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.

Recurrence rate of herpetic uveitis in patients on long-term oral acyclovir.

We examined the recurrence rate of herpetic uveitis (HU) in 13 patients (group A) treated prophylactically with long-term systemic acyclovir (600-800 mg/day) and compared it with that of 7 patients with no prophylactic therapy (group B). HU was diagnosed on the basis of a history of dendritic or disciform keratitis accompanied by iridocyclitis and iris atrophy. The study population consisted of 12 men and 8 women with a mean age at onset of uveitis of 52.9 years (range 19-78 years). All patients were followed for at least 8 months. The mean follow-up time of patients on long-term oral acyclovir was 26.0 months. In this group, only one patient experienced a single recurrent episode of uveitis while on 600-800 mg/day of acyclovir therapy; two additional patients had recurrence of HU within 16.2 months after the acyclovir dose was tapered below 600 mg/day. In striking contrast, 16 recurrences occurred in the 7 patients of group B (p < 0.05). Of these, the initial recurrence occurred within an average of 4.3 months following cessation of therapy. There was a significant difference (p < 0.05) in the mean recurrence-free interval between patients in group A (24.6 months) and those in group B (3.4 months). Herpetic uveitis is a serious ocular disease in which recurrence of inflammation results in severe ocular complications. The long-term use of oral acyclovir may be of benefit in the prevention of recurrences, and hence may reduce the blinding complications of this disease. Efforts at completing a randomized, placebo-controlled trial on this matter by the Herpes Epithelial Disease Study Group were unsuccessful due to insufficient patient recruitment.

Herpes simplex keratitis in children.

Ophthalmic findings are reported in 31 eyes of 28 children with herpes simplex keratitis. Twenty two had dendritic ulcers, and nine had geographic ulcers or disciform stromal keratitis. After resolution of keratitis, 80% (19/22) of children with dendritic ulcers achieved corrected visual acuity of 6/9 or better, 50% (11/22) had induced astigmatism, 45% (9/22) had one to five recurrences. In the group with geographic or disciform lesions, 89% (8/9) had reduced corrected vision, 78% (7/9) had induced astigmatism which was predominantly against the rule, and 87% (7/9) had one to six recurrences.

HSV-2 alters retinal physiology and morphology bilaterally in mice.

Anterior chamber inoculation of 10(4) PFU of the MS strain of HSV-2 resulted in physiologic and morphologic changes in the retina of the inoculated and the uninoculated eyes. In the inoculated eyes, electroretinogram (ERG) depression was first detected on day 3 and abolished ERGs on day 8 postinoculation (PI). The decrease in the ERGs was rapid and the time course was similar for all of the eyes. In spite of a 90% decrease in the amplitude of the b-wave, the retinal sensitivity did not change. Of 23 eyes tested on or after day 10 PI, none had normal, 4.3% had reduced, and 95.6% had abolished ERGs. In the uninoculated eyes, ERG depression was first detected on day 8 and abolished ERGs on day 12 PI. The course of the ERG depression was more variable, and some of the eyes showed a decrease in retinal sensitivity. Of the 22 eyes tested on or after day 17 PI, 18% had normal, 32% had reduced, and 50% had abolished ERGs. The majority (17/33) of the retinas of the inoculated eyes showed panretinal necrosis, although 7 of 33 retinas had pathology confined to the outer layers of the retina. In the uninoculated eyes, only 5 of 30 retinas were necrotic and 14 of 30 retinas had pathology limited to the outer layers of the retina. These observations suggested that the physiologic and morphologic changes progress through two stages: an early stage with reduced ERGs and pathology limited to the outer retinal layers, and a second stage in which the ERG is abolished and the pathologic changes extend into the inner retina. Not all retinas progress to the second stage.

[The indices from an electrophysiological study of the eye in herpetic lesion of the cornea]. / Pokazateli élektrofiziologicheskogo issledovaniia glaza pri gerpeticheskom porazhenii rogovitsy.

