Functional and morphologic comparison of two methods to produce transient retinal ischemia in the rat.

OBJECTIVES: Much of our knowledge of the pathophysiology of retinal ischemic injury is from a multitude of studies that use in vitro or in vivo animal models of retinal ischemia followed by reperfusion. The objective of this study was to compare histopathologic and electrophysiologic (electroretinography) parameters using two different models of transient retinal ischemia: high intraocular pressure (HIOP) and suture ligation of the optic nerve (SL). METHODS: Transient retinal ischemia was induced using the HIOP model or the SL model in the Sprague-Dawley rat for either 30 or 60 minutes. Histopathologic outcome was determined at 1 and 7 days after ischemia. In addition, electroretinography (ERG) was performed at 2 hours, I day, 3 days, and 7 days after ischemia. RESULTS: At 1 and 7 days after 30 minutes of ischemia, there were no significant histopathologic abnormalities in the retina with either model, except for a slight decrease of the cell count in the ganglion cell layer (GCL) with the SL method. After 60 minutes of ischemia, there was significant thinning of the inner retina. There was a significant early dropout of cells at 1 day in the inner nuclear layer (INL) in the HIOP method compared to the SL method where the dropout was delayed and gradually progressive. Dropout of cells in the GCL was early (I day) and gradually progressive in both models but more severe in HIOP than SL. There was a significant decrease in the ERG b-wave amplitudes as early as 2 hours after both 30 and 60 minutes of ischemia compared to preischemic baselines. CONCLUSIONS: The degree of retinal injury after transient retinal ischemia was more severe at 1 day after reperfusion in the HIOP method compared to the SL method but was similar at 7 days in both models. Furthermore, our data suggests that functional assessment of ischemic damage by electroretinography may be a more sensitive parameter than conventional histopathologic quantification. The timing of either measurement relative to the ischemic stimulus is critical because histologic measurements performed too early after ischemia may underestimate the degree of injury.

Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia.

Emerging evidence supports an important role for caspases in neuronal death following ischemia-reperfusion injury. This study assessed whether cell specific caspases participate in neuronal degeneration and whether caspase inhibition provides neuroprotection following transient retinal ischemia. We utilized a model of transient global retinal ischemia. The spatial and temporal pattern of the active forms of caspase 1, 2 and 3 expression was determined in retinal neurons following ischemic injury. Double-labeling with cell-specific markers identified which cells were expressing different caspases. In separate experiments, animals received various caspase inhibitors before the induction of ischemia. Sixty minutes of ischemia resulted in a delayed, selective neuronal death of the inner retinal layers at 7 days. Expression of caspase 1 was not detected at any time point. Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons. Caspase 3 also peaked at 24 h in both the inner nuclear and outer nuclear layers and was predominantly expressed in photoreceptor cells and to a lesser extent in amacrine neurons. The pan caspase inhibitor, Boc-aspartyl fmk, or an antisense oligonucleotide inhibitor of caspase 2 led to significant histopathologic and functional improvement (electroretinogram) at 7 days. No protection was found with the caspase 1 selective inhibitor, Y-vad fmk. These observations suggest that ischemia-reperfusion injury activates different caspases depending on the neuronal phenotype in the retina and caspase inhibition leads to both histologic preservation and functional improvement. Caspases 2 and 3 may act in parallel in amacrine neurons following ischemia-reperfusion. These results in the retina may shed light on differential caspase specificity in global cerebral ischemia.

Sarcomatous transformation of the orbit in a patient with Paget's disease.

OBJECTIVE: To report the clinical and pathologic features of sarcomatous transformation of the skull with involvement of the orbit, in Paget's disease. DESIGN: Interventional case report. PARTICIPANT: An 83-year-old woman with Paget's disease who experienced progressive proptosis of the left eye. INTERVENTION: Fine-needle aspiration biopsy of the orbital mass. RESULTS: Cytologic examination revealed round to oval malignant cells with wispy cytoplasm, consistent with the diagnosis of sarcoma. The patient died shortly after institution of orbital radiation therapy and systemic steroid therapy. CONCLUSIONS: Proptosis related to Paget's disease is uncommon, and only rarely is it a result of sarcomatous transformation. Sarcomatous transformation of the skull involving the orbit should be included in the differential diagnosis of progressive proptosis in patients with Paget's disease.

