Von Szily Research Articles

Proposing a Neurotropic Etiology for Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Relentless Placoid Chorioretinitis.

To reassess the underlying pathophysiology of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and relentless placoid chorioretinitis (RPC) through comparison with the non-inoculated eye of the von Szily animal model of neurotropic viral retinal infection. Narrative review. Literature reports of isolated neurotropic viral entities and rising serological viral titers in APMPPE after presentation support a potential direct infective etiology. In general, viral transport along axons results in mitochondrial stasis and disruption of axoplasmic flow. Clinical manifestations of axoplasmic flow disruption in APMPPE/RPC may signify the passage of virus along the neuronal pathway. From a case series of 11 patients, we demonstrate a timely, spatial, and proportional association of optic disc swelling with APMPPE lesion occurrence. Signs within the inner retina appear to precede outer retinal lesions; and acute areas of outer nuclear layer (ONL) hyperreflectivity appear to be the result of coalescence of multiple hyperreflective foci resembling axonal spheroids (which occur as a consequence of axoplasmic disruption) and follow the Henle fiber layer neurons. Underlying areas of retinal pigment epithelium (RPE) hyper-autofluorescence follow ONL hyperreflectivity and may signify localized infection. Areas of apparent choriocapillaris hypoperfusion mirror areas of RPE/Bruch's membrane separation and appear secondary to tractional forces above. Increases in choroidal thickness with lesion occurrence and focal areas of choriocapillaris hypoperfusion are observed in both APMPPE/RPC and the von Szily model. The neurotrophic infection model provides significant advantages over the existing primary choriocapillaris ischemia hypothesis to account for the range of imaging signs observed in APMPPE and RPC.

Infant perception of von Szily contours

This habituation–dishabituation study examined infants’ perception of subjective von Szily contours, the illusory effect of which is generated by horizontal disparity and half-occlusions. In these contours, a foreground surface appears to partially occlude a background surface. In Experiment 1, participants aged 4 and 5 months were habituated to a von Szily figure and were then tested for their ability to perceive the difference between the habituation figure and the same figure with reversed depth relations. The infants displayed significant novelty preferences during the posthabituation period. This observation indicates that 4- and 5-month-olds respond to the stereoscopically specified depth difference between the two surfaces of von Szily figures. In Experiment 2, participants aged 4 and 5 months were tested for the ability to conduct modal completion, that is, to perceive the surface that is stereoscopically shifted into the foreground as a whole. The infants were habituated to a von Szily figure and then examined for their ability to distinguish between complete and incomplete versions of the foreground surface. Longer looking at the incomplete posthabituation pattern indicates modal completion; the infants recognize the complete pattern as familiar and regard the incomplete pattern as novel. Similarly, Experiment 3 investigated whether infants aged 5 and 7 months amodally complete the background surface, that is, the surface that is partially covered by the foreground surface. Experiment 2 found modal completion in 5-month-olds. Experiment 3 established that 5- and 7-month-olds have developed some ability to conduct amodal completion. In sum, infants perceive the depth information in von Szily contours and conduct modal and amodal completion.

Intravitreal treatment with antisense oligonucleotides targeting tumor necrosis factor-α in murine herpes simplex virus type 1 retinitis

Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine known to participate in intraocular inflammatory disease. This study investigated whether treatment with intravitreal antisense-oligonucleotides (ASON) targeting TNF-α mRNA affects the progression of herpes simplex virus 1 (HSV-1) retinitis in mice. The in vivo uptake of the oligonucleotid after intravitreal injection was determined with FITC-labeled TNF-α ASON. HSV-retinitis was induced on day 0 by the injection of HSV-1 (KOS strain) into the anterior chamber (AC) of the right eyes of BALB/c mice (von Szily model). The left contralateral eyes were injected intravitreally on day 7 with TNF-α ASON, sequence-unspecific control ASON (CON), or buffer. The clinical course of retinitis, ocular inflammatory cell-infiltration, TNF-α expression in the eye by ELISA, delayed-type hypersensitivity (DTH) reaction, virus-neutralizing antibody titers in the serum, uptake of [3H]thymidine from regional lymph node (rln) cells, and viral content in the eyes were determined. In vivo, strong fluorescence of FITC- TNF-α ASON was detected in the choroid and retina up to 3days after intravitreal injection, but none in the rln. After treatment of eyes with ASON, decreased expression of TNF-α in the eye, and reduced incidence and severity of retinitis on day 10 after infection (P < 0.05) could be found. The other parameters were not significantly influenced after TNF-α ASON treatment. TNF-α participates in the pathology of HSV-1 retinitis. Local inhibition of TNF-α mRNA by intraocular TNF-α ASON injection did not influence the systemic HSV-specific immune response or the antiviral response in the eye, but reduced ocular inflammatory bystander damage.

