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.

In vivo confocal microscopy after herpes keratitis.

PURPOSE: To describe the confocal microscopic findings, with special reference to corneal subbasal nerves, after herpes simplex virus (HSV) keratitis. METHODS: In this study, 16 HSV eyes and 14 contralateral eyes of 16 patients, diagnosed with unilateral HSV keratitis 1-12 months earlier by the presence of dendritic corneal ulceration or microbiologic confirmation, were examined by in vivo confocal microscopy for evaluation of corneal morphology. RESULTS: Herpes simplex virus eyes: In 2 eyes the surface epithelial cells appeared large, and no abnormalities were observed in the basal epithelial cells. In 2 eyes subbasal nerve fiber bundles were completely absent, in 3 eyes there was a reduced number of long nerve fiber bundles, and in 11 eyes the subbasal nerve plexus appeared normal. In 10 corneas, highly reflective dendritic structures were found at the level of the basal epithelial cells. Frequently these structures were found in the vicinity of stromal fibrosis. Areas with increased abnormal extracellular matrix were found in 11 eyes. Stromal nerves were not visualized in all corneas, but appeared normal when observed. Contralateral eyes: No abnormalities were observed in the epithelium. All corneas presented with a normal subbasal nerve plexus, but in 2 eyes dendritic particles were observed. Three corneas presented with activated keratocytes and increased amounts of abnormal extracellular matrix. CONCLUSIONS: When visualized by confocal microscopy, the subbasal nerve plexus appears relatively unaffected in cases with resolved HSV keratitis. Unidentified dendritic structures, presumably Langerhans cells, are frequently seen at the level of the basal epithelium in corneas with a history of herpetic disease.

Correlation between antibody titers and clinical disease in ocular herpes simplex virus infection

O trabalho comparou os títulos de anticorpo (IgG) segundo a gravidade da doença clínica na infecçäo ocular pelo vírus do herpes. O teste ELISA substituiu outros métodos tradicionais de detecçäo e quantificaçäo de anticorpos em doenças causadas por vírus. O teste ELISA requer um mínino de preparaçäo de reagente e os resultados säo disponíveis dentro de 5 horas. Näo houve nenhuma correlaçäo entre o nível do título e o quadro clínico. Um teste anti-HSV positivo pode ser útil, mas näo é indicador da presença do vírus na superfície ocular porque 73p/cento dos indivíduos foram positivos no título (1:710)

[Sudden blindness in an AIDS patient. Simultaneous infection with cytomegalovirus and herpes simplex viruses and development of malignant non-Hodgkin lymphoma]. / Plötzliche Erblindung bei einem AIDS-Patienten. Gleichzeitige Infektion mit Zytomegalie und Herpes simplex-Viren und Auftreten eines malignen Non-Hodgkin-Lymphoms.

A 50 year old patient with non-diagnosed HIV-infection at onset of his illness developed impairment of vision and temporary double vision combined with severe hemianopsia. With normal fundus and suspicious Herpes simplex iritis therapy with Acyclovir was started. Primarily the patient showed a good response to the therapy and loss of vision could be prevented. After 4 weeks CMV-retinitis developed. In spite of Gancyclovir therapy manifestation of total loss of vision after 6 weeks. Autopsy demonstrated signs of simultaneous a CMV-infection of the retina and a herpes simplex-infection of the optic nerve combined with a Non-Hodgkin-Lymphoma of the optic tract.

Mechanisms of protection against herpes simplex virus type 1-induced retinal necrosis by in vitro-activated T lymphocytes.

