Prelaminar Optic Nerve Head Research Articles

Effects of experimental glaucoma in Lama1nmf223 mutant mice

To identify changes in response to experimental intraocular pressure (IOP) elevation associated with the laminin α1 nmf223 mutation in mice.Laminin mutant (LM) mice (Lama1nmf223) and C57BL/6J (B6) mice in two age groups each (4–5 months and >1 year) underwent intracameral microbead injections to produce unilaterally elevated IOP. We assessed axonal transport block of immunofluorescently labeled amyloid precursor protein (APP) after 3 days and retinal ganglion cell (RGC) axon loss after 6 weeks. Light, electron and fluorescent microscopy was used to study baseline anatomic differences and effects of 3-day IOP elevation in younger LM mice.In younger mice of both LM and B6 strains, elevated IOP led to increased APP block in the retina, prelaminar optic nerve head (preONH), unmyelinated optic nerve (UON), and myelinated optic nerve (MON). APP blockade not significantly different between younger B6 and LM mouse strains. Older LM mice had greater APP accumulation in both control and glaucoma eyes compared to older B6, however, accumulation was not significantly greater in LM glaucoma eyes compared to LM controls. Axon loss at 6 weeks was 12.2% in younger LM and 18.7% in younger B6 mice (difference between strains, p = 0.22, Mann Whitney test). Untreated LM optic nerve area was lower compared to B6 (nerve area, p < 0.0001, t-test). Aberrant axon bundles, as well as defects, thickening and reduplication of pia mater, were seen in the optic nerves of younger LM mice.Axonal transport blockade significantly differed between old B6 and old LM mice in control and glaucoma eyes, and younger LM mice had abnormal axon paths and lower optic nerve area.

Choroidal Thickness in Eyes with Band Atrophy of the Optic Nerve from Chiasmal Compression.

Background The choroid is a vascular tissue that helps maintain retinal and prelaminar optic nerve head function. Choroidal thickness has been previously studied in diseases accompanied by retinal neural loss, but the relationship between the two sets of measurements is not clear. In eyes with temporal hemianopia as a result of chiasmal compression lesions (CCL), retinal neural loss tends to be greater in the nasal than the temporal hemiretina, a fact that may be useful in evaluating the effect of inner retinal layer loss on choroidal thickness. Purpose To evaluate macular and peripapillary choroidal thickness on swept-source optical coherence tomography (SS-OCT) in eyes with temporal hemianopia as a result of chiasmal compression and in healthy controls. Methods 33 eyes of 26 patients with band atrophy of the optic nerve and temporal visual field defects as a result of previously treated suprasellar tumors (CCL group) and 40 eyes of 21 healthy controls underwent SS-OCT scanning. The thickness of the peripapillary retinal nerve fiber layer (pRNFL), the peripapillary choroid (pChoroid), the macular RNFL (mRNFL), the macular ganglion cell layer (mGCL), and the macular choroid (mChoroid) was expressed globally and by sector (peripapillary quadrants and macular hemifield and quadrants). Ratios between macular nasal and temporal hemifield and quadrantic measurements were calculated using generalized estimated equation models, and the two groups were compared. Results The pRNFL, mRNFL, and mGCC thicknesses were significantly smaller in the CCL group than in the control group (64.67 ± 10.53 μm, 29.68 ± 5.80 μm, and 80.60 ± 10.17 μm vs. 103.78 ± 12.23 μm, 39.89 ± 3.82 μm, and 105.51 ± 7.76 μm, respectively; p < 0.001). For the choroid, the only difference between the groups was increased macular nasal hemifield and superonasal quadrant thickness in CCL (222.47 ± 61.05 μm and 230.45 ± 58.59 μm in the CCL group, respectively vs. 190.68 ± 52.54 μm and 197.65 ± 54.80 μm in the control group, respectively; p < 0.05). The temporal/nasal ratios were significantly higher for the mRNFL and mGCC parameters and significantly lower for the mChoroid parameters in the CCL group, except for the superotemporal/superonasal quadrant ratio. Conclusions The choroid does not thin after the inner retinal layer becomes damaged due to CCL and may even be thicker in some areas with corresponding severe retinal neural loss. While further studies are needed to interpret these findings, choroidal thinning is most likely not secondary to optic nerve disease-related inner retinal neural loss.

