SD-OCT to distinguish papilledema from pseudopapilledema.

CASES REPORT: Two patients presented with headache and bilateral papillary edema. Patient 1 was found to have a papilledema (P) with intracranial pressure of 32cmH2O. Patient 2 was found to have a migraine with a pseudopapilledema (PP) (optic nerve head drusen). SD-OCT was used to image the optic disc, subretinal hyporeflective space (SHS), and alpha-angle (Aα). DISCUSSION: Optic disc SD-OCT may be useful for differentiating disc morphology in P and PP. The area of the SHS and the Aα were higher in the P patient than in the patient with PP.

Rat optic nerve head anatomy within 3D histomorphometric reconstructions of normal control eyes.

The purpose of this study is to three-dimensionally (3D) characterize the principal macroscopic and microscopic relationships within the rat optic nerve head (ONH) and quantify them in normal control eyes. Perfusion-fixed, trephinated ONH from 8 normal control eyes of 8 Brown Norway Rats were 3D histomorphometrically reconstructed, visualized, delineated and parameterized. The rat ONH consists of 2 scleral openings, (a superior neurovascular and inferior arterial) separated by a thin connective tissue strip we have termed the "scleral sling". Within the superior opening, the nerve abuts a prominent extension of Bruch's Membrane (BM) superiorly and is surrounded by a vascular plexus, as it passes through the sclera, that is a continuous from the choroid into and through the dural sheath and contains the central retinal vein (CRV), (inferiorly). The inferior scleral opening contains the central retinal artery and three long posterior ciliary arteries which obliquely pass through the sclera to obtain the choroid. Bruch's Membrane Opening (BMO) is irregular and vertically elongated, enclosing the nerve (superiorly) and CRV and CRA (inferiorly). Overall mean BMO Depth, BMO Area, Choroidal Thickness and peripapillary Scleral Thickness were 29 µm, 56.5 × 10(3) µm(2), 57 µm and 104 µm respectively. Mean anterior scleral canal opening (ASCO) and posterior scleral canal opening (PSCO) radii were 201 ± 15 µm and 204 ± 16 µm, respectively. Mean optic nerve area at the ASCO and PSCO were 46.3 × 10(3)±4.4 × 10(3) µm(2) and 44.1 × 10(3)±4.5 × 10(3) µm(2) respectively. In conclusion, the 3D complexity of the rat ONH and the extent to which it differs from the primate have been under-appreciated within previous 2D studies. Properly understood, these anatomic differences may provide new insights into the relative susceptibilities of the rat and primate ONH to elevated intraocular pressure.

The role of TGF-ß in the pathogenesis of primary open-angle glaucoma.

Transforming growth factor-ß2 (TGF-ß2) is found in increasing amounts in aqueous humor and reactive optic nerve astrocytes of patients with primary open-angle glaucoma (POAG), a major cause of blindness worldwide. The available data strongly indicate that TGF-ß2 is a key player contributing to the structural changes in the extracellular matrix (ECM) of the trabecular meshwork and optic nerve head as characteristically seen in POAG. The changes involve an induction in the expression of various ECM molecules and are remarkably similar in trabecular meshwork cells and optic nerve head astrocytes. The ECM changes in the trabecular meshwork most probably play a role in the increase of aqueous humor outflow resistance causing higher intraocular pressure (IOP). In the optic nerve head, TGF-ß2-induced changes might contribute to deformation of the optic nerve axons causing impairment of axonal transport and neurotrophic supply and leading to their continuous degeneration. The increase in IOP further adds mechanical stress and strain to optic nerve axons and accelerates degenerative changes. In addition, high IOP might induce the expression of activated TGF-ß1 in trabecular meshwork cells and optic nerve head astrocytes; this again might significantly lead to the progress of axonal degeneration. The action of TGF-ß2 in POAG is largely mediated through the connective tissue growth factor, whereas the activities of TGF-ß1 and -ß2 are modulated by the blocking effects of bone morphogenetic protein-4 (BMP-4) and BMP-7, by gremlin that inhibits BMP signaling and by several species of microRNAs.