Influence of Antisense Oligonucleotides Targeting Tumor Necrosis Factor-α on Experimental Herpetic-Induced Chorioretinitis of Mouse Eye

Objective: To investigate the effect on the pathological process of topical treatment with antisense oligonucleotides (ASON) targeting tumor necrosis factor-α (TNF-α) in experimental herpes simplex virus type-1 (HSV-1)-induced chorioretinitis of mouse eye. Methods: 50 BALB/c mice were randomly divided into two different groups (25 mice in each group). The Von Szily model was induced in mice by inoculating 1×10⁵ plaque-forming units of HSV-1 (KOS strain) into the anterior chamber of the right eye. In one group, FITC-labeled ASON targeting TNF-α was injected subconjunctively into the left eye on days –1, 1, and 4, whereas phosphate buffer was used in the same way on the same days in another group. The clinical appearances were observed after infection each day and the eyes were examined histologically. The TNF-α content of retina and choroid were measured by ELISA. Results: After infection, acute inflammation appeared in the right eye of both groups. As for the non-inoculated eye, the inflammation in the ASON group was significantly decreased compared to the PBS group. The number of inflammatory cells in the ASON group was significantly lower than in the PBS group, especially in the choroid, retina and ciliary body. The TNF-α content in the choroid and retina of the ASON group was diminished. Conclusion: The results suggested that TNF-α ASON reduced the content of TNF-α in mouse eyes, and this topical treatment decreased the inflammatory reaction. It may be an effective method for treating HSV-1-induced chorioretinitis in the clinic.

Subconjunctival antisense oligonucleotides targeting TNF-α influence immunopathology and viral replication in murine HSV-1 retinitis

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) in immunopathology and viral replication in the contralateral eye in the von Szily model of herpes simplex virus (HSV)-1 acute retinitis. In vivo distribution was analyzed after subconjunctival injection of FITC-labeled antisense oligonucleotides (ASON). After HSV-1 (KOS) was injected in the right anterior chamber (AC) in BALB/c mice, the course of the contralateral retinitis was evaluated. The left eyes were treated with either TNF-alpha ASON, sequence-unspecific control (CON), or buffer. The ocular TNF-alpha content was quantified by ELISA. The delayed-type hypersensitivity (DTH) reaction, uptake of [3H]thymidine from regional lymph nodes (rln)- and spleen cells, serum-neutralizing antibodies, and viral titer in the eyes were evaluated. After subconjunctival injection, FITC-labeled ASON were found in the choroid and retina. In the TNF-alpha ASON-treated eyes, TNF-alpha expression and the incidence and severity of retinitis were reduced on day 8 postinfection (PI) (p < 0.05). On day 10 PI, higher viral titers were only seen in the eyes of the TNF-alpha ASON group (p < 0.05), and retinitis was slightly more severe on day 12 PI. While the HSV-1 specific [3H]thymidine uptake from rln cells was higher in the TNF-alpha ASON mice (p < 0.05), the [3H]thymidine uptake from spleen cells, the DTH response, and the neutralizing-antibody titers did not differ between the groups. After regional blockade of TNF-alpha in experimental HSV-1 retinitis TNF-alpha seems to possess an antiviral capacity against HSV-1 in the contralateral eye and participates in the immunopathology of HSV-1-induced acute retinitis.

Two Patients With the von Szily Reaction: Herpetic Keratitis and Contralateral Retinal Necrosis

To present two patients with prior unilateral, herpetic keratitis who developed acute retinal necrosis (ARN) in the contralateral eye. These cases have noticeable similarities to the von Szily reaction. This describes the development of a contralateral retinitis subsequent to an anterior chamber injection of herpes simplex virus (HSV). Interventional case series. Retrospective chart and literature review. The first patient had neonatally acquired herpetic keratitis and developed ARN at age 21. Polymerase chain reaction of a vitreous biopsy detected HSV type-2 (HSV-2). The second patient was clinically diagnosed with ARN contralateral to varicella zoster keratitis. A detailed literature search located seven prior case reports with a von Szily reaction. These resembled our two cases except none had HSV-2 or years of latency from keratitis to retinitis. Clinicians need to be cognizant of the von Szily reaction.