Electrophysiologic studies were conducted in 34 patients with herpetic lesions of the cornea (35 eyes with the active process and 33 clinically healthy fellow eyes). The control group included 30 healthy persons (60 eyes). In the control group, the threshold of electric sensitivity of the eye was 25.1 mcA, on the average. In the examined groups, it increases to 31.9 mcA (p less than 0.0017) in the group of patients with herpetic keratitis and to 28.7 mcA (p less than 0.05) in the group of patients with clinically healthy fellow eyes. The average value of optic nerve lability was 54.5 Hz in the control group. Reduced lability was recorded in group I--48.6 Hz (p less than 0.001) and in group II--52.6 Hz (p less than 0.02). No statistically significant differences in electrographic values were found. The electrophysiologic studies of eyes with localization of herpetic process in the cornea have shown the involvement of internal layers of the retina and the optic nerve into the pathological process. Similar changes appear in the clinically healthy fellow eyes as well, but to a lesser degree. The determination of the threshold of electric sensitivity and lability of the optic nerve can be used for diagnosing changes in internal layers of the retina and the optic nerve in herpetic keratitis.

Role of peptidergic neurons in ocular herpes simplex infection in mice.

Peptide-containing nerve fibers (peptidergic fibers) abundantly innervate the mammalian cornea. We investigated their role in ocular herpes simplex infection in mice by using capsaicin, which causes degeneration and permanent loss of peptidergic neurons in neonates and temporary peptide depletion in adult animals. The corneas of neonatally denervated BALB/c mice were observed for capsaicin-induced keratitis at 11-14 wk of age and were then infected bilaterally with herpes simplex virus 1 (HSV-1); trigeminal (TG) ganglia were cocultivated 6 wk later to establish the rate of latent infection. We also applied capsaicin eye drops to adult BALB/c mice that had been infected with HSV-1 6 wk earlier, and measured viral shedding before, and 3 days and 2 months after, administration of capsaicin drops; TG ganglia of these animals were cocultivated at 3 days and 2 months after capsaicin application. Neurotrophic keratitis was found in 81% of neonatally denervated animals; mortality rate due to HSV-1 infection was reduced from 80% in the controls to 24% in the capsaicin-treated group, and recovery of latent virus by cocultivation was reduced by 50%. Viral shedding could not be produced by capsaicin eye drops in adult animals infected with HSV-1. However, recovery of latent virus was significantly reduced in TG ganglia sampled 3 days and 2 months after capsaicin drops were instilled. Our findings suggest 1) that peptidergic fibers play a crucial role in the establishment of trigeminal HSV-1 latency and 2) that reactivation of latently infected ganglia can be inhibited by topical capsaicin.

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.

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.

Recurrent HSV-1 corneal epithelial lesions induced by timolol iontophoresis in latently infected rabbits.

Herpes simplex virus type 1 (HSV-1) ocular shedding and recurrent corneal epithelial lesions were assessed following ocular iontophoresis of 0.01% timolol at 0.8 mAmp for 8 min for 3 consecutive days in 17 rabbits latently infected with HSV-1 strain McKrae. The collection of ocular tear film for the detection of HSV-1 ocular shedding and the slit lamp biomicroscopic evaluation for HSV-1 epithelial lesions began on day 4 after the first iontophoresis and continued for 7 consecutive days. The tear film was collected on a Dacron swab with care being taken to avoid swabbing the corneal epithelium. The observed HSV-1 lesions were characterized as deep punctate lesions, dendritic lesions and geographic epithelial defects. The ratio of total days of eyes exhibiting HSV-1 epithelial lesions to the total number of observation days was 113/235 (48%). There were 46 punctate lesions, 27 dendritic lesions and 40 geographic epithelial defects. The ratio of positive swabs to total swabs was 77/235 (33%). Of the 113 positive lesion days, 65 (58%) were associated with a positive swab. Of the 77 positive swabs, 65 (84%) were associated with an epithelial lesion. Of the 122 negative lesion days, 110 (90%) were associated with a negative swab. Of the 158 negative swabs, 110 (70%) were associated with no epithelial lesions. By chi-square analysis, there was a significant association between HSV-1 swabs and HSV-1 lesions (P less than 0.001). These results demonstrate that ocular iontophoresis of timolol induces both HSV-1 ocular shedding and recurrent HSV-1 corneal epithelial lesions in rabbits latently infected with HSV-1 strain McKraw.

Corneal nerves are necessary for adrenergic reactivation of ocular herpes.

