Local Functional and Histological Changes after Intraretinal Ganglion Cell Axotomy in Macaque Retina

Abstract

Abstract: : Purpose: Prior studies have shown that multifocal electroretinogram (mfERG) responses from normal monkey eyes contain signals that are likely to be generated by ganglion cell (GC) activity. Such evidence was derived from experimental conditions that have widespread effects throughout the retina and/or optic nerve, such as intravitreal injections of pharmacologic agents, optic nerve transection, or experimental glaucoma. Pathologic events and visual field loss, however, are often localized, as in human glaucoma. It remains unknown whether focal lesions (ganglion cell loss in relative isolation from global optic nerve effects) can be detected using the mfERG. The purpose of this experiment was to assess the effects of a focal retinal nerve fiber bundle axotomy on mfERG responses. Methods: mfERGs, standard full-field ERGs (fERG) and pattern-ERGs (PERG) were obtained at baseline and monthly after focal laser treatments induced a ‘bundle defect’ within the supero-temporal nerve fiber layer (NFL) of the left eye in one macaque monkey. Three mfERG stimulus protocols were compared: a standard fast m-sequence flicker, a "global-field flash" paradigm (Sutter et al, 1999), and a slowed m-sequence (8 video frames per m-step). Optic nerve and retinal structural changes were studied histologically using standard H/E techniques and immunohistologic stains for glial fibrillar acidic protein (GFAP) and neurofilament (NF). Results: The NFL bundle defect was plainly visible both proximally and distally to the site of the photoablation. A focal notch corresponding to the NFL defect was present within the neuro-retinal rim of the optic disk. Histologic results showed near total loss of the GC layer and NFL, with preservation of more distal retinal layers in the area upstream from the axotomy; local GFAP expression was increased in both retina and optic nerve. PERG and fERG parameters remained within the normal range for 30 control animals. mfERGs showed selective loss of high-frequency components for responses located within the arcuate region corresponding to the NFL defect. Functional loss was most easily detected using the slowed m-sequence stimulus. Conclusions: Focal loss of ganglion cell function in the macaque retina can be detected using the mfERG. The slowed m-sequence stimulus may have performed best because of its relatively lower mean luminance – which may enhance mfOPs in the normal retina due to rod-cone interactions.

Keywords: electrophysiology: clinical • ganglion cells • nerve fiber layer