Ki-1-positive anaplastic large-cell lymphoma of the eyelid.

Ki-1-positive anaplastic large-cell lymphoma is an uncommon form of non-Hodgkin lymphoma. It lies within a spectrum of recently identified lymphoproliferative disorders. The entities within this spectrum share similar clinical and histopathologic characteristics that can make the diagnosis challenging. We report a case of Ki-1-positive anaplastic large-cell lymphoma involving the right upper eyelid of a 45-year-old woman and describe the light microscopic, immunohistochemical, and ultrastructural features. A pertinent review of the English-language literature is presented.

Calcified scleral plaques imaged on orbital computed tomography.

PURPOSE: To identify calcified scleral plaques on orbital computed tomography. METHODS: We identified all orbital computed tomographic scans at one center from January 1, 1994, through December 31, 1994. Orbital computed tomographic scans of 145 patients were reviewed to determine the presence or absence of the typical appearance of calcified scleral plaques on film. RESULTS: Of the 145 scans reviewed, nine (6.2%) demonstrated calcified scleral plaques. Seven (22.6%) of 31 scans obtained on patients older than 70 years demonstrated calcified scleral plaques. CONCLUSIONS: Calcified plaques of the sclera commonly appear on orbital computed tomographic scans, especially in elderly patients. This entity should be included in the differential diagnosis of ocular calcifications. Familiarity with the computed tomographic findings of calcified scleral plaques may help ophthalmologists and radiologists distinguish them from intrascleral metallic foreign bodies.

Differing roles of adenosine receptor subtypes in retinal ischemia-reperfusion injury in the rat.

Adenosine has been shown to be a major component of the retina's endogenous reaction to ischemia. In earlier studies, the significant changes in adenosine concentration that occur during ischemia and the ensuing reperfusion period were documented. While previous studies have shown that adenosine is a mediator of the changes in blood flow that occur in response to ischemia, hypoxia, and hypoglycemia in the retina, little is known about other functional effects that result from these changes in adenosine concentration. Accordingly, the influence of adenosine receptor blockade on the functional and histological outcome following ischemia in rats was examined. Specific antagonists of the adenosine A1 and A2a receptors were injected systemically, prior to ischemia of either 5, 30, or 60 min. The recovery of the electroretinogram a and b waves was followed for up to 7 days after ischemia, and retinal structure was examined by light microscopy. The adenosine A1 receptor antagonist DPCPX attenuated recovery after retinal ischemia of either 5 or 30 min, while the A2a receptor antagonist CSC dramatically protected retinal function and structure even with ischemia lasting up to 60 min. It was concluded that blockade of the A2a receptor, possibly combined with stimulation of the A1 receptor, may represent a potential new strategy for the prevention of ischemic damage in the retina.

Sinus histiocytosis with massive lymphadenopathy involving the orbit: reversal of compressive optic neuropathy after chemotherapy.

A 38-year-old woman from Antigua had compressive optic neuropathy of the right eye caused by orbital involvement with sinus histiocytosis. There was also nasal sinus involvement and massive cervical lymphadenopathy resulting in radiographic compression of the airway and carotid sheath. Because of the compressive optic neuropathy and threat to the airway and carotid perfusion, the patient underwent a 6-month chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone. After chemotherapy, the visual dysfunction resolved in correlation with diminution of the orbital mass, and marked regression of the cervical lymphadenopathy. This case demonstrates the potential efficacy of chemotherapy in the treatment of compressive optic neuropathy in cases of orbital sinus histiocytosis with massive lymphadenopathy.