In BALB/c mice, acute retinal necrosis occurs in the uninoculated eye 8 to 10 days following uniocular anterior chamber inoculation of the KOS strain of herpes simplex virus type 1 (HSV-1). Retinitis in the uninjected eye can be prevented if HSV-1-specific immune effector cells that have been restimulated with virus in vitro are administered intravenously within 1 day of anterior chamber inoculation of virus. We explored further the mechanism of protection afforded by these activated immune effector cells. The results of our studies revealed that optimal protection from retinitis required in vitro restimulation, since infusion of 50 x 10(6) HSV-1-primed but nonrestimulated cells could not protect as well as 10 x 10(6) activated cells. Analysis of both restimulated and nonrestimulated cells showed that only in vitro-restimulated cells were cytotoxic to HSV-1-infected syngeneic target cells. From these studies, we concluded that the ability to kill virus-infected target cells contributed to optimal protection achieved by intravenous administration of activated immune effector cells. Furthermore, T-cell subset depletion of activated immune effector cells demonstrated that both L3T4+ and Lyt-2+ T cells in the transfer inoculum contributed to protection. Additional studies revealed that although the transferred immune effector cells reached the injected eye within 24 h, virus replication in the injected eye was not affected. In the uninjected eye, virus titers were low, consistent with protection of this eye from retinitis. Taken together, the virus recovery results suggest that the interaction of virus with intravenously administered HSV-1-specific immune effector cells which limits virus spread and/or replication of virus probably occurred within the central nervous system and prevented the second wave of virus from entering the uninoculated eye.

An analysis of the subpopulations in draining lymph node cells and MHC antigen induction in murine herpetic keratitis.

The protective role of T cell subsets in corneal herpes simplex virus type 1 (HSV-1) infection has been studied. However, the relative contribution of, and the role played by, each particular T cell subset still remain a controversial issue. We studied sequentially the appearance of major histocompatibility (MHC) and viral antigens in HSV-1 infected corneas of Balb/C mice and related them to induction of T cell subsets in local lymph nodes and corneal lesions. Immunohistochemical study has revealed a marked increase of expression of class II MHC antigen in the corneal stromal cells, while class I MHC antigen gradually increased in the corneal epithelium and stroma. Further immunohistochemical survey has revealed that L3T4 antigen bearing and Lyt 2 antigen bearing cells were induced to a similar extent with an equal rapidity in the local lymph nodes as well as in the corneal stroma. Transfer of these subpopulations to syngeneic nude mice showed that they played a role to prevent severe outcome of corneal herpetic infection. These results indicate that the corneal stroma is a major site of the host's immunological activities and both L3T4 and Lyt 2 bearing cells are equally important for the prevention of corneal herpetic infection.

Herpes simplex stromal and endothelial keratitis. Granulomatous cell reactions at the level of Descemet's membrane, the stroma, and Bowman's layer.

Fifty-three (25%) of 215 keratectomy specimens of patients with herpes simplex stromal keratitis displayed granulomatous reactions at the level of Descemet's membrane (50/53), midstroma (13/53), and Bowman's layer (5/53). Using an immunoperoxidase technique, herpes simplex virus (HSV) antigens were detected in keratocytes, endothelial cells, and foci of epithelioid histiocytes and multinucleated giant cells around Descemet's membrane. Both granulomatous reactions and HSV antigens were identified significantly more often in specimens with ulcerative necrotizing stromal keratitis than in those from patients with stromal scarring or nonulcerative nonnecrotizing keratitis (P less than 0.00001 and P less than 0.005, respectively). Herpes simplex virus antigens also were present in endothelial cells adjacent to foci of granulomatous reactions around Descemet's membrane in association with disciform stromal scarring. To our knowledge, this is the first demonstration of HSV antigens in human corneal endothelial cells and in the granulomatous reactions at the level of Descemet's membrane.

[Retinal lymphoma, retinal necrosis: identification of retinal viral particles and anti-herpetic antibodies in the vitreous body]. / Lymphome rétinien, nécrose rétinienne: identification de particules virales rétiniennes et d'anticorps anti-herpétiques dans le vitré.

Clinical data and histopathologic report of the association of a retinal malignant lymphoma and acute retinal necrosis. Demonstration of virus particle and vitreous herpetic antibodies.