Retinal and optic nerve head pathology in Susac's syndrome.

PURPOSE: This article describes the first retinal histopathologic findings in a patient with Susac's syndrome (SS). DESIGN: Observational case report. PARTICIPANT: A 51-year-old white woman diagnosed with SS. METHODS: Eyes from a 51-year-old white woman diagnosed with SS were obtained at autopsy. One retina was dissected and processed for adenosine diphosphatase (ADPase) flat embedding. Selected areas were processed further for transmission electron microscopy. MAIN OUTCOME MEASURES: Histopathologic examination using ADPase flat-embedding technique. RESULTS: There were vaso-occlusive changes in the retinal periphery resulting in small areas of capillary dropout. Cross-sections demonstrated serous filled spaces between the retinal blood vessels and the internal limiting membrane. Lumens adjacent to these spaces appeared compressed and sometimes closed, but without thrombosis. Decreased ADPase activity in some peripheral blood vessels suggested endothelial cell dysfunction and vaso-occlusion. In the optic nerve head, numerous corpora amylacea were observed in the vicinity of capillaries with thickened walls and narrow lumens. Transmission electron microscopy demonstrated thickened and amorphous vascular basal lamina and open endothelial cell junctions in some retinal blood vessels. CONCLUSIONS: The serous deposits with compression of retinal vessel lumens observed histologically probably represent the so-called string of pearls described clinically in SS. Chronic extension of these serous deposits along the vessel wall possibly are the cause of retinal arterial wall plaques as described by Gass and other investigators. In the optic nerve head, corpora amylacea are probably a result of microinfarcts resulting from optic nerve head capillary angiopathy. Accumulation of amorphous material in the basal lamina, loss of viable endothelial cells, and capillary dropout suggest that SS may be an endotheliopathy.

Astrocytes in glaucomatous optic neuropathy.

Glaucoma, the second most prevalent cause of blindness worldwide, is a degenerative disease characterized by loss of vision due to loss of retinal ganglion cells. There is no cure for glaucoma, but early intervention with drugs and/or surgery may slow or halt loss of vision. Increased intraocular pressure (IOP), age, and genetic background are the leading risk factors for glaucoma. Our laboratory and other investigators have provided evidence that astrocytes are the cells responsible for many pathological changes in the glaucomatous optic nerve head (ONH). Over several years, in vivo and in vitro techniques characterized the changes in quiescent astrocytes that lead to the reactive phenotype in glaucoma. Reactive astrocytes alter the homeostasis and integrity of the neural and connective tissues in the ONH of human and experimental glaucoma in monkeys. During the transition of quiescent astrocytes to the reactive phenotype altered astrocyte homeostatic functions such as cell-cell communication, migration, growth factor pathway activation, and responses to oxidative stress may impact pathological changes in POAG. Our data also suggests that the creation of a non-supportive environment for the survival of RGC axons through remodeling of the ONH by reactive astrocytes leads to progression of glaucomatous optic neuropathy.

Thermal injury induces heat shock protein in the optic nerve head in vivo.

PURPOSE: To investigate the induction of heat shock protein (Hsp)70 in the optic nerve head by localized laser application in transpupillary thermotherapy (TTT). METHODS: TTT was performed on the right eye of Norwegian brown rats with an 810-nm diode laser installed on a slit lamp biomicroscope. The laser was aimed at the center of the optic nerve head with a 50-microm spot size. Various exposures (range, 60-200 mW) were used with an exposure duration of 60 seconds, and the various exposure durations (range, 1-5 minutes) were used with a power of 100 mW. Twenty hours after laser irradiation, immunohistochemical staining and Western blot analyses were performed. For morphologic analysis of the optic nerve head, confocal scanning laser ophthalmoscopy and scanning electron microscopy were performed. RESULTS: In the control eyes, Hsp70 was detected minimally in the optic nerve tissues by immunohistochemistry. After TTT, Hsp70 in the optic nerve tissue was induced more than in the control eyes. By Western blot, Hsp70 expression was found to increase progressively after TTT as the power was increased, but it also decreased slightly at powers >140 mW. The optimal setting of TTT without tissue damage was determined to be 100 mW for 60 seconds. CONCLUSIONS: Transpupillary laser irradiation of the optic nerve head induces Hsp70 expression. This result can be applied to the neuroprotective experiments in glaucoma by enhancement of a natural cytoprotective stress response.

