Showing papers by "Harry A. Quigley published in 2011"

Retinal ganglion cell loss in a rat ocular hypertension model is sectorial and involves early optic nerve axon loss

Abstract: We recently showed that RGC degeneration in DBA/2J mice is sectorial and that within the sectors of degeneration there are many RGCs that maintain gene expression after they can no longer be retrogradely labeled from the superior colliculus.1 Among these putatively disconnected RGCs, many have accumulation of phosphorylated neurofilaments (pNF) in their somas and dendrites, a cellular redistribution observed in RGCs after severe axonal injuries.2–4 However, given that some have argued that the DBA/2J mouse model does not recapitulate nonpigmentary glaucoma, an important priority was to determine whether key neuropathologic features observed in DBA/2J are conserved in other animal models of glaucoma. In addition, because RGC degeneration is asynchronous and related to aging in DBA/2J, more acute animal models may be preferable for establishing the sequence of progressive changes in glaucoma. Two popular rat glaucoma animal models, increasing IOP by injection of hypertonic saline into episcleral vessels5 or laser injury to aqueous humor outflow channels,6,7 produce degenerations that are generally similar in extent, pattern, and mechanism.8 Although the IOP increase observed in these models is more acute and generally higher than in typical human open angle glaucoma, the degeneration is faster and more synchronous than in DBA/2J mice. Here, we use one such model to confirm and further investigate the chronology of several neuropathologic features first described in DBA/2J mice.

Calibration of the TonoLab Tonometer in Mice with Spontaneous or Experimental Glaucoma

Abstract: It is essential to measure intraocular pressure (IOP) accurately in experimental glaucoma research. Mouse models permit genetic manipulations in the elucidation of glaucoma pathogenesis and treatment, but the tiny size of the mouse's eye presents a challenge to accurate tonometry. Various solutions have been devised for IOP measurement in the mouse, including needle cannulation through the cornea, use of existing commercial tonometers such as the pneumatonograph and TonoPen (Reichert, Inc., Depew, NY), and modifications of other commercial tonometers.1–10 The validity of noninvasive tonometry in the mouse eye has been confirmed in several strains under anesthesia.11–14 McKinnon et al.15 concluded: “TonoLab tonometry is technically easier than TonoPen tonometry, and has become the IOP measurement technique of choice” for experimental glaucoma in the mouse. In the DBA/2J mouse, spontaneous increase in IOP occurs, and many experiments have been conducted, often with needle cannulation used for tonometry. It may be preferable not to puncture the cornea repeatedly to monitor IOP, but it has not been shown that tonometry accurately reflects IOP in spontaneous or induced glaucoma in the mouse. Continuous IOP monitoring with implantable devices is under development, but has not been reported for mouse eyes. Sappington et al.16 have recently published a mouse model of glaucoma involving injection of beads into the anterior chamber. We have modified this model by first injecting beads (of 6 μm diameter) followed by viscoelastic injection. In a companion report, we confirm that the mouse eye enlarges significantly with chronic IOP elevation, as was first documented in the DBA/2J mouse. Enlargement of the eye could alter tonometric accuracy. Hence, we performed calibration studies in mouse eyes with bead/viscoelastic experimental glaucoma and their fellow eyes, studying younger and older mice of three different strains, as well as DBA/2J mice after development of spontaneous glaucoma. One previous study compared TonoLab (TioLat, Helsinki, Finland) IOP measures with needle cannulation, but without testing a range of IOP.17 To our knowledge, this is the first extensive calibration study of tonometry in both spontaneous and induced mouse glaucoma.