Sinus histiocytosis with massive lymphadenopathy involving the orbit: reversal of compressive optic neuropathy after chemotherapy

A 38-year-old woman from Antigua had compressive optic neuropathy of the right eye caused by orbital involvement with sinus histiocytosis. There was also nasal sinus involvement and massive cervical lymphadenopathy resulting in radiographic compression of the airway and carotid sheath. Because of the compressive optic neuropathy and threat to the airway and carotid perfusion, the patient underwent a 6-month chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone. After chemotherapy, the visual dysfunction resolved in correlation with diminution of the orbital mass, and marked regression of the cervical lymphadenopathy. This case demonstrates the potential efficacy of chemotherapy in the treatment of compressive optic neuropathy in cases of orbital sinus histiocytosis with massive lymphadenopathy (Au)

The role of the p53 protein in the selective vulnerability of the inner retina to transient ischemia.

PURPOSE: To determine whether the p53 protein plays a role in the selective vulnerability of the inner retina to transient ischemia. METHODS: Transient retinal ischemia was induced using a high intraocular pressure (HIOP) model in the Sprague-Dawley rat for 60 minutes. Histopathologic outcome was determined 7 days after ischemia. In addition, analysis for evidence for apoptosis (TdT-dUTP terminal nick-end label [TUNEL] staining) and p53 protein expression (immunohistochemistry) was performed at several points during the reperfusion period. In a separate set of experiments, wild-type mice and two groups of transgenic mice, one homozygous and the other heterozygous for the p53 null gene, were also subjected to HIOP for 60 minutes, and histopathology was performed 7 days later. RESULTS: At 7 days subsequent to 60 minutes of ischemia in the rat, there was marked thinning of the inner retinal layers. There were scattered TUNEL-positive cells within the inner retina, peaking at 24 to 48 hours and persisting for at least 7 days. p53 immunochemistry demonstrated elevated protein levels within the inner retina; this finding peaked at 24 to 48 hours but was no longer present at 4 days after ischemia. TUNEL staining of the inner retina of the mouse was most prominent 24 hours subsequent to ischemia but persisted at 48 hours. Seven days subsequent to 60 minutes of ischemia in the wild-type and transgenic mice, histopathologic evaluation demonstrated preservation of the retinal histoarchitecture in the heterozygous group compared with the wild-type or homozygous animals. CONCLUSIONS: These data further support the hypothesis that the delayed cell death that occurs after transient retinal ischemia is, in part, apoptotic. In addition, they suggest a role for the p53 protein in the selective vulnerability of the inner retina to transient ischemia. p53 protein may be a target for future therapeutic agents in the treatment of disorders of the retina where ischemia plays a pathogenetic role.

Lymphomatoid granulomatosis presenting as an isolated unilateral optic neuropathy. A clinicopathologic report.

A 41-year-old woman presented with a unilateral optic neuropathy that progressed to no light perception 7 weeks later. The patient was hospitalized for progressive dyspnea; respiratory failure ensued and the patient died 10 days after admission. Antemortem pulmonary biopsies and the results of necropsy revealed lymphomatoid granulomatosis with extensive involvement of the lungs and left optic nerve. This is the first case report of lymphomatoid granulomatosis presenting as a unilateral optic neuropathy.

Preconditioning provides complete protection against retinal ischemic injury in rats.