Early demonstrations of subjective contours, amodal completion, and depth from half-occlusions: "stereoscopic experiments with silhouettes" by Adolf von Szily (1921).

If all-black figures are used, certain monocular appendages to binocular shapes are seen in depth, either nearer (when in a medial position) or further (when in a lateral position) than the binocular shape itself. These appendages also link to form subjective contours in front of the binocular shape or amodal completions behind it. These and other discoveries by von Szily, made before 1921, anticipate a number of modern findings.

Pharmacomanipulation of HSV-1 induced chorioretinitis in mice.

In the von Szily mouse model, intracameral inoculation of herpes simplex virus type-1 (HSV-1) results in inflammation of the ipsilateral anterior segment with relative chorioretinal sparing and destructive contralateral chorioretinitis. We studied the effect of the systemic antiviral agent acyclovir (ACV) and anti-HSV-1 antibody therapy in this model. Contralateral chorioretinitis developed in none of the 18 mice receiving ACV from post-inoculation day (pid) 1 (p < 0.0001), in 6 of 10 (60%) mice when treatment was delayed until pid 7 (p = 0.40) and in 14 of 18 (77%) controls. Contralateral disease developed in 8 of 16 (50%) mice that received anti-HSV-1 antibody from pid 1 (p = 0.02), in 13 of 16 (81%) treated from pid 5 (p = 0.64), in 7 of 8 (87.5%) treated from pid 7 (p = 1.0) and in 17 of 20 (85%) controls. We conclude that early treatment with ACV or anti-HSV-1 antibody reduces the incidence of contralateral chorioretinitis in mice.

Dominant vererbbare Pupillarpigmentzysten - Eine Verlaufsbeobachtung

In 1969 Meyer described in this journal a family suffering from multiple congenital pigmented pupillary cysts with dominant mode of inheritance. The therapy--total iridectomy and photocoagulation of the cysts--resulted in only a temporary improvement in visual acuity. The cysts were between 1.5 and 5.0 mm in diameter. The present author recently examined a member of this family with severe contusion of the left eyeball. The trauma had evidently opened the residual embryonal ring sinus of the fetal iris system (von Szily). While the traumatic mydriasis persisted, the cysts did not refill.

Herpes Simplex Virus Type 1: A Cause of the Acute Retinal Necrosis Syndrome

The authors have isolated herpes simplex virus type 1 (HSV-1) from the vitreous of two patients with acute retinal necrosis. Clinical and laboratory data suggest that one case represented a primary HSV-1 infection, whereas the other case appeared to be a recurrent HSV-1 infection. In the primary case, changes on magnetic resonance imaging (MRI) suggest spread of the virus posteriorly to both optic tracts and the lateral geniculate ganglia. This case shares many features with the “von Szily” experimental model for HSV retinitis in the mouse.

Pilots through 125 years of ophthalmologic science and practice. Aurel von Szily (1880-1945)

Pilots through 125 years of ophthalmologic science and practice. Aurel von Szily (1880-1945)

Routes of viral spread in the von Szily model of herpes simplex virus retinopathy.

Intraocular inoculation of herpes simplex virus type 1 (HSV-1) in one eye of rabbits results in encephalitis and contralateral necrotizing viral retinopathy. The effects of viral inoculation site and optic nerve (ON) transection on the spread of virus to the brain and contralateral eye in this model were investigated. A surgical technique was developed for transection of the retrobulbar optic nerve posterior to the entrance of the central retinal vessels. HSV-1 was inoculated into the AC or vitreous of one eye in normal rabbits and in rabbits with one ON transected, either ipsilateral or contralateral to the side of inoculation. Animals were followed clinically for signs of disease. Encephalitis and contralateral retinopathy (CR) occurred following both AC and vitreous inoculation of virus, although CR developed later in AC-inoculated rabbits. Ipsilateral retinopathy (IR) developed in 83% of vitreous-inoculated rabbits, but in only 5% of AC-inoculated animals. IR developed 8 days after the onset of CR in the AC-inoculated group. ON transection on the side of virus inoculation prevented development of CR only in vitreous-inoculated rabbits. ON transection on the side opposite virus inoculation prevented CR regardless of the site of inoculation. These findings suggest that HSV-1 can leave the inoculated eye by multiple routes depending on the site of virus inoculation, but that virus reaches the retina of the contralateral eye via the optic nerve.

Retrobulbar administration of steroids in herpes simplex uveitis. Efficacy of treatment in rabbits.