Adaptive optics ophthalmoscopy: results and applications.

PURPOSE: The living human eye's optical aberrations set a limit to retinal imaging in the clinical setting. Progress in the field of adaptive optics has offered unique solutions to this problem. The purpose of this review is to summarize the most recent advances in adaptive optics ophthalmoscopy. METHODS: Adaptive optics technology has been combined with flood illumination imaging, confocal scanning laser ophthalmoscopy, and optical coherence tomography for the high resolution imaging of the retina. RESULTS: The advent of adaptive optics technology has provided the technical platform for the compensation of the eye's aberration and made possible the observation of single cones, small capillaries, nerve fibers, and leukocyte dynamics as well as the ultrastructure of the optic nerve head lamina cribrosa in vivo. CONCLUSIONS: Detailed imaging of retinal infrastructure provides valuable information for the study of retinal physiology and pathology.

Vascular changes associated with chorioretinal and optic nerve colobomas in rats (Crj: CD(SD), IGS).

OBJECTIVE: Three female adult rats (Crj: CD(SD) IGS) with colobomatous anomalies were investigated. MATERIALS AND METHODS: The microvascular changes of the coloboma were studied using the techniques of fluorescein angiography, histology and scanning electron microscopy (SEM) of vascular corrosion casts. RESULTS: Fluorescein angiography revealed the pits of the optic disk as a dark hole with some abnormalities in vessel arrangement. Light microscopy confirmed the presence of attenuated lamina cribrosa, retinal dysplasia and marked dilation of the retinal veins. SEM revealed that the optic disk coloboma formed a crater-like pit and that central retinal vessels ran a tortuous course along the bottom and side of the crater. Capillaries in the optic nerve head were missing in the affected area. The central retinal veins were thick and had various changes such as strangulation, rough surface structures, mural voids and evaginations, which represent loss of integrity of the vascular wall. CONCLUSIONS: These vascular changes that are associated with colobomatous anomalies may impede the retinal circulation and be responsible for the fluctuating fluorescein pattern during fluorangiogram of affected animals. The lesions of the vascular wall may increase the subretinal fluid due to the leakage of fluid, thus causing the maculopathy or serous retinopathy, which is frequently associated with posterior pole coloboma.

Transforming growth factor-beta-regulated gene transcription and protein expression in human GFAP-negative lamina cribrosa cells.

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy, which is a major cause of worldwide visual impairment and blindness. Pathological hallmarks of the glaucomatous optic nerve head (ONH) include retinal ganglion cell axon loss and extracellular matrix (ECM) remodeling of the lamina cribrosa layer. Transforming growth factor-beta (TGF-beta) is an important pro-fibrotic modulator of ECM metabolism, whose levels are elevated in human POAG lamina cribrosa tissue compared with non-glaucomatous controls. We hypothesize that in POAG, lamina cribrosa (LC) glial cells respond to elevated TGF-beta, producing a remodeled ONH ECM. Using Affymetrix microarrays, we report the first study examining the effect of TGF-beta1 on global gene expression profiles in glial fibrillary acidic acid (GFAP)-negative LC glial cells in vitro. Prominent among the differentially expressed genes were those with established fibrogenic potential, including CTGF, collagen I, elastin, thrombospondin, decorin, biglycan, and fibromodulin. Independent TaqMan and Sybr Green quantitative PCR analysis significantly validated genes involved in regulation of cell proliferation (platelet-derived growth factor [PDGF-alpha]), angiogenesis (vascular endothelial growth factor [VEGF]), ECM accumulation and degradation (CTGF, IL-11, and ADAMT-S5), and growth factor binding (ESM-1). Bioinformatic analysis of the ESM-1 promoter identified putative Smad and Runx transcription factor binding sites, and luciferase assays confirmed that TGF-beta1 drives transcription of the ESM-1 gene. TGF-beta1 induces expression and release of ECM components in LC cells, which may be important in regulating matrix remodeling in the lamina cribrosa. In disease states such as POAG, the LC cell may represent an important pro-fibrotic cell type and an attractive target for novel therapeutic strategies.

