease, virus isolation and typing revealed 154 patients with herpes simplex virus type 1 and three patients with type 2 infections. In 219 isolates that were examined for neutralization by specific antisera, for growth in human fibroblasts, and, in part, for temperature sensitivity, there were found substantial strain differences in addition to the type-specific characteristics. The clinical features of each of the three type 2 infections are described in detail. A suggestive correlation found between clinical courses and virus growth characteristics of the type 1 strains indicates that further virologic differentiation of these strains would be useful.

Ocular involvement associated with chronic Epstein-Barr virus disease.

Ocular involvement with acute Epstein-Barr virus infection is usually limited to a transient follicular conjunctivitis, although other lesions have been reported. Chronic Epstein-Barr virus infection has recently gained attention, but ocular manifestations have not been emphasized. We describe three patients with chronic infection with prominent ocular involvement. Bilateral uveitis was noted in all patients, ranging from an anterior uveitis that was responsive to steroids to a severe panuveitis with vitritis, cataract, optic disc swelling, and macular edema. In one patient, topical acyclovir ointment resulted in a substantial decrease in the inflammatory reaction when added to systemic acyclovir therapy. Another patient displayed a keratitis that resolved with topical steroid therapy. Cataract and vitreous surgery were also beneficial in the management of these patients.

Oral acyclovir reduces the incidence of recurrent herpes simplex keratitis in rabbits after penetrating keratoplasty.

To determine if acyclovir sodium prevents postoperative herpes simplex virus type 1 (HSV-1) recurrences, 21 rabbits harboring latent HSV-1 underwent uniocular autograft penetrating keratoplasty. All operated-on eyes were treated with topical and subconjunctival dexamethasone sodium phosphate. Ten of the 21 rabbits also received oral acyclovir (intravenous acyclovir was given at the time of surgery). Postoperatively, 9 (82%) of 11 operated-on eyes in rabbits not treated with acyclovir had positive HSV-1 ocular cultures. In acyclovir-treated rabbits, however, none of the 10 operated-on eyes had positive ocular cultures. In addition, 9 (82%) of 11 of the operated-on eyes had geographic ulcers develop in the non-acyclovir-treated rabbits, compared with 1 (10%) of 10 in the acyclovir-treated rabbits. Finally, stromal keratitis appeared in 5 (56%) of 9 of the operated-on eyes in non-acyclovir-treated rabbits and 1 (12%) of 8 of the operated-on eyes in acyclovir-treated rabbits. The results of this study indicate that acyclovir significantly lowered the incidence of HSV-1 ocular shedding, geographic ulceration, and stromal keratitis in a rabbit autograft penetrating keratoplasty model.

The role of herpesvirus type 1 thymidine kinase in experimental ocular infections.

Herpesvirus type 1 thymidine-kinase-negative mutants are readily selected for in tissue culture and in humans by acyclovir, a promising antiviral agent. We investigated the ocular pathogenicity of thymidine-kinase-negative mutants in the rabbit. The natural course of untreated keratitis induced by the herpesvirus type 1 thymidine-kinase-negative strain was characterized by superficial dendrites and geographic ulcers that healed spontaneously without loss of corneal clarity. We also studied the relationship between herpesvirus type 1 thymidine-kinase activity and virulence in the rabbit with three strains of herpesvirus type 1: NIH thymidine-kinase-positive (100% thymidine-kinase activity), NIH thymidine-kinase-intermediate (25% thymidine-kinase activity), and NIH thymidine-kinase-negative (0% thymidine-kinase activity). Despite comparable ocular titers, the NIH thymidine-kinase-positive strain proved to be the most virulent, causing significantly (P less than .002) more keratitis, encephalitis, and death than the other strains.

Herpetic stromal keratitis-evidence for cell-mediated immunopathogenesis.

Immunofluorescence, histological, and electron microscopic observations were made on rabbit corneas from animals with experimentally induced stromal keratitis following intracorneal injection with the RE strain of herpes simplex virus. Electron microscopic observations were also made on human corneas obtained from patients with a history of herpetic stromal disease. Viral antigens were demonstrated by immunofluorescence in keratocytes of rabbit corneas with herpetic stromal keratitis. Electron microscopic observations and viral culture failed to reveal the presence of viral particles in these tissues. Lymphocytes, a major infiltrating cell type found in both the rabbit and human corneas, were often found in intimate contact with degenerating keratocytes.