Efficacy of retrobulbar injections of dexamethasone on the von Szily model of herpes simplex chorioretinitis was tested in rabbits. Herpesvirus hominis was injected into the anterior chamber of one eye of 45 rabbits. In each, a uveitis developed in the injected eye. In 36 animals a chorioretinitis appeared 7 to 12 days later in the uninoculated eye. Retrobulbar steroid or placebo therapy was begun in matched animals after clinical signs of posterior chorioretinitis appeared. Eyes were examined daily by an observer not informed of the nature of the treatment. Clinical changes were correlated with photographs, viral titrations, and histologic examinations. A definite anti-inflammatory effect was observed during a short course of retrobulbar steroid therapy, although the final outcome was not altered. This short-term clinical improvement occurred without any significant increase in virus multiplication.

Light and electron microscopic studies of the marginal sinus (v. Szily) in the developing human eye.

In an investigation of the iris of 54 human embryos/fetuses it was not possible to observe the sinus of von Szily—also called the marginal sinus—in well-fixed material, whereas it was often noticed in material with inadequate fixation.

Corneal lesions in myotonic dystrophy.

Myotonic dystrophy is a disorder ofparticular interest to ophthalmologists since some degree of cataract is almost universal and being manifest early in the course of the disease may first bring the patient to seek medical advice. Other ocular signs include ptosis, blepharitis, extraocular muscle palsies, macular or more widespread retinal disturbance, and (rarely) corneal lesions (Junge, I966). Corneal lesions were first described by von Szily (i 9I8) and other case reports have appeared from time to time (Maillard, I926; Birnbacher, 1927; Vena Rodriguez, 1963; Calmettes, Geraud, and Deodati, I 964). Several workers studying ocular involvement in a large series of patients with myotonic dystrophy have also reported corneal lesions (Klein, in I 958; Pendefunda, Cernea, and Dobrescu, I 964; Junge, I 966; Burian and Burns, 1967) . The following case is that of a patient with established myotonic dystrophy whose presenting symptoms were due to corneal lesions which progressed to such a degree as to require keratoplasty.

Spontaneous nonpigmented iris cysts.

EPITHELIAL cysts arising spontaneously in the iris are classified in two groups—intra-epithelial and stromal.¹The intra-epithelial cysts are made up of pigmented epithelium, and they are regarded as remnants of von Szily's marginal sinus of the iris that have not been obliterated.^2-3 The stromal cysts are situated within the iris stroma and are lined by nonpigmented epithelium. The latter may be multilayered and may contain goblet cells. The origin of these cysts is still controversial.^2-5Some observers hold the opinion that they arise from the surface ectoderm displaced, probably, at the time of formation of the lens vesicle.^6-8Others^9-12believe that they develop from aberrant cells from the most anterior portion of the optic vesicle whiel it is still unpigmented. The histopathologic features of such cysts excised by iridectomy have been illustrated repeatedly,^{1,7-9, 13-18}but we have found only one report describing such

Sympathectomy and immunologically induced bilateral eye reactions in the rabbit.

Introduction If a sterile foreign protein is injected into rabbit vitreous and about two weeks later the same antigen is given intravenously, an acute aseptic inflammatory reaction not only occurs in the uveal tract of the eye into which the material was previously injected but may also occur to less degree in the contralateral eye. These bilateral eye reactions have been experimentally produced and described by Woods, 1 Guillery, 2 von Szily, 3 Marchesani, 4 Seegal and Seegal, 5 Schlaegel, 6,7 Foss, 8 Schlaegel and Wilson, 9 and Schmedtje. 10,11 Different explanations have been proposed for bilateral eye reactions following the aggravation of only one eye. In the case of the experimentally produced reactions just described in the rabbit, an explanation emphasizing local tissue antibodies was offered by Foss. 8 He suggested that the original antigen, injected intraocularly, not only sensitizes the cells of the eye into which the material

Experimental studies on early lens changes after roentgen irradiation. I. Morphological and cytochemical changes.

