Functional and structural analysis of the visual system in the rhesus monkey model of optic nerve head ischemia.
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PURPOSE: A redistribution of neurochemicals has been identified in the visual cortex of monkeys with laser-induced glaucoma. Examined were functional, structural, and neurochemical changes to the retina, optic nerve, and central visual system in a nonhuman primate model of optic nerve head (ONH) ischemia caused by sustained unilateral administration of endothelin (ET)-1 to the optic nerve. METHOD: ET-1 or sham control solution was delivered by osmotic minipump to the retrolaminar region of one optic nerve of rhesus monkeys (Macaca mulatta) for 1.5 years. ONH topography and blood flow velocity were serially studied with scanning laser tomography and laser Doppler flowmetry, respectively. Retinal and cortical electrophysiologic measurements from pattern-derived stimuli were obtained quarterly. Immunohistochemistry was used to identify the distribution of calbindin (CB) and c-Fos labeled neurons in the visual cortex areas V1 and V2, and lateral geniculate nucleus (LGN). Retinal ganglion cell counts and optic nerve axon density were determined by light microscopy. RESULTS: No significant changes in retinal and ONH morphology, ONH blood flow velocity, and retinal and cortical pattern-derived functional activity were detected. Measurement of CB-positive cell density in V1 and V2 showed a significant decrease in CB labeling to the contralateral side of the ET-1-treated eye (P < 0.04). CB-positive cells were present in the magnocellular layers of the LGN with no differences noticed between the ET-1- and sham-treated eyes. c-Fos-labeled neurons were found in striate area V1 and extrastriateV2 of both groups. No c-Fos labeling was observed in the LGN. CONCLUSIONS: Administering ET-1 to the orbital optic nerve alters neuronal metabolic activity in the visual cortex in rhesus monkeys. Metabolic activity reductions in the visual cortex precede the ability to detect functional and structural alterations in the retina, ONH, and visual cortex in this animal model. (+info)
Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina.
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PURPOSE: To determine whether anterior ischemic optic neuropathy and compressive optic neuropathy in humans alter the photopic flash ERG and to investigate the cellular origins of the waves that are affected by pharmacologic agents in primates. METHODS: Photopic flash ERGs were recorded differentially, with DTL electrodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n = 17, anterior ischemic optic neuropathy [AION]; n = 5, compressive optic neuropathy) and 25 age-matched control subjects and in 17 eyes of 13 monkeys (Macaca mulatta). The stimulus consisted of brief (<5 ms) red (lambda(max) = 660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue background of 3.7 log sc td (lambda(max) = 460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P < 2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tetrodotoxin (TTX) (1.2-2.1 microM; n = 7), TTX+N-methyl-d-aspartate (NMDA; 1.4-6.4 mM; n = 7), and cis-2, 3 piperidine dicarboxylic acid (PDA; 3.3-3.8 mM; n = 3). RESULTS: The PhNR amplitude was significantly reduced in both symptomatic (P = 3.4 x 10(-8)) and asymptomatic (P = 0.036) eyes of patients with AION or compressive optic neuropathy (P = 0.0054) compared with control subjects. The PhNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P < 0.05) similar to previous findings in open-angle glaucoma. The a-wave also was reduced significantly in the symptomatic eye (P = 0.0002) of patients with AION. The i-wave, a positive wave on the trailing edge of the b-wave peaking around 50 ms, became more prominent in eyes in which the PhNR was significantly reduced. In monkeys, the PhNR was eliminated by TTX. The a-wave at the peak and later times was reduced by TTX, further reduced by NMDA, and eliminated after PDA in response to the red stimuli. PDA also eliminated the i-wave. CONCLUSIONS: PhNR amplitude is significantly reduced in eyes with open-angle glaucoma, AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG. There also are small spike-driven contributions to the a-wave elicited by full-field red stimuli. The i-wave, which becomes more prominent when the PhNR is reduced, has origins in the off-pathway distal to the ganglion cells. (+info)
Elevated plasma levels of interleukin 8 in patients with acute anterior ischaemic optic neuropathy.