PURPOSE: The objectives of this study were to examine whether preconditioning can decrease ischemic damage to the retina, by electroretinographic assessment of visual function and by histologic examination of retinal structure; to investigate the time course of the effectiveness of preconditioning; and to determine whether protein synthesis is involved. METHODS: Retinal ischemia was produced for 60 minutes in anesthetized Sprague-Dawley rats. Recovery after ischemia was measured by electroretinography for a maximum period of 7 days. Retinal sections that were sliced 1 micron thick were examined 7 days after ischemia. Retinal ischemia for 5 minutes constituted the preconditioning stimulus. To assess the time course of preconditioning, animals first underwent preconditioning and then 60 minutes of ischemia 1, 24, 72, or 168 hours later; or they underwent a 5-minute sham experiment and 60 minutes of ischemia 24 hours later. An additional group of rats received 0.4 mg/kg cycloheximide, the protein synthesis inhibitor, intraperitoneally before preconditioning and underwent 60 minutes of ischemia 24 hours later. RESULTS: In contrast to the nonpreconditioned rats, preconditioned rats had complete recovery of the a- and b-waves compared with preischemic baseline amplitudes, and ischemia-induced histologic damage was completely prevented when preconditioning was performed 24 or 72 hours (but not 168 hours) before ischemia. Separation of preconditioning and 60 minutes of ischemia by 1 hour caused an even greater impairment of functional retinal recovery compared with that seen in sham-preconditioned rats. Severe histologic damage was also noted. Block of protein synthesis by cycloheximide completely attenuated the protective effect of preconditioning. CONCLUSIONS: Preconditioning induces profound retinal tolerance to ischemia in vivo. The absence of a protective effect of preconditioning when there was a 1-hour or a 168-hour separation between the preconditioning stimulus and ischemia and the inhibition of preconditioning by cycloheximide support the hypothesis that a transient change in protein expression is necessary to provide this protection.

An immortalized cell culture from a malignant mixed tumor of the lacrimal gland.

Tumor cells from a malignant mixed tumor of the lacrimal gland were maintained in tissue culture for more than 55 generations. Comparative immunohistochemical analysis was performed on whole tumor sections and on the tumor cell culture to define the origin of the cells in culture. The cultured cells expressed cytokeratin, smooth-muscle actin, S-100 protein, and vimentin and were negative for glial fibrillary acidic protein. Tumor sections expressed cytokeratin but were negative for muscle-specific actin, vimentin, and glial fibrillary acidic protein. Through tissue culture studies of salivary gland epithelial neoplasias, which are very similar to lacrimal gland epithelial neoplasias, pluripotential stem cells have been identified. Similar tissue culture analysis of lacrimal gland epithelial neoplasms can be a valuable tool for studying the origin of these uncommon tumors.

Advancing wave-like epitheliopathy. Clinical features and treatment.

PURPOSE: The purpose of the study is to describe an entity referred to as advancing wave-like epitheliopathy and successful treatment of this keratopathy with 1% silver nitrate solution. METHODS: Eleven eyes of 7 patients were identified with advancing wave-like epitheliopathy. A thorough history and physical examination was performed on each patient, and attempts were made to identify the cause for the epitheliopathy. Six eyes with associated visual loss due to the epitheliopathy involving the visual axis were treated with 1% silver nitrate solution to the superior conjunctival limbus. RESULTS: Possible causes for the epitheliopathy included use of antiglaucomatous medications or contact lens care solutions (6 of 11 eyes), soft contact lens wear (4 of 11 eyes), a history of ocular surgery (3 of 11 eyes), or the presence of an underlying dermatologic or inflammatory disorder (3 of 11 eyes). All patients treated with 1% silver nitrate solution (6 of 6 eyes) experienced resolution of their symptoms with either complete or partial resolution of the epitheliopathy. CONCLUSIONS: Advancing wave-like epitheliopathy is a keratopathy characterized by centripetally advancing waves of coarse, irregular epithelium arising from the superior limbus. The cause appears to be multifactorial. Symptoms include ocular redness, irritation, and a decrease in visual acuity if the visual axis is involved. Application of 1% silver nitrate solution to the superior limbus is well tolerated and effective in treating this condition.

Apoptosis in the retina.

An enormous interest in cell death over the past several years has catapulted apoptosis to the forefront of scientific research. Apoptosis has been found to mediate cell deletion in tissue homeostasis, embryological development and immunologic function. It also occurs in pathological situations including cancer and AIDS, and is implicated in a variety of ocular diseases. This review presents a brief history of apoptosis and the proper evidence needed in order to claim that apoptosis is taking place. A summary and critique of important investigations concerning the genetic and biochemical regulation of apoptosis is presented, as well as a focus on other studies drawing a connection between apoptosis and cell death in physiological and pathological situations.