Optic disc drusen: a systematic review : Up-to-date and future perspective.

Optic disc drusen (ODD) are acellular deposits in the prelaminar optic nerve head. The most accredited theory is that they are secondary to abnormalities in axonal metabolism and degeneration, but the pathogenesis is not clear to date. Although ODD are often considered a benign condition, the great majority of patients with ODD show visual field defects and are at higher risk for developing anterior ischemic optic neuropathy. ODD are classified as superficial or buried, with the latter being often misdiagnosed as papilledema with optic nerve head swelling, leading to an unnecessary investigation for causes of increased intracranial pressure. The recent technological improvements in OCT imaging which allowed an earlier and more certain diagnosis even of the smallest ODD, renovated the interest around this pathology. However, an updated systematic review is still missing. Therefore, the aim of this work is to provide a concise yet comprehensive overview of the current state of art, focusing on pathophysiology, clinical presentation, diagnostic methods, treatment modalities and potential future perspectives of this condition.

Prevalence of Optic Disc Drusen in Young Patients With Nonarteritic Anterior Ischemic Optic Neuropathy: A 10-Year Retrospective Study.

Nonarteritic anterior ischemic optic neuropathy (NAION) in young patients (age ≤50) accounts for a minority of all cases of NAION and is more highly associated with crowding of the optic nerves and bilateral involvement than NAION in older patients. Optic disc drusen (ODD) are likewise associated with crowded optic nerves and are located in the prelaminar optic nerve head where they could contribute to NAION pathogenesis. The purpose of this study was to determine the prevalence of ODD in the eyes of young NAION patients using modern imaging methods and to compare it to the baseline 1.8%-2.0% prevalence of ODD in the general population. In this retrospective study, all young NAION patients (ages 18-50 years, inclusive) seen in 2 tertiary care neuro-ophthalmology clinics (in London, Canada and Copenhagen, Denmark) in the ten-year interval between April 1, 2009, and March 31, 2019, were identified and their medical charts reviewed. Patients were included in the study if ODD were diagnosed by any method (including ophthalmoscopy, ultrasound [US], fundus autofluorescence [FAF], computed tomography [CT], or any optical coherence tomography [OCT] method), or if ODD were excluded by enhanced-depth imaging OCT (EDI-OCT) using the ODD Studies (ODDS) Consortium protocol. The presence or absence of ODD was recorded for each eye. There were 37 eligible patients (74 eyes). Mean age of NAION onset was 38.5 ± 10.0 years, and 23 patients (62%) were men. Patients had undergone the following methods of ODD detection: ophthalmoscopy (37 patients), EDI-OCT (36 patients), FAF (31 patients), US (9 patients), and CT orbits (8 patients). We found a prevalence of ODD of 56.7% in NAION-affected patients and 53.3% in NAION-affected eyes. Only 35.9% of ODD were visible on ophthalmoscopy. Twenty of 21 ODD patients (95.2%) had bilateral ODD. Age of onset and sex did not differ significantly between the ODD-positive group and the ODD-negative group. EDI-OCT outperformed any combination of ophthalmoscopy, US, FAF, and CT at detecting ODD. ODD were found with much higher prevalence in young patients with NAION than in the general population and were usually bilateral and buried. ODD may contribute to NAION pathogenesis by exacerbating an underlying compartment syndrome in the crowded "disc at risk." EDI-OCT may be the best imaging modality for ODD detection in future studies.

