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

This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Ab- group. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients.

Invited Commentary 8. Danesh-Meyer HV, Wong A, Papchenko T, Matheos K, Stylli S, Nichols A, Frampton C, Daniell M, Savino PJ, Kaye AH. Optical coherence tomography predicts visual outcome for pituitary tumors. J Clin Neurosci. 2015;22:1098-1104. 9. Qiao N, Ye Z, Shou X, Wang Y, Li S, Wang M, Zhao Y. Discrepancy between structural and functional visual recovery in patients after trans-sphenoidal pituitary adenoma resection. Clin Neurol Neurosurg. 2016;151:9-17. 10. Lee J, Kim SW, Kim DW, Shin JY, Choi M, Oh MC, Kim SM, Kim EH, Kim SH, Byeon SH. Predictive model for recovery of visual field after surgery of pituitary adenoma. J Neurooncol. 2016;130:155-164. 11. Moon CH, Hwang SC, Ohn YH, Park TK. The time course of visual field recovery and changes of retinal ganglion cells after optic chiasmal decompression. Invest Ophthalmol Vis Sci. 2011;52:7966-7973. 12. Seddon HJ. Three types of nerve injury. Brain. 1943;66:238-288. 13. Feinsod M, Selhorst JB, Hoyt WF, Wilson CB. Monitoring optic nerve function during craniotomy. J Neurosurg. 1976;44:29-31. Form Versus Function: A State of Disunion? Fiona Costello, MD "Form and function should be one, joined in a spiritual union." -Frank Lloyd Wright F rank 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 NeuroOphthalmology 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. Departments of Clinical Neurosciences and Surgery, University of Calgary, Calgary, Canada. Address correspondence to Fiona Costello, MD, Foothills Medical Centre, Clinical Neurosciences, 12 floor, 1403 - 29th Street NW, Calgary, Alberta T2N 2T9, Canada; E-mail: fiona.costello@ calgaryhealthregion.ca Costello: J Neuro-Ophthalmol 2017; 37: 13-16 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 crosssectional 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. 15 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Invited Commentary 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 mm 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 16 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 structuralfunctional paradigms in the afferent visual pathway model. REFERENCES 1. Costello F. The afferent visual pathway: designing a structuralfunctional paradigm of multiple sclerosis. ISRN Neurol. 2013;2013:134858. 2. Kaushik M, Graham SL, Wang C, Klistorner A. A topographical relationship between visual field defects and optic radiation changes in glaucoma. Invest Ophthalmol Vis Sci. 2014;55:5770-5775. 3. Tieger M, Hedges TR, Ho J, Erlich-Malona N, Vuong LN, Athappilly GK, Mendoza-Santiesteban CE. Ganglion cell complex loss in chiasmal compression by brain tumors. J Neuroophthalmol. 2017;37:7-12. 4. Fraser CL, Tan I, Klistorner. Clinical-neuroimaging-OCT correlation in multiple sclerosis. J Neuroophthalmol. 2017;37:80. 5. Murphy MC, Conner IP, Teng CY, Lawrence JD, Safiulah Z, Wang B, Bilonick RA, Kim SG, Wollstein G, Schuman JS, Chan KC. Retinal structures and visual cortex activity are impaired prior to clinical vision loss in glaucoma. Sci Rep. 2016;6:31464. 6. Hood DC, Anderson SC, Wall M, Kardon RH. Structure versus function in glaucoma: an application of a linear model. Invest Ophthalmol Vis Sci. 2007;48:3662-3668. 7. Ye C, Lam DS, Leung CK. Investigation of floor effect for OCT RNFL measurement. Invest Ophthalmol Vis Sci. 2012;52:176. 8. Costello F, