Patients with various types of optic neuropathy including ischemic, inflammatory, and pseudotumor cerebri were imaged with high-resolution imaging systems to assess their retinas at a cellular level in vivo. One en face flood–illumination imaging system equipped with AO (AO-flood–illuminated fundus camera) and two FDOCT systems, one of them equipped with AO (AO-FDOCT) have been used for this study. Each system has unique strengths: the AO-flood–illuminated fundus camera is optimized to produce clear images of the cone mosaic, whereas FDOCT systems allow clear imaging of the entire retinal thickness and sectioning of individual retinal layers in three dimensions, from which thickness maps can be created. AO-FDOCT has the added advantage of sufficient transverse resolution for visualization of individual cellular structures, such as the junction between inner and outer segments of cones and gaps between adjacent cones. Combining all these attributes from each system made it possible to examine cellular structures in three dimensions in living eyes of patients.
A limitation of this study is the small number of subjects. This deficit has to be considered when reviewing the results. The results in this article will be used as a foundation to recruit and study more patients from each type of optic neuropathy over time. Also, as we establish a larger normative database for various age groups, in vivo retinal images from normal subjects will be used to achieve a more direct comparison with diseased retinas instead of using histology data.
The pathogenesis of optic neuropathies has been studied extensively, but these studies have typically focused on inner retina. Hayreh41,42
showed that there are two types of ischemic optic neuropathy: anterior and posterior. The anterior form is caused by interference with the posterior ciliary artery supply to the optic nerve head and retrolaminar part of the optic nerve, which, in turn, results in visual loss and optic disc edema progressing to optic atrophy in a month or two. The posterior form is due to occlusion of nutrient arteries to the posterior part of the optic nerve and eventually atrophy develops, but in the initial stages, the optic disc appears normal despite visual loss. In contrast, Francois43
showed that ischemic optic neuropathy is caused by an obstruction of the vascular axial system of the juxtabulbar optic nerve and involves a greater part of the optic nerve.
The pathogenesis of optic neuritis is presumed to be inflammation or demyelination of the optic nerve, similar to that seen in MS.3
Patients with optic neuritis are more likely to develop MS in the future. Systemic and local infectious and inflammatory disorders can also cause optic neuritis (e.g., adjacent infection of the meninges, sinuses, or orbit may spread to involve the optic nerve).3
Although a variety of factors are implicated as potential causes of pseudotumor cerebri, most cases reveal no clearly identifiable underlying cause.44
The syndrome of pseudotumor cerebri presents with symptoms and signs of elevated intracranial pressure without additional neurologic abnormality. Common visual symptoms are optic disc pallor, visual field loss, and thinning of the NFL.
According to Köllner’s rule, optic nerve diseases usually result in red-green color defects, whereas those diseases that affect the outer retina cause blue-yellow defects. However, patients with glaucoma mostly show the blue-yellow color defect.45–49
This fact suggests that the color vision defect in glaucoma is more consistent with a retinal degeneration process than one involving only the optic nerve. Schneck and Haegerstrom-Portnoy18
and Menage et al.19
reported that patients with optic neuritis show mixed blue-yellow and red-green color defects, instead of the expected red-green defects. This observation further supports the implication of inner and outer retinal involvement in optic neuropathies.
To our knowledge, scant attention has been paid to the integrity of photoreceptors in optic neuropathies. It would be surprising if sustained prolonged visual field loss were accom panied by changes restricted to the nerve fiber layer and ganglion cells without affecting other retinal layers, including photoreceptors. All the patients we tested exhibited a strong association between structural changes in cone photoreceptors and loss of visual sensitivity as well as thinning of the three-layer inner retinal complex. The overall map of inner retinal layer thickness (composed of the NFL, GCL, and IPL) matched the visual field results closely, showing thinning at the locations where visual sensitivity was reduced.
In healthy retina, cones are generally densely packed with a common angular tuning toward the pupil center; hence, under normal imaging conditions (i.e., imaging light entering the pupil through its center) all the cones are detected and produce a regular cone mosaic. However, if cones undergo structural changes due to disease, (1) they may become less reflective as the refractive index difference between inner and outer segments decreases, (2) the direction of angular tuning may change due to less structural support around the cones, and/or (3) they may disappear altogether, leaving behind empty spaces. All these changes may contribute to dark spaces in the en face AO-flood images and indistinct OS/RPE layer in the OCT images. The SCE-imaging technique can be used to address the presence of misaligned cones in these dark spaces by using their waveguide properties. In characterizing the nature of these dark spaces, visual sensitivity is also useful. We have obtained such measures through visual fields and found positive relations with the extent of the dark spaces. Additional tests could include direct stimulation of these dark spaces using AO-guided microperimetry. At this point, we cannot be sure what proportion of the dark spaces in the en face images are made up of misaligned cones or completely dysfunctional cones. Nevertheless, our data demonstrated the validity of SCE imaging in partially characterizing the identity of dark spaces in en face images. In both OCT images, the main structural changes besides thinning of the NFL were detected at the junction of the OS and RPE, whereas the IS/OS was well defined in all cases.