Pathologic observations made by retinal biopsy.

The authors report four cases in which retinal biopsy findings yielded unexpected or previously unreported diagnoses in patients with inflammatory retinitis. The tissue diagnoses included Wegener's retinal vasculitis in an immunosuppressed patient with a clinical diagnosis of cytomegalovirus retinitis, a novel viral form in the retina of a patient with cytomegalovirus retinitis, a case of acute retinal necrosis due to cytomegalovirus infection in an immunologically normal adult, and a case of ganciclovir-resistant herpes family viral retinitis. These cases illustrate the use of retinal biopsy in obtaining tissue for diagnosis and guiding treatment in selected cases of retinitis.

[Pathological analysis of 100 cases of severe deep stromal herpetic keratitis].

Based on the pathological observation of 100 cases of severe deep stromal herpetic keratitis, the author suggested the classification of the disease, according to the nature and progression of the chronic inflammation, into 2 categories of the acute active stage (40%) and chronic progressive stage (60%), which were in agreement with the clinical manifestations and also satisfactorily explained the pathogenetic basis of the clinical types. Inflammatory granuloma appeared in 21% of the cases, indicating that the corneal lesions were still in progress.

Herpes simplex virus-specific antibodies present in tears during herpes keratitis.

We examined the specificity and levels of antibodies present in rabbit tears after induced infection of the rabbit cornea. Two strains of herpes simplex virus-1 (HSV) with different patterns of ocular disease were used: RE which produces stromal disease, and F which produces epithelial disease. We found that (i) IgG, IgA, and IgM antibodies were produced, (ii) the number of specific HSV antigens recognized by these antibodies was no significantly different, and (iii) postinfection (PI) timing and concentration of antibodies varied according to the disease pattern of the virus strain. The animals infected with strain F produced high levels of IgG antibodies early PI which remained constant, while IgA and IgM antibodies also increased early PI but declined after Day 16 PI. Animals infected with strain RE showed low levels of IgA and IgM antibodies which remained low. IgG antibodies increased early PI but declined at Day 16 PI. These differences in times of appearance and in amounts of antibodies in tears may be related to the clinical course of the disease. It has been shown that stromal disease has an immunopathologic basis. Inflammation, cellular infiltration of lymphocytes, and plasma cells are seen in the stroma of RE-infected animals, but these are not present in the stroma of F-infected animals. Infectious virus was not isolated from corneal explants taken from animals during the quiescent stage of the disease. The difference in pathogenicity cannot be explained in terms of specificity of tear antibodies. Even though the disease patterns were different, the number and types of HSV polypeptides recognized by both sets of tears was similar. Consequently, we believe that the immunopathology seen in the stromal disease may be due to the anatomical site of HSV antigens, rather than to differences in specificity of tear antibodies.

The effect of cellular immune tolerance to HSV-1 antigens on the immunopathology of HSV-1 keratitis.

Previous studies have revealed that herpes simplex virus type 1 (HSV-1) corneal stromal lesions do not develop in the absence of a cell-mediated immune (CMI) response to HSV-1 antigens. HSV-1 glycoprotein C (gC) has been shown to play an important role in the induction of the cytotoxic T lymphocyte (CTL) response to HSV-1 infections at anatomical sites other than the eye. Here we report that a deletion mutant lacking gC (gC-39) when used to infect the corneas of A/J mice was a poor inducer of both CTL and delayed type hypersensitivity (DTH) responses. We have also followed histologically and immunohistochemically the course of HSV-1 stromal disease in A/J mice following topical corneal (TC) infection with wild type (WT) HSV-1, TC infection with gC-39 HSV-1, and simultaneous TC and anterior chamber (TC + AC) infection with WT HSV-1. The latter type of infection has been shown to induce a profound state of DTH and CTL tolerance of HSV-1 antigens. Following TC infection with WT HSV-1, stromal disease progressed to severe ulcerative keratitis with neovascularization by day 21. Histologic and immunohistochemical analysis revealed a predominantly mononuclear infiltrate consisting of numerous plasma cells as well as L3T4+ (T helper/inducer) and Lyt-2+ (T suppressor/cytotoxic) T lymphocytes. Following TC infection with gC-39, or simultaneous TC + AC infection with WT HSV-1, the severity of stromal disease did not progress beyond day 7. On day 21, there was at most a mild stromal cellular infiltrate consisting predominantly of polymorphonuclear neutrophils. These findings indicate that early stromal disease consists of a nonspecific inflammatory response, but severe stromal disease involves a CMI response to HSV-1. AC injection of HSV-1 inhibits the CMI response, thereby halting the progression of stromal disease. Similarly, gC-39, a poor inducer of CMI responses, is also a poor inducer of stromal disease.