Herpes simplex virus type 1 (HSV-1) can infect the cornea and achieve ganglionic latency. HSV-1 can later be activated by a variety of effectors although the exact mechanism of reactivation is unknown. Rabbits harboring latent HSV-1 strain McKrae can be induced to shed virus by ocular iontophoresis of epinephrine to the cornea. No studies have been done to investigate if corneal nerves are necessary for epinephrine induction of HSV-1 ocular shedding. We did penetrating keratoplasty (PKP) in one eye each of 23 rabbits; the other eye served as an unoperated control. The surgery effectively denervates the area of the transplant for up to 90 days. Eighteen rabbits carrying latent HSV-1 strain McKrae received corneas from uninfected rabbits. Five uninfected rabbits with no latent virus received corneas from rabbits harboring latent HSV-1. On days 10-14 after penetrating keratoplasty, 24 eyes in the HSV-1 latent group and all ten uninfected eyes received iontophoresis of 0.01% epinephrine (0.8 mAmps for 8 min or 0.6 mAmps for 6 min) once daily for 3 days by means of an eye cup whose diameter was less than the diameter of the transplant. Six rabbits in the HSV-1 latent group received intravenous injections of cyclophosphamide (75 mg/kg) and dexamethasone (4 mg/kg). Following iontophoretic or immunosuppressive induction, the eyes were swabbed daily for 9 days. Of the 12 rabbits with latent virus which were treated by iontophoresis, one of the transplanted eyes and eight of the nontransplanted eyes were induced to shed virus. The mean duration of shedding in the nontransplanted eyes was 3.25 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural activity from the acutely infected HSV-1 rabbit cornea.

Herpes simplex virus type 1 (HSV-1) infections of the human cornea are often accompanied by abnormal sensations. In this study, a combination of physiological and structural methods was used to examine the innervation of the corneas of rabbits with HSV-1 lesions of varying severity. Degeneration of the plexiform neural layer adjacent to dendritic lesions and surrounding normal neurology provided a basis for the limited physiological changes. Extensive degeneration of the corneal innervation at all levels occurred within the anesthetic area of the geographic lesion. Abnormal physiological activity characterized by hyperexcitability and loss of stimulus specificity were included in the physiological profile. Collateral sprouts seen in the geographic lesion were suggested as an anatomical substrate for the abnormal neural activity. Thus, the neural changes could be associated with the severity of HSV-1 lesions.

Return of human corneal sensitivity after penetrating keratoplasty.

To evaluate the reinnervation of corneal grafts, we studied 91 eyes of 79 patients for the return of sensitivity one month to ten years following penetrating keratoplasty for various corneal disorders including keratoconus, Fuchs' dystrophy, herpes simplex keratitis, aphakic and pseudophakic bullous keratopathy, glaucoma, trauma, and interstitial keratitis. Using the Cochet-Bonnet esthesiometer, a sensation was recorded in the center of the graft no earlier than 18 months. We found a progressive return of sensitivity from the periphery toward the center of the graft. Regression analysis indicated a rate of return of sensitivity that averaged 0.029 mm/mo for each diagnostic category except herpes simplex keratitis. The slope of the return of sensitivity in the group with herpes simplex keratitis was essentially flat, showing no central progression. None of the eight patients with herpes simplex keratitis had a sensation recorded further than 0.5 mm from the wound margin.

Effects of cyclosporine A on clinical and immunological parameters in herpes simplex keratitis.

The immunosuppressive effects of cyclosporine A (CyA) on the clinical and antiviral immune responses were examined in experimental herpes simplex virus (HSV) keratitis in the rabbit in order to clarify the role that immune lymphocytes play in herpetic stromal disease. Cyclosporine A was administered intramuscularly to rabbits daily starting from the time of corneal infection with HSV until day 14 postinfection. Control HSV-infected rabbits received daily injections of the solvent vehicle alone. HSV-infected rabbits receiving CyA treatment showed more severe and persistent stromal keratitis, and a greater incidence and duration of virus recovery from the cornea. Suppression of cellular immune responses to T cell mitogens, B cell mitogens (anti-rabbit immunoglobulins), and HSV antigens were observed in the CyA treatment group. These results show that in CyA-treated HSV-infected rabbits the antiviral immune responses are inhibited. Acute viral infections with cytopathic viruses such as HSV may therefore be more dramatic, suggesting that CyA may facilitate the potentiation of HSV infections ordinarily suppressed by immune cells.