Evaluation of a combined index of optic nerve structure and function for glaucoma diagnosis

Abstract: The definitive diagnosis of glaucoma is currently based on congruent damage to both optic nerve structure and function. Given widespread quantitative assessment of both structure (imaging) and function (automated perimetry) in glaucoma, it should be possible to combine these quantitative data to diagnose disease. We have therefore defined and tested a new approach to glaucoma diagnosis by combining imaging and visual field data, using the anatomical organization of retinal ganglion cells. Data from 1499 eyes of glaucoma suspects and 895 eyes with glaucoma were identified at a single glaucoma center. Each underwent Heidelberg Retinal Tomograph (HRT) imaging and standard automated perimetry. A new measure combining these two tests, the structure function index (SFI), was defined in 3 steps: 1) calculate the probability that each visual field point is abnormal, 2) calculate the probability of abnormality for each of the six HRT optic disc sectors, and 3) combine those probabilities with the probability that a field point and disc sector are linked by ganglion cell anatomy. The SFI was compared to the HRT and visual field using receiver operating characteristic (ROC) analysis. The SFI produced an area under the ROC curve (0.78) that was similar to that for both visual field mean deviation (0.78) and pattern standard deviation (0.80) and larger than that for a normalized measure of HRT rim area (0.66). The cases classified as glaucoma by the various tests were significantly non-overlapping. Based on the distribution of test values in the population with mild disease, the SFI may be better able to stratify this group while still clearly identifying those with severe disease. The SFI reflects the traditional clinical diagnosis of glaucoma by combining optic nerve structure and function. In doing so, it identifies a different subset of patients than either visual field testing or optic nerve head imaging alone. Analysis of prospective data will allow us to determine whether the combined index of structure and function can provide an improved standard for glaucoma diagnosis.

Evaluation of an Algorithm for Detecting Visual Field Defects Due to Chiasmal and Postchiasmal Lesions: The Neurological Hemifield Test

Abstract: Visual field testing is central to the diagnosis and management of glaucoma and other diseases affecting the visual system. Automated perimetry is now used routinely to identify and monitor visual field defects quantitatively over time. To assist clinicians in the interpretation of automated perimetry, several algorithms have been developed that include statistical measures (e.g., mean deviation and pattern standard deviation), artificial neural network analysis,1–3 and rule-based systems, including the Glaucoma Hemifield Test (GHT).4,5 Although the diagnosis of neurologic disease is critical for patients and clinicians, the software provided for field analysis has tended to focus on glaucoma management. We are aware of only one commercial system designed to help identify neurologic disease from visual fields, and it is no longer available.6 The GHT exploits the tendency of glaucoma to damage the upper and lower fields differentially by comparing corresponding clusters of three to six test points above and below the horizontal midline. The method is effective in identifying glaucomatous visual field loss.7 In contrast, neurologic diseases that affect the visual pathway at or posterior to the optic chiasm produce visual field defects that respect the vertical midline, due to the segregation at the chiasm of retinal ganglion cell axons arising from the nasal and temporal retina. Clinicians may identify these homonymous or heteronymous neurologic patterns by manual inspection of the field data, but until now there has been no automated analysis of the quantitative differences across the vertical midline. To address this need, we created a neurologic hemifield test (NHT) to improve the detection of chiasmal and postchiasmal field loss.

The Scleral Inflation Response of Mouse Eyes to Increases in Pressure

Abstract: Glaucoma is one of the leading causes of blindness in the world. Evidence suggests that the stress generated in the eye wall by an elevated intraocular pressure plays a role in damaging the visiontransmitting retinal ganglions cells. However, the relationship between the connective tissue’s mechanical properties and how it affects the cellular function is not understood. The purpose of this study was to measure the inflation response of intact C57/BL6 (control) mouse sclera to increases in intraocular pressure, comparing old (11 month) and young (2 month) animals. Mouse eyes were enucleated, mounted by the cornea to a custom fixture, cannulated and immersed in PBS. An active feedback, pressure-controlled syringe pump inflated the cannulated eyes in a series of load-unload and ramp-hold creep tests. A CCD video camera attached to a microscope imaged the expanding scleral surface at 0.5Hz. Scleral displacement was measured with a digital image correlation program. After testing, fresh tissue thickness measurements were taken on scleral slices at multiple locations. An optimized inverse finite element analysis was performed to fit a non-linear anisotropic material model to the experimental data, and material parameters are compared between groups.