Collagen fibrillar network in the optic nerve head of normal monkey eyes and monkey eyes with laser-induced glaucoma--a scanning electron microscopic study.

PURPOSE: To examine the three-dimensional organization of collagen fibrils in the lamina cribrosa of normal monkey eyes and monkey eyes with laser-induced glaucoma. METHODS: Intraocular pressure elevation and glaucomatous optic discs were obtained in one eye of three adult monkeys by repeated applications of argon laser to the chamber angle. The monkey eyes were enucleated, and the collagen fibrillar network was investigated by scanning electron microscopy after cell maceration with 10% sodium hydroxide and conductive staining. RESULTS: In normal monkey eyes, round to oval shaped regular laminar pores through which axon bundles exited were observed in the lamina cribrosa. The straight, column-like pores or openings were formed by multilayered laminar plates that aligned vertically in parallel with the optic nerves. The surface of the laminar plates was covered by delicate, loosely arranged collagen fibrils. The inner surface of the pores was smooth, made up of well-packed collagen fibers. In glaucomatous eyes, the laminar pores were clogged by tightened collagen fibrils. The inner surface of the pores was irregular, and the pores were narrowed or distorted. CONCLUSIONS: Alterations in the three-dimensional organization of collagen fibrils were demonstrated in the optic nerve head of glaucomatous monkey eyes. The architectural changes may affect the flexibility and resilience required of the lamina cribrosa in supporting optic nerve fibers.

The ultrastructure of parapapillary chorioretinal atrophy in eyes with secondary angle closure glaucoma.

BACKGROUND: The present study was performed to investigate the ultrastructure of deep retinal layers and choroid corresponding to the parapapillary chorioretinal atrophy in eyes with secondary angle-closure glaucoma. METHODS: The glaucomatous eyes included two eyes enucleated due to iris ring melanoma with high intraocular pressure and one eye with neovascular glaucoma enucleated due to ocular pain. The control eyes included one eye enucleated due to choroidal malignant melanoma with normal intraocular pressure and one eye enucleated during surgery for supramandibular carcinoma. These eyes were studied with light and electron microscopy. RESULTS: In the region of parapapillary chorioretinal atrophy of glaucomatous eyes, the retinal pigment epithelial cells showed degenerative changes, such as loss of basal infoldings and microvilli, degenerated mitochondria, vacuolar degeneration and irregular distribution of melanin granules. The photoreceptors were decreased in number in this area of glaucomatous eyes. The lumen of the choriocapillary vessels adjacent to the optic nerve was collapsed. CONCLUSION: These results elucidate the fine structures of deep retina and choroid in the region of parapapillary chorioretinal atrophy of glaucomatous eyes, and suggest that the reduced choroidal perfusion might be the pathogenetic mechanism of glaucomatous parapapillary chorioretinal atrophy.

Fundus lesions in malignant hypertension. II. A pathologic study of experimental hypertensive optic neuropathy.