A method to quantify regional axonal transport blockade at the optic nerve head after short term intraocular pressure elevation in mice

Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity greater than the 97.5th percentile value of control eyes (suprathreshold pixels). This method segregated images with APP blockade from those with normal transport of APP. The fraction of suprathreshold pixels was significantly higher following IOP elevation than in normotensive controls in the unmyelinated ONH and myelinated nerve regions (paired analyses, p = 0.02 and 0.003, respectively, N = 12), but not in retina or prelaminar ONH (p = 0.91 and 0.08, respectively). The mean intensity of suprathreshold pixels was also significantly greater in glaucoma than in normotensive controls in prelaminar ONH, unmyelinated ONH and myelinated optic nerve (p = 0.01, 0.01, 0.002, respectively). Using this method, subconjunctival glyceraldehyde, which is known to worsen long-term RGC loss with IOP elevation, also produced greater APP blockade, but not statistically significant compared to glaucoma alone. Systemic losartan, which aids RGC axonal survival in glaucoma, reduced APP blockade, but not statistically significant compared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma.

Clinical characteristics of autoimmune optic neuritis

AbstractAutoimmune disorders of the central nervous system often involve autoimmune inflammation of the anterior visual pathways. Autoimmune optic neuritis can be categorized as: (i) isolated optic neuritis; (ii) relapsing isolated optic neuritis: (iii) chronic relapsing inflammatory optic neuropathy; (iv) neuromyelitis optica spectrum disorders‐associated optic neuritis; or (v) multiple sclerosis‐associated optic neuritis. Studies of serum‐specific autoantibodies, such as aquaporin‐4 and myelin oligodendrocyte glycoprotein, have revealed some underlying mechanisms of autoimmune optic neuritis. However, the etiology and pathogenesis of most cases of autoimmune optic neuritis remain unclear. The following clinical features of autoimmune optic neuritis are profoundly affected by the unique structure of the human anterior visual pathways: (i) vulnerability to swelling of the intracanalicular optic nerve as a result of the limited space within the bony canal; (ii) inflammatory cell infiltration through the subarachnoid space, pia and pial septa; (iii) compartmentalized dynamics of cerebrospinal fluid as a result of the cul‐de‐sac anatomy of the optic nerve; (iv) permeability of the prelaminar optic nerve head as a result of the lack of classical blood–brain barrier characteristics; and (v) retinal abnormalities, which are a diagnostic window of neurodegenerative processes of the optic nerves and/or brain. Future studies are required to configure a systemic nosology for optic neuritis with international consensus, elucidate specific diagnostic biomarkers, carry out clinical trials of the acute and chronic phases of the disease etiologies, and elucidate possible neuroprotective and remyelinating treatments.

Intraretinal and Intra-optic Nerve Head Silicone Oil Vacuoles Using Adaptive Optics

The authors report the in vivo visualization through multimodal imaging of silicone oil in the vitreous cavity, optic nerve, and retina of a patient 11 years after surgical removal of the main tamponade. Contact B-scan ultrasonography revealed countless small echogenic particles in the vitreous cavity and a hyperreflective structure within the optic nerve head. Swept-source optical coherence tomography showed multiple round hyporeflective spaces within the substance of the prelaminar optic nerve head. Adaptive optics imaging revealed numerous particles in the optic nerve head and within the retina in the same plane as the photoreceptors, with similar size and shape to the silicone oil droplets in the vitreous cavity. The authors hypothesize that in this case, the silicone oil droplets in the retina and optic nerve head may be associated with the patient's otherwise unexplained progressive visual loss.

Peripapillary ring: histology and correlations

To assess the histologic correlate of the peripapillary ring (PPR) as the optic disc boundary, to measure it histomorphometrically and to assess its associations with glaucoma and axial length. Using a light microscope, we measured the width of the PPR and optic nerve pia mater. We additionally had measured the axial length, length of parapapillary beta and gamma zones, and thickness of the sclera and choroid. The study included 83 human globes with a mean axial length of 26.1±3.3mm (range: 20.0-35.0mm). In the non-highly myopic (axial length <26.5mm) non-glaucomatous eyes, mean PPR width was 55±14μm (range: 26-88μm) and mean thickness of the optic nerve pia mater was 52±22μm (range: 20-84μm). PPR width and pia mater thickness were significantly associated with each other (p=0.001; correlation coefficient r=0.37). PPR width increased significantly with longer axial length (p=0.001; r=0.35) and with the length of the peripapillary scleral flange (p=0.02; r=0.34). Pia mater thickness increased significantly with longer axial length (p=0.03; r=0.24) and with presence of glaucoma (p=0.03). In eyes without parapapillary gamma zone, PPR was covered or was at least touched by the end of Bruch's membrane and separated the peripapillary choroid from the prelaminar optic nerve head tissue. In eyes with parapapillary gamma zone, PPR was the continuation of the optic nerve pia mater and reached the undersurface of the peripapillary retinal nerve fibre layer. In these eyes, Bruch's membrane started in a distance of up to 5mm from PPR, and the thin space of peripapillary choroid ended by an attachment of Bruch's membrane to the thinned sclera. Peripapillary ring width (mean: 55±14μm) increases slightly with longer axial length and is independent of glaucoma. It is strongly correlated with the pia mater thickness and is the continuation of the pia mater to the ocular surface.