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BACKGROUND/AIM: Alterations of the immune system may have a role in thrombogenesis. Artery sites occluded with thrombi apparently release pro-inflammatory cytokines. Non-arteritic anterior ischaemic optic neuropathy (NAION) results from occlusion of the blood supply to the optic nerve. The aim of this study was to analyse levels of pro-inflammatory cytokines in patients with acute event of NAION. METHODS: Study participants included 10 patients (12 eyes) with NAION and 20 age matched controls with the same risk factors for atherosclerosis disease. Peripheral blood samples were obtained immediately at the acute onset of NAION. Plasma interleukin 8 (IL-8), IL-6, and tumour necrosis factor alpha (TNF-alpha) levels were measured immediately following diagnosis and during the follow up intervals. RESULTS: The plasma levels of IL-8 were significantly higher in NAION patients at the time of diagnosis in comparison to the control group (p = 0.002), and decreased during the follow up period (6-12 months) (p = 0.05). There were no differences in plasma levels of IL-6 and TNF-alpha between NAION patients and controls, either in the acute phase or during the follow up period. CONCLUSION: Plasma levels of IL-8 are elevated during the acute phase of NAION, but not IL-6 and TNF-alpha. These elevated levels are in accordance with other acute vascular thrombosis. The clinical significance of these findings should be further evaluated. (+info)
Neurotrophin and Trk expression by cells of the human lamina cribrosa following oxygen-glucose deprivation.
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BACKGROUND: Ischemia within the optic nerve head (ONH) may contribute to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG). Ischemia has been reported to increase neurotrophin and high affinity Trk receptor expression by CNS neurons and glial cells. We have previously demonstrated neurotrophin and Trk expression within the lamina cribrosa (LC) region of the ONH. To determine if ischemia alters neurotrophin and Trk protein expression in cells from the human LC, cultured LC cells and ONH astrocytes were exposed to 48 hours of oxygen-glucose deprivation (OGD). Also cells were exposed to 48 hours of OGD followed by 24 hours of recovery in normal growth conditions. Cell number, neurotrophin and Trk receptor protein expression, neurotrophin secretion, and Trk receptor activation were examined. RESULTS: Cell number was estimated using an assay for cell metabolism following 24, 48 and 72 hours of OGD. A statistically significant decrease in LC and ONH astrocyte cell number did not occur until 72 hours of OGD, therefore cellular protein and conditioned media were collected at 48 hours OGD. Protein expression of NGF, BDNF and NT-3 by LC cells and ONH astrocytes increased following OGD, as did NGF secretion. Recovery from OGD increased BDNF protein expression in LC cells. In ONH astrocytes, recovery from OGD increased NGF protein expression, and decreased BDNF secretion. Trk A expression and activation in LC cells was increased following OGD while expression and activation of all other Trk receptors was decreased. A similar increase in Trk A expression and activation was observed in ONH astrocytes following recovery from OGD. CONCLUSIONS: In vitro conditions that mimic ischemia increase the expression and secretion of neurotrophins by cells from the ONH. Increased Trk A expression and activation in LC cells following OGD and in ONH astrocytes following recovery from OGD suggest autocrine/paracrine neurotrophin signaling could be a response to ONH ischemia in POAG. Also, the increase in NGF, BDNF and NT-3 protein expression and NGF secretion following OGD also suggest LC cells and ONH astrocytes may be a paracrine source of neurotrophins for RGCs. (+info)
Ischemic optic neuropathy following spine surgery.
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Perioperative visual loss (POVL) is a devastating injury that has been reported infrequently after nonocular surgery. The most common cause of POVL is ischemic optic neuropathy (ION). Increasing numbers of cases of ION are being reported after spine surgery, but the etiology of postoperative ION remains poorly understood. After a MEDLINE search of the literature, we reviewed published case reports of ION, specifically those reported after spine surgery performed with the patient in the prone position. Most of the cases involved posterior ION (PION, n = 17), and the remainder anterior (AION, n = 5). Most patients had no or few preoperative vascular disease risk factors. All except one PION and 2 of 5 AION cases reported symptom onset within the first 24 hours after surgery. Visual loss was frequently bilateral (40% of AION, 47% of PION cases). Mean operative time exceeded 450 minutes. The lowest average intraoperative mean arterial blood pressure was 64 mm Hg and the mean lowest intraoperative hematocrit was 27%. The average blood loss was 1.7 L for AION and 5 L for PION patients. PION patients received an average of 8 L of crystalloid solution and 2.2 L of colloid intraoperatively. This compilation of case reports suggests that a combination of prolonged surgery in the prone position, decreased ocular perfusion pressure, blood loss and anemia/hemodilution, and infusion of large quantities of intravenous fluids are some of the potential factors involved in the etiology of postoperative ION. However, levels of blood pressure and anemia intraoperatively were frequently at levels considered acceptable in anesthesia practice. The etiology of postoperative ION remains incompletely understood. Potential strategies to avoid this complication are discussed. (+info)
Why cotton wool spots should not be regarded as retinal nerve fibre layer infarcts.