Oral acyclovir in the management of herpes simplex ocular infections.

Acyclovir, an oral antiviral agent that inhibits viral DNA replication, was used to treat 27 patients (16 males, 11 females) (mean age, 50 years) with vision-threatening herpes simplex virus (HSV) infections. Twenty patients had active stromal keratitis or keratouveitis, four had controlled nonnecrotizing stromal keratitis but could not taper topical medications, and four eczema patients with previous HSV infections had intraocular surgery (1 of these patients also is included in the 20 with active stromal keratitis). All 20 patients with active stromal keratitis or keratouveitis improved on acyclovir, all four patients using acyclovir postoperatively were disease-free while on the drug, but only two of the four patients using acyclovir to assist tapering topical medications were successful. There has been only one recurrence during a cumulative 194 months while on acyclovir. Thirteen patients have remained on acyclovir, and three who stopped acyclovir had prompt recurrences. Acyclovir seems to be a promising adjunct antiviral agent for the treatment of recalcitrant epithelial, stromal, or uveal disease secondary to HSV.

Protection against herpetic ocular disease by immunotherapy with monoclonal antibodies to herpes simplex virus glycoproteins.

In this paper we describe the ability of monoclonal antibodies to prevent herpetic stromal or interstitial keratitis following corneal infection in an outbred mouse model. Monoclonal antibodies recognizing antigenic determinants on glycoproteins B, C, D, and E of herpes simplex virus type 1 were injected intraperitoneally into CF-1 outbred mice 24 or 48 h following inoculation of the cornea with the RE strain of herpes simplex virus type 1. Passive, postexposure immunization with monoclonal antibodies had little effect on the severity of the initial corneal infection or the frequency of latent viral infections in the trigeminal ganglia, except for virus-neutralizing antibodies specific for glycoproteins B and D. A significant correlation was found between the severity of epithelial keratitis and the frequency of latent ganglionic infections. However, immunization with monoclonal antibodies protected the mice against encephalitis and prevented the development of necrotizing stromal keratitis that leads to permanent corneal scarring and blindness. This form of herpetic ocular disease does not respond to antiviral chemotherapy. Since nonneutralizing monoclonal antibodies were just as effective in prevention of encephalitis and stromal keratitis as ones that neutralized the virus in vitro, and antibodies were not administered until 24 or 48 h after corneal inoculation, we suggest that inactivation of infectious virus is not the only protective mechanism in this model.

Indications for penetrating keratoplasty: a clinicopathological review of 511 corneal specimens.

During the four-and-a-half year period from January 1982 to June 1986, 511 penetrating keratoplasty specimens were submitted to the Pathology Department of The Royal Victorian Eye and Ear Hospital. Seventy per cent were from patients of the RVEEH and the remainder were submitted from outside the Hospital. The cases were classified both clinically and pathologically. The most frequent diagnosis was keratoconus, followed by scarring, regrafts, bullous keratopathy, acute or chronic ulceration, corneal dystrophies and a small miscellaneous group. Post-herpetic scarring was the most common cause of scarring. Bullous keratopathy was usually aphakic in origin in 1982, but after 1983 pseudophakic bullous keratopathy (PBK) was the most common cause of bullous keratopathy. Acute ulceration was usually bacterial in origin, not infrequently with hypopyon.