Herpes simplex dendritic keratitis after keratoplasty.

We treated three patients with herpes simplex dendritic keratitis that occurred between three and 11 months after keratoplasty. The patients had no history of herpetic infection. The eyes of two of the patients were grafted for corneal scarring of undetermined origin. The eye of the third patient was grafted for pseudophakic bullous keratopathy. At the time of onset of dendritic keratitis, all three patients were receiving either maintenance or higher doses of topical corticosteroids. All infections responded to topical antiviral treatment. The findings in these patients illustrate the importance of considering herpes simplex keratitis in the differential diagnosis of all late-onset epithelial defects in the corneal graft, even in the absence of a history of herpes simplex keratitis.

Varicella dendritic keratitis.

A 7-year-old boy and a 3-year-old girl suffered from unilateral disciform keratitis and iritis associated with varicella. While they were treated with topical corticosteroid, idoxuridine, and atropine drops, dendritic lesions typical of herpes zoster appeared four months after the onset of eruptive skin lesions. Using the direct immunofluorescent method, we showed varicella-zoster virus antigen in the epithelial cells scraped from the dendritic lesion.

Neuroretinitis associated with herpes simplex encephalitis in an adult.

A 48-year-old man who died of herpes simplex encephalitis had a bilateral papillitis at autopsy. Intranuclear inclusion bodies were especially numerous within the ganglion cells and inner nuclear layer of the macula and consisted of typical virions by electron microscopy. Contiguous spread from the brain to the eyes may have occurred via the optic nerves. Clinically, the disk and retinal changes were misinterpreted as being caused by papilledema. Papillitis should be included in the differential diagnosis of disk swelling in adults with suspected Herpesvirus hominis infection of the central nervous system.

Immunosuppression and eye disease. First Vail lecture.

Several viral, fungal, and protozoal diseases of the eye are significantly associated with immunologic deficiencies. Of the viral agents, cytomegaly and herpes simplex and zoster cause a discrete necrotizing retinopathy that has the characteristics of vascular occlusion. Measles may result in a delayed retinopathy that is predominantly macular and associated with subacute progressive encephalopathy. Of the fungal agents, Candida and Aspergillus are apt to involve the eye, beginning as choroidal lesions with extension forward to involve the pigment epithelium and retina secondarily. Mucor and Cryptococcus are less common. Toxoplasmosis is the one ocular protozoal disease whose incidence is increased by immunosuppression, and, like the viral diseases, is characterized by a discrete necrotizing retinopathy and probably results from activation of dormant organisms in the retina. Autoimmunity undoubtedly plays an important role in eye disease but its ocular pathogenesis is obscure.

New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty.

PURPOSE: To report a series of patients with no previous history of herpes simplex virus (HSV) infection who had new onset of herpetic keratitis after penetrating keratoplasty (PK). DESIGN: Noncontrolled, retrospective case series. METHODS: We included in the study the patients who had new onset of herpetic keratitis after penetrating keratoplasty for corneal diseases unrelated to HSV infection who were seen at the Cornea Service at Wills Eye Hospital (Philadelphia, Pennsylvania) from January 1996 to December 2002. The diagnosis of HSV epithelial keratitis was based on clinical characteristics of either a classic herpetic dendrite, a geographic ulcer, or a nonhealing epithelial defect that responded only to antiviral therapy. RESULTS: Fourteen patients were included in the study. Eight of these (57%) had presented with a geographic ulcer whereas six patients (43%) had a classic dendrite. The most common primary corneal disease that led to PK was pseudophakic bullous keratopathy (36%), followed by keratoconus (29%), Fuchs dystrophy (21%), and corneal scar unrelated to HSV (14%). CONCLUSIONS: The ophthalmologist should be aware of the possibility of herpetic keratitis in eyes after PK, even in patients with no previous history of HSV infection.