[Use of cyclosporin A eyedrops in the prevention of corneal graft rejection in man. I. Preoperative development of 4 eyes with metaherpetic keratitis]. / Usage de la cyclosporine A collyre dans la prévention du rejet de greffe de cornée chez l'homme. I. Evolution préopératoire de 4 yeux atteints de kératite métaherpétique.

Topical cyclosporine A (2%) has been used to prevent corneal graft rejection in high risk patients. The treatment was begun 48 h at least before surgery. 3 patients (4 eyes) suffering from metaherpetic keratitis were placed under this treatment for a long time due to the delay to obtain a corneal donor. Their observation while treated showed a remarkable slow-down of the inflammation both in conjunctivae and corneas. This confirms if necessary the role of T lymphocytes in metaherpetic corneal diseases and the clinical modulation effect of cyclosporine A on these T cells.

Herpetic keratitis therapy to reduce recurrence.

Since the herpes simplex virus locates latently in the ganglia and is reactivated by certain triggers, the important problem in treatment is to prevent or reduce recurrence. The present study investigates the role of mechanical debridement in lessening the recurrence of dendritic keratitis in patients with herpetic epithelial keratitis. Group A was treated with mechanical debridement plus IDU, Group B with IDU alone. Also studied was the effect of steroid subconjunctival injection on herpetic recurrence in patients with herpetic stromal keratitis: Group C was treated with intravenous infusion of pepsin-treated gamma-globulin (PTGG) and steroid subconjunctival injection, Group D with steroid subconjunctival injection alone and Group E with intravenous infusion of PTGG alone. The recurrence rates of dendritic keratitis were 19% in Group A and 40% in Group B (average follow-up periods: 24 and 25 months). The recurrence rates of stromal keratitis were 61% in Group C, 64% in Group D, and 36% in Group E (average follow-up periods: 20, 19 and 15 months). The difference between Groups D and E was statistically significant (chi 2 test, P less than 0.05). The recurrence rates of dendritic keratitis were 18% in Group C, 21% in Group D and 7% in Group E. In conclusion, mechanical debridement tended to reduce the recurrence of herpetic epithelial keratitis and steroid subconjunctival injection to increase the recurrence of epithelial or stromal keratitis.

Ocular pathogenicity of herpes simplex virus.

As a relatively small, discrete organ that contains a number of widely different cell types the eye provides an intriguing system in which to study fundamental aspects of virus/cell interactions. Such aspects are considered with particular reference to herpes simplex virus and the pivotal role of virus/neuron interactions in the development of ocular disease. Three aspects of this interaction are discussed: the entry of virus into the eye latency in the trigeminal ganglion nerve damage.

Clinical findings after zosteriform spread of herpes simplex virus to the eye of the mouse.

When herpes simplex virus (HSV) is inoculated onto the snout of the inbred strain NIH mouse, clinical disease of the eye ensues only after a delay, due to spread of virus to the eye occurring via neural pathways. This report is concerned with the detailed description of eye disease. Physical signs observed include mydriasis, iritis and keratitis. The incidence of combinations of physical signs has been analysed by the computer and presented as pie-charts to show the complexity and evolution of the eye disease.

Spontaneous resolution of herpes simplex blepharoconjunctivitis in children.

We observed three children, aged 1 year 8 months to 9 years 7 months, in whom herpes simplex blepharoconjunctivitis resolved promptly without treatment. A fourth child, 8 years old, developed probable toxic manifestations from topical vidarabine. These manifestations, as well as the blepharoconjunctivitis, resolved when the medication was discontinued. Herpes simplex ocular infection without corneal involvement in children is usually benign and self-limited.

Tear film flow and stability in herpes simplex keratitis and chronic blepharitis.

Tear film flow and stability studies were carried out in patients suffering from herpes simplex keratitis and chronic blepharitis by performing Schirmer test I and tear film break-up-time (BUT) measurements. In herpes simplex keratitis the values of BUT were within normal limits. Values of Schirmer test I were significantly higher (t-test, P less than 0.001) in these patients and are considered to be due to reflex hypersecretion of tears. Schirmer test I was found to be unaffected, whereas the values of BUT seen were significantly lower (t-test, P less than 0.001) in patients suffering from chronic blepharitis. These lower values of BUT can perhaps be attributed to the altered resurfacing of precorneal tear film as a result of changes in the lid margins.