Immunologic modulation of virus-induced pathology in a murine model of acute herpetic retinal necrosis.

Unilateral inoculation of herpes simplex virus Type 1 (KOS strain) into the anterior chamber of BALB/c eyes produces an ocular disease with a distinctive differential pattern of retinal pathology. Specifically, the retina of the inoculated eye remains histologically intact, whereas the contralateral retina becomes necrotic. We demonstrate that retinal necrosis in opposite uninjected eyes directly correlates with the presence of herpes simplex viral antigens, whereas the intact retinas of virus-injected eyes are devoid of immunocytochemically detectable viral antigens. Immunosuppression or lack of a thymus results in bilateral retinal necrosis, with positive immunoperoxidase staining for viral antigens in both eyes. We have shown previously that retinal protection in both eyes can be restored to irradiated recipients by adoptive transfer of spleen cells from mice primed by AC injection of HSV. Our results with reconstituted and normal mice suggest that virus-mediated cytopathic effects underlie contralateral retinal necrosis since HSV antigens are localized to areas of retinal necrosis and their presence precedes the local inflammatory response; immunosuppression does not alter the development of contralateral retinal necrosis. They also indicate that ipsilateral retinal preservation reflects T cell-mediated inhibition of viral spread to retinas of injected eyes. Reconstitution of irradiated recipients with AC primed donor cells prevents immunohistochemically detectable virus and retinal necrosis in both eyes. In all experimental groups we failed to detect viral antigens in the absence of retinal pathology.

Histopathology of herpes simplex virus keratouveitis.

Twenty-four eyes removed for complications of HSV keratitis were studied histopathologically. There were 20 men and 4 women with an average age of 61 years. Severe keratitis was seen in 14, moderate in 7, and mild in 3 eyes. Common features associated with severe keratitis were: acute perforation, granulomatous keratitis with giant cells in the stroma and Descemet's region, stromal inflammatory cells, angle-closure, severe iridocyclitis with diffuse or focal infiltration of lymphocytes and plasma cells, low-grade vitritis, choroiditis, and/or retinal periphlebitis. Specimens with moderate to mild keratitis had a similar distribution of inflammation but a lower incidence of granulomatous keratitis.

The antiherpesvirus activity and cytotoxicity of sangivamycin.

Sangivamycin, 4-amino-5-carboxamido-7-(beta-D-ribofuranosyl)-pyrrolo[2,3-d]-pyrimidine is a structural analog of adenosine belonging to a group of nucleosides classified as pyrrolopyrimidines. Sangivamycin, an adenosine deaminase resistant analog, was found to inhibit the replication of three strains of herpes simplex virus type 1 (HSV-1) by 50% (ED50) at a concentration approximately equal to the concentration which inhibits cell growth by 50% (LD50). Both Vero cells and rabbit corneal stromal cells in exponential growth were about 10-fold more sensitive to the drug than quiescent cells. The selectivity indices of sangivamycin indicated that the drug was not a highly selective antiviral agent and, therefore, would offer no advantage over drugs currently available for the treatment of herpetic keratitis.

Pseudomelanoma of the iris in herpes simplex keratoiritis.

A 37-year-old white man with a long history of recurrent herpetic keratitis presented with a rapidly enlarging pigmented iris lesion. The primary diagnostic concern was that the lesion might be a malignant melanoma. A biopsy of the mass was done and proved it to be a granuloma with granulomatous arteritis and infarction of the iris. In a patient with a history of recurrent ocular inflammation, such a hypersensitivity granuloma should be considered in the differential diagnosis of iris melanoma.