SINCE it was first shown that roentgen ray cataract could be produced experimentally in mature animals (in guinea pigs by Bossuet, 1 in 1909, and in rabbits by Aulamo, 2 in 1928), the question of the primary site of radiation injury to the lens and the pathogenesis of the lesion have been discussed by many investigators on the basis of experimental and clinical evidence and have been studied systematically by a few. Most investigators have favored the concept of direct radiation damage to the lens (Bossuet, 1 Politzer, 3 Rohrschneider, 4 Peter, 5 Grzedzielski, 6 Okusawa, 7 Leinfelder and Kerr, 8 Goldmann and Liechti, 9 von Szily, 10 Kruckmann, 11 Poppe 12 ), whereas others, on the basis of the clinical characteristics of the cataract, have preferred the hypothesis of an indirect radiation effect induced by damage to the structures of the ciliary processes, with consequent nutritional disturbance of the lens

Chronic Choroiditis Produced with Streptococcus Viridans and Streptococcus Haemolyticus in Normal and in Immunized Rabbits

Received for publication, August 28, 1941. Aided by grants from the John and Mary R. Markle Foundation, the Ophthalmological Foundation, and the Ettinger Fund. 1. Koske, F.: Arb. a. d. k. Gsndhtsamte. 22: 411, 1905; Stock, W.: Beitr. z. path. Anat. u. z. allg. Path. 43: 470, 1908; Guillery, H.: (1) Arch, f. Augenh. 48: 242, 1911; 78: 11, 1914; Dold, H. and Rados, A.: Deutsche med. Wchnschr. 39: 1492, 1913; Rosenow, E. C: J. Infect. Dis. 17: 403, 1915; Woods, A. C: Arch. Ophth. 45: 451, 1916; Irons, E. E. Brown, E. V. L., and Nadler, W. H.: J. Infect. Dis. 18: 315, 1916; Meisser, J. G., and Gardner, B. S.: J. Am. Dent. A. 9: 578. 1922; Haden, R. L.: Arch. Int. Med. 32: 828, 1923; Benedict, W. L., von Lackum, W. H. and Nickel, A. C: Arch. Ophth. 56: 116, 1927; Brown, A. L. and Dummer, C: Arch. Ophth. 2: 573, 1929; Berens, C, Nilson, E. L. and Chapman, G. H., Am. J. Ophth. 19:1060,1936. 2. Berens, C, Angevine, D. M., Guy, L. and Rothbard, S.: Am. J. Ophth. 21: 1315, 1938; Brown, A. L.: Arch. Ophth. 12: 730, 1934. 3. Nicholle, M. and Abt, G.: Ann. Inst. Pasteur 22: 132, 1908; Sattler, C. H.: Arch. f. Augenh. 64: 390, 1909; Kummel, R.: (1) Arch, f. Ophth. 77: 393, 1910; 79: 528, 1911; Seegal, D. and Seegal, B. C, Proc. Soc. Exper. Biol. 8c Med. 27: 390, 1930; Mott, E. and Kesten, H. D.: J. Exper. Med. 53: 815, 1931; Thompson, R., Gallardo, E. and Khorazo, D.: Am. J. Ophth. 19: 852, 1936; MacLean, A. L.: Tr. Am. Ophth. Soc. 34: 324, 1936. immunological reactions in connection with local immunity. The pathological lesions have usually been characterized by an acute inflammatory process in the form of an iridocyclitis, or less frequently as an acute choroiditis, but chronic inflammatory lesions have been rare, with the exception of tuberculous uveitis.4 Von Szily,5 however, described chronic choroiditis in rabbits produced by the intravenous injection of beef uveal pigment, and after 2 weeks an injection of similar material into the vitreous of the eye. The animals were permitted to survive for 1 week after the ocular injection. Fuchs and Meller6 and Wibaut7 also described chronic choroiditis in rabbits that were first sensitized to human, cow, or horse serum by intravenous injection and after 2 weeks were given an intraocular injection of the same antigen. An acute inflammatory reaction of the uveal tract was noted in animals killed within 3 days; but if the animals were permitted to live longer, the inflammatory reaction became chronic in many instances.

OCULAR REACTIONS TO DIPHTHEROID BACILLI

In 1929 Marchesani 1 reported the results of experimental work done with a strain of Bacillus subtilis which he had isolated from the sympathogenic eye of a person with mild sympathetic ophthalmia. By repeated intraocular injections of this organism into one eye of a number of rabbits he produced choroiditis in the opposite eye. The lesion consisted of a focal accumulation of mononuclear cells in the choroid. He expressed the belief that the choroiditis thus produced was dependent on paired organ sensitivity of the two eyes which allowed the antigen to localize in the second eye. At a later date 2 he repeated these experiments with Bacillus xerosis and Staphylococcus albus and apparently obtained similar results. Iga 3 and von Szily 4 repeated these experiments with B. subtilis and showed that a similar metastatic choroiditis could be produced by repeated intravenous and intraorbital injections of this organism. They concluded that