Retinal ischemia leads to apoptosis which is ameliorated by aurintricarboxylic acid.

Transient retinal ischemia results in a delayed cell death of the inner retinal layers. This study demonstrates that this ischemic cell death occurs, at least in part, through apoptosis. The general endonuclease inhibitor, aurintricarboxylic acid, protected rat retinal cells from ischemic cell damage when administered before the onset of ischemia and, more importantly, when administered 6 hr after the insult. Thus, the demonstration that transient retinal ischemia results in cell damage as a result of apoptosis opens new therapeutic strategies aimed at lessening retinal damage as a result of this process.

Ischemia induces significant changes in purine nucleoside concentration in the retina-choroid in rats.

Adenosine, produced from the decomposition of adenosine triphosphate, is believed to provide protective effects during ischemia. On the other hand, adenosine metabolites may serve as precursors for oxygen free radical formation. The time course of formation of adenosine and its purine metabolites was studied during retinal ischemia in rats. Concentrations of adenosine and its purine nucleoside metabolites inosine, hypoxanthine, and xanthine in the retina-choroid of ketamine/xylazine-anesthetized rats were measured during retinal ischemia using high performance liquid chromatography. Quantitative measurements were made possible in the small tissue mass through the use of internal standards. Ischemia was induced by ligation of the central retinal artery. In each rat, one eye was ischemic while the other served as a non-ischemic control. Eyes were frozen in situ at 1, 5, 10, 20, 30, 60, and 120 min of ischemia. The retina-choroid was then removed from the frozen eyes and analysed. Significant increases in the concentrations of adenosine, inosine, and hypoxanthine in ischemic compared to control retina-choroid were detectable within 1 to 5 min of the onset of ischemia, and within 10 min for xanthine. Increase in adenosine concentration in ischemic relative to control retina-choroid plateaued at 30 min of ischemia, while inosine and hypoxanthine concentrations increased continuously. The increase in xanthine concentration was exponential throughout the measurement period. This study documented the time-related changes in purine nucleoside concentration during ischemia. Prolonged ischemia results in ongoing production of xanthine, which by serving as a precursor for oxygen free radical formation, could be a pathogenic factor in prolonged retinal ischemia.

Extralimbal Trantas' dots: a clinicopathologic report.

We report a 29-year-old man with a recurrent history of conjunctival redness, itching, and tearing, who was first seen with transient, multiple Trantas' dots bilaterally on the bulbar, forniceal, and palpebral conjunctiva. Conjunctival scrapings and biopsy revealed histopathologic features consistent with Trantas' dots. To our knowledge, this is the first case report that clearly documents the occurrence of extralimbal Trantas' dots on the bulbar, forniceal, and palpebral conjunctiva.

Acinic cell carcinoma of the lacrimal gland.

An 18-year-old woman underwent exenteration of the right orbit for tumor recurrence 3 years subsequent to external-beam irradiation for a lacrimal gland tumor diagnosed as an "adenocarcinoma." Light microscopy of the exenteration specimen revealed an acinic cell carcinoma of the lacrimal gland, with a predominant microcystic (latticelike) pattern of growth. Cytoplasmic vacuoles and the secretion within the microcysts stained positive with periodic acid-Schiff with and without alpha-amylase, alcian blue (at a pH of 2.5), mucicarmine, and colloidal iron with and without hyaluronidase. This histochemical staining for epithelial mucins supports the theory that the lacrimal gland, although serous in type, may also function as a modified mucus gland. There was cytoplasmic immunopositivity for keratin (CAM 5.2, KAE 1-3); immunostaining for vasoactive intestinal polypeptide was negative. Electron microscopy disclosed undifferentiated features of intercalated duct cells. We speculate that the lack of immunoreactivity for vasoactive intestinal polypeptide may be correlated with the predominantly undifferentiated intercalated duct cell features observed ultrastructurally.