Accelerated renovascular hypertension produces optic nerve changes ranging from optic disc edema to optic atrophy. To elucidate the pathogenesis of hypertensive optic neuropathy, the optic nerves from 12 monkeys (23 eyes) with accelerated renovascular systemic hypertension were studied by electron and light microscopy. Within 21 months, the animals demonstrated the entire spectrum of pathologic changes. In the optic nerves with optic disc edema, the prelaminar optic nerve exhibited vasoconstriction with subsequent axonal hydropic swelling, axolemma disruption, and glial swelling. In retrolaminar myelinated optic nerve, vasoconstriction was more severe, with endothelial swelling and pericytic degeneration resulting in intramyelinic vacuoles and glial swelling. Optic disc edema appeared to result from axonal hydropic swelling secondary to ischemic infarct, followed by loss of axons and gliosis in the prelaminar optic nerve. The retrolaminar myelinated nerve showed prominent microglial reaction and eventual atrophy of axons and glia. Ischemia seemed to play a major role in hypertensive optic neuropathy, which represents anterior ischemic optic neuropathy.

Pathology of human cystoid macular edema.

The light and electron microscopic findings are reviewed in two patients who had eyes enucleated for peripheral choroidal malignant melanomas. Preoperatively, cystoid macular edema was documented by fluorescein angiography in the melanoma-containing eye in both patients. Intracytoplasmic swelling (edema) of the Müller (glial) cells is the anatomical basis for the macular edema. Intercellular (extracellular) collections of fluid probably are late, endstage results of the process that result form prolonged, excessive, intracellular edema, cell death and disruption. The process probably rests on an ischemic basis, as evidenced by severe changes in the microvasculature. In the one patient in whom the optic nerve was available for study, marked intracellular swelling (edema) of glial cells in the lamina choroidalis of the optic nerve head was present, associated with compression of the adjacent axons. The nearby temporal, parapapillary retina also showed edema of Müller cells, and compression of the nerve fibers (ganglion cell axons), suggesting a more widespread process than was clinically evident. Again, severe changes were present in the microvasculature, both in the optic nerve and parapapillary retina. The underlying cause of the microvasculature changes that lead to ischemia, perhaps an intrinsic pharmacologic agent, is yet to be found.

Ocular malformation involving tissue of neural-crest derivation.

A 5-month-old infant had an enlarged left eye removed for a possible intraocular malignancy. The eye had a thin cornea, a superior staphyloma, a completely cupped optic nerve head and no iris or lens. Histopathologic study showed little corneal or uveal stroma, small rudiments of ciliary body superiorly with no smooth muscle, pigment epithelium and nonpigmented neuroepithelium that lined the entire interior of the globe, focal superior retinal dysplasia and a focal superior scleral thickening containing a melanotic malformation. Except for the absence of the lens and the presence of neuroepithelium behind the cornea, all of the findings might be explained by a defect in ocular neural-crest tissue, either as a primary lesion of a portion of the cephalic neural crest (crest embryopathy) or secondary to a local mesodermal malformation.

Pathology and pathogenesis of drusen of the optic nervehead.

This report describes the findings of a clinicopathologic correlative study of 18 cases of drusen of the optic nervehead and reports on the observations of the first ultrastructural study of this disease in the literature. From these observations, the processes of formation of drusen of the optic nervehead are proposed: abnormal axonal metabolism leads to intracellular mitochondrial calcification. Some axons rupture and mitochondria are extruded into the extracellular space. Calcium is heavily deposited in the extracellular mitochondria. Small calcified microbodies are produced and calcium continues to deposit on the surface of these nidi to form drusen. We conclude that drusen are definitely related to axonal degeneration of the optic nervehead.

An ultrastructural study of melanocytomas (magnocellular nevi) of the optic disk and uvea.

We examined by light and electron microscopy five melanocytomas from four patients. Two types of cells were observed in each tumor. The predominant cell type in most of the tumors studied consisted of plump polyhedral nevus cells that contained numerous giant melanosomes. These cells showed advanced differentiation. They appeared to be metabolically inactive and to have been the cause of the heavy pigmentation and benign nature of these tumors. The second variant of melanocytoma cells were smaller spindle-shaped cells that were lightly pigmented. Other morphologic features of these cells such as high nucleus-cytoplasm ratio, prominent nucleolus, nuclear membrane infolding, numerous mitochondria, prominent rough endoplasmic reticulum, and free ribosomes, indicated a metabolically active cell, which may explain the infiltrating behavior of these tumors.