Invited Commentary: Form Versus Function: A State of Disunion?

“Form and function should be one, joined in a spiritual union.” —Frank Lloyd Wright Frank Lloyd Wright was referring to an architectural paradigm with this iconic quote, but the concept of interdependence between form and function is equally germane to our understanding of the afferent visual pathway (1). As a functionally eloquent and anatomically elegant region of the central nervous system (CNS), the afferent visual pathway has been aptly characterized as “a chain of hierarchically organized and synaptically linked neurons that maintain strong topographic connectivity” (2). As such, it represents an ideal model to study both the acute and chronic effects of lesions affecting any of its constituent parts, from retina to cortex. Because the afferent visual pathway is amenable to study with sensitive measures of function and structural integrity, this model potentially could allow us to elucidate mechanisms of neurologic injury and repair for a wide variety of CNS disorders (1). Two publications in this issue of the Journal of Neuro-Ophthalmology have challenged the notion that form and function are synergistically linked in the afferent visual pathway. In a series of patients with chiasmal syndromes, Tieger et al (3) described patterns of ganglion layer loss that could be used to facilitate early detection of compressive lesions. These investigators also highlighted several cases in which visual field recovery manifested post-decompression, despite the persistent ganglion layer thinning as measured by optical coherence tomography (OCT). Similarly, Fraser and Klistorner (4) illustrated a pattern of ganglion cell loss corresponding to the homonymous visual field defect caused by a demyelinating optic tract lesion. Again, permanent structural deficits were noted with OCT despite recovery of the homonymous field loss. To better understand the apparent disconnect between form and function in these reports, we must carefully consider the accuracy of our measures of form and the sensitivity of our measures of function. To this end, consider the experience of our glaucoma colleagues who have long grappled with the clinical implications of this conundrum: namely, establishing a structural-functional paradigm that, early in the disease course, identifies patients at risk for vision loss. This approach seems apropos given that glaucoma is viewed by many as a neurodegenerative disorder associated with progressive loss of retinal ganglion cells and their axons within the optic nerve, with effects on afferent visual pathway structures that parallel those of primary CNS disorders (5). While visual field testing with automated perimetry has become the mainstay in capturing visual deficits in patients with glaucoma and other optic neuropathies, patient-related factors including fatigue and reliability often hamper interpretation of results. Attempts to correlate form and function in glaucoma also have been encumbered by the fact that OCT and automated perimetry values tend to vary from day to day. This becomes problematic in cross-sectional studies when results from a single time point are analyzed (6). Furthermore, many studies, including the report by Tieger et al (3), have compared averaged automated perimetry data with mean OCT measures. However, a more sensitive approach would be to compare local visual field sensitivity to local retinal nerve fiber layer (RNFL) loss, so that regional relationships can be identified. Hood et al (6) have pointed out that reliance on automated perimetry values expressed as an average of decibel units is a potential confounder in defining structural-functional relationships in glaucoma. These values should be antilogged before averaging and then logged again after averaging to more accurately reflect the correlation between retinal ganglion cell integrity and visual field sensitivity. In general, structure-function correlations will be limited by any factor that negatively impacts the sensitivity and reliability of the psychophysical test being used to detect vision loss. In the afferent visual pathway model, there also are inherent limitations associated with structural markers of neuroaxonal integrity currently available. The presence of an OCT “floor effect” means that RNFL thickness cannot fall below approximately 30 µm regardless of the extent of optic nerve injury (7). Consequently, patients with severe structural damage in the afferent visual pathway may not manifest detectable changes in RNFL thickness or ganglion layer values, even in the context of progressive vision loss caused by optic neuropathy. Numerous reports have suggested that there is a threshold of OCT RNFL and ganglion layer integrity which needs to be breached before vision loss manifests in patients with demyelinating, glaucomatous, and compressive optic neuropathies (5,8–10). Based on the so-called “tipping point” theory, the apparent disconnect between structure and function in the reports by Tieger et al (3) and Fraser et al (4) could be due to the fact that not enough structural damage occurred for permanent visual field deficits to develop. Finally, cortical adaptive responses may account for differences in visual recovery between patients with comparable OCT measures of structural damage in the afferent visual pathway. Differences in the “cortical reserve” between patients may be based on factors such as: the age of the patient when the injury was sustained; disease duration; and the underlying pathogenic mechanism of tissue damage. In glaucoma, inner retinal layer thinning, optic nerve cupping, and altered activity in the visual cortex manifest before detectable visual field and impairment, suggesting a role for neuro-plasticity (5). Thus, in determining structural-functional correlations, the afferent visual pathway might best be viewed as a whole, which is greater than the sum of its parts, as it is highly adaptive to injury. Any perceived disunion between form and function should challenge us to explore potential sources of error with our current measuring “yardsticks” and consider the contributions of cortical adaption affecting visual recovery. Future studies designed to rigorously follow patients throughout all phases of their disease will be of tremendous value in establishing the validity, and more importantly the utility, of emerging structural-functional paradigms in the afferent visual pathway model.

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