Qualitative and Quantitative Morphologic Changes in the Vasculature and Extracellular Matrix of the Prelaminar Optic Nerve Head in Eyes with POAG

To analyze the vasculature and extracellular matrix changes in the prelaminar region (PreLR) of the optic nerve head (ONH) and in the peripapillary sclera of eyes with primary open-angle glaucoma (POAG) and age-matched control eyes. In histologic sagittal sections of 46 eyes with POAG and 45 control eyes (donor ages, 20-96 years), the peripapillary sclera and penetrating vessels were investigated ultrastructurally and with antibodies against elastin, podocalyxin, and α-actin. Within the PreLR, the number and density of capillaries and the thickness of their connective tissue sheaths (CTSs) were quantified. The composition of the CTS was analyzed by using antibodies against collagen types I, III, IV, and VI, and elastin. Areas within the PreLR containing capillaries with thick or thin CTSs were determined. There were no glaucomatous changes in the peripapillary elastic fibers and in the arterial capillaries in the periphery of the PreLR. In the center of the PreLR, the capillaries gained a CTS that was significantly thicker in POAG eyes than in control eyes, and the area containing capillaries with thick CTSs was significantly larger. These data did not correlate with axon counts. Lack of glaucomatous changes in elastic fibers of the scleral suspension of the ONH seems to prevent occlusion of penetrating vessels. In the PreLR, thickening of the capillary CTS and enlargement of the area containing capillaries with thickened CTS could increase diffusion time and may impair nutrition of the neuronal tissue.

Oxidative injury to blood vessels and glia of the pre-laminar optic nerve head in human glaucoma

Glaucoma is a leading cause of irreversible world blindness. Oxidative damage and vascular injury have been implicated in the pathogenesis of this disease. The purpose of this study was to determine in human primary open angle glaucoma whether oxidative injury occurs in pre-laminar optic nerve blood vessels and glial cells. Following IRB approval, sections from post-mortem primary open angle glaucoma eyes ( n = 5) with mean age of 77 ± 9 yrs (±SD) were compared to normal control eyes ( n = 4) with mean age 70 ± 9 yrs (Eye Bank of Canada). Immunostaining with nitrotyrosine, a footprint for peroxynitrite-mediated injury, was performed and sections were double-labeled with markers for vascular endothelial cells, perivascular smooth muscle cells, and astrocytes with CD34, smooth muscle actin (SMA), and glial fibrillary acidic protein (GFAP), respectively. Immunostaining was captured in a masked fashion using confocal microscopy, and defined regions of interest for blood vessels and glial tissue. Intensity measurements of supra-threshold area in pixels as percent of the total number of pixels were calculated using ImageJ (NIH) and compared using two-tailed Mann–Whitney nonparametric tests between glaucoma and control groups. Colocalization coefficients with cell-specific markers were determined and compared with random coefficients of correlation. Increased nitrotyrosine immunoreactivity was observed in pre-laminar optic nerve head blood vessels of primary open angle glaucoma eyes compared to controls and this difference was statistically significant (1.35 ± 1.11% [±SD] vs. 0.01 ± 0.01%, P = 0.016). NT-immunoreactivity was also increased in the glial tissue surrounding the pre-laminar optic nerve head in the glaucoma group and compared to controls, and this difference was statistically significant (18.37 ± 12.80% vs. 0.08 ± 0.04%, P = 0.016). Colocalization studies demonstrated nitrotyrosine staining in vascular endothelial and smooth muscle cells, in addition to astrocytes. Correlation coefficients for CD34, SMA, and GFAP were 0.37, 0.52, and 0.64, respectively. Oxidative injury is present in blood vessels and astrocytes in the pre-laminar optic nerve head in human primary open angle glaucoma. Peroxynitrite-mediated oxidative injury, whether primary or secondary, may contribute to the pathobiology of glaucoma disease.