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Cotton wool spots (CWSs) comprise localised accumulations of axoplasmic debris within adjacent bundles of unmyelinated ganglion cell axons. Their formation is widely held to reflect focal ischaemia from terminal arteriolar occlusion, but credible evidence supporting this view is lacking. CWSs are here purported to be nothing more than sentinels of retinal nerve fibre layer pathology, hence their recommended redesignation "cotton wool sentinels." After branch arteriolar occlusion, CWSs evolve as boundary sentinels of infarction, their uniform width suggesting a glial constraint to axonal expansion. In pre-proliferative diabetic retinopathy, CWSs form a C-shaped chain nasal to the disc and around the macula where they constitute sentinels of ischaemia affecting the entire retinal mid-periphery. The polymorphous CWSs evolving during acute panretinal hypoperfusion represent sentinels of an ischaemic penumbra. Those surrounding the disc in Purtscher's traumatic angiopathy are sentinels of neuronal damage from transient venous hyperdistension that overwhelms the protection afforded by peripapillary axonal decompartmentalisation. (+info)
Computerized expert system for evaluation of automated visual fields from the Ischemic Optic Neuropathy Decompression Trial: methods, baseline fields, and six-month longitudinal follow-up.
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PURPOSE: To validate a computerized expert system evaluating visual fields in a prospective clinical trial, the Ischemic Optic Neuropathy Decompression Trial (IONDT). To identify the pattern and within-pattern severity of field defects for study eyes at baseline and 6-month follow-up. DESIGN: Humphrey visual field (HVF) change was used as the outcome measure for a prospective, randomized, multicenter trial to test the null hypothesis that optic nerve sheath decompression was ineffective in treating nonarteritic anterior ischemic optic neuropathy and to ascertain the natural history of the disease. METHODS: An expert panel established criteria for the type and severity of visual field defects. Using these criteria, a rule-based computerized expert system interpreted HVF from baseline and 6-month visits for patients randomized to surgery or careful follow-up and for patients who were not randomized. RESULTS: A computerized expert system was devised and validated. The system was then used to analyze HVFs. The pattern of defects found at baseline for patients randomized to surgery did not differ from that of patients randomized to careful follow-up. The most common pattern of defect was a superior and inferior arcuate with central scotoma for randomized eyes (19.2%) and a superior and inferior arcuate for nonrandomized eyes (30.6%). Field patterns at 6 months and baseline were not different. For randomized study eyes, the superior altitudinal defects improved (P = .03), as did the inferior altitudinal defects (P = .01). For nonrandomized study eyes, only the inferior altitudinal defects improved (P = .02). No treatment effect was noted. CONCLUSIONS: A novel rule-based expert system successfully interpreted visual field defects at baseline of eyes enrolled in the IONDT. (+info)
Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis.
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OBJECTIVE: To evaluate the frequency of visual manifestations at presentation in an Italian population-based cohort of patients with biopsy-proven giant cell arteritis (GCA), and to investigate predictors for the development of permanent visual loss. METHODS: We identified 136 Reggio Emilia (Italy) residents with biopsy-proven GCA diagnosed between 1986 and 2002. Medical records of these 136 patients were reviewed, and demographic, clinical, and laboratory data were collected.Multivariate analysis with multiple logistic regression models was performed to identify the best predictors of visual loss. RESULTS: Visual manifestations developed in 41 patients (30.1%). Partial or total visual loss was observed in 26 patients (19.1%). Anterior ischemic optic neuropathy was seen in 24 patients, and 2 patients had central retinal artery occlusion. Unilateral vision loss occurred in 19 patients, and bilateral visual loss in 7. In 25 patients, visual loss developed before glucocorticoid therapy for GCA was started. The age at disease onset was significantly higher in patients with permanent visual loss compared with those without it. The frequency of systemic signs/symptoms and erythrocyte sedimentation rate (ESR) and C-reactive protein values at diagnosis were significantly lower in patients with permanent visual loss. By multivariate logistic regression, the only statistically significant predictor for the development of permanent visual loss was the absence of high levels of ESR at diagnosis (tertile 2: Odds ratio [OR] 0.08; tertile 3: OR 0.11). Other predictors included in the model were the absence of systemic manifestations (OR 0.24), an older age at disease diagnosis (quintile 5: OR 5.60), and the presence of an elevated platelet count at diagnosis (OR 4.99), however they were only of borderline statistical significance. CONCLUSION: The proportion of Italian patients with GCA that developed visual loss was similar to that reported from other countries. The patients with low inflammatory response had a higher risk of visual loss. (+info)