Comparative Anatomy of the Optic Nerve Head and Inner Retina in Non-Primate Animal Models Used for Glaucoma Research

To judge the information of experimental settings in relation to the human situation, it is crucial to be aware of morphological differences and peculiarities in the species studied. Related to glaucoma, the most important structures of the posterior eye segment are the optic nerve head including the lamina cribrosa, and the inner retinal layers. The review highlights the differences of the lamina cribrosa and its vascular supply, the prelaminar optic nerve head, and the retinal ganglion cell layer in the most widely used animal models for glaucoma research, including mouse, rat, rabbit, pig, dog, cat, chicken, and quail. Although all species show some differences to the human situation, the rabbit seems to be the most problematic animal for glaucoma research.

Enhanced Tenascin Expression Associated with Reactive Astrocytes in Human Optic Nerve Heads with Primary Open Angle Glaucoma

Tenascin is a large extracellular matrix glycoprotein expressed in neural and non-neural tissues. In the central nervous system, tenascin is synthesized by astrocytes during development and wound healing, forming barriers and affecting neurite outgrowth. In this study we examined tenascin expression in optic nerve heads of normal and glaucomatous eyes and found that there is upregulation of tenascin mRNA and protein in reactive astrocytes from human glaucomatous optic nerve heads compared to normal age-matched controls. In the prelaminar region there was a band of tenascin immunoreactivity around the blood vessels of glaucomatous, but not in normal eyes. However, tenascin mRNA was only localized to astrocytes, suggesting that astrocytes are the cellular source of tenascin. In the lamina cribrosa, tenascin immunoreactivity and gene expression were localized to astrocytes in the cribriform plates and inside the nerve bundles. In the post-lamina region, tenascin immunoreactivity and gene expression were localized to astrocytes lining the pial septum immediately adjacent to the lamina cribrosa. In normal optic nerve heads, tenascin expression at the mRNA and protein levels was confined to clusters of astrocytes at the level of Bruch's membrane in the prelaminar optic nerve head. In glaucoma, enhanced expression of tenascin may be protective to the axons of the retinal ganglion cells by providing a barrier for humoral and/or blood-borne factors that may cause further neural damage. However, the precise role of tenascin in glaucomatous optic neuropathy is not yet elucidated.

The Oxygen Distribution in the Prelaminar Optic Nerve Head of the Cat

Oxygen-sensitive microelectrodes were used to measure oxygen profiles from the prelaminar region of the cat optic nerve head. From the profiles, the oxygen distribution of this tissue was determined. Changes in oxygen levels in response to flicker stimulation were obtained. Also, the regulatory ability of this tissue was assessed by acutely increasing IOP and by presenting the cat with periods of hyperoxia. The cells in the optic nerve head were found to exist in the same oxygen environment as cells of the inner retina. Oxygen tensions usually varied between 0 and 40 mmHg, with the mean being between 10 and 20 mmHg. There was no difference in oxygen levels between central and peripheral parts of the optic nerve head, nor was there a difference as a function of depth. Different levels of light adaptation of the retina had no effect on oxygen levels in the optic nerve head, but flicker stimulation of the retina resulted in decreases in tissue oxygen tension. A small number of experiments in which the intraocular pressure was raised showed that oxygen levels in the optic nerve head were not drastically altered during acute decreases in perfusion pressure. Based on the size of changes in tissue oxygen tensions during hyperoxia, it appeared that blood vessels in the optic nerve head constricted in response to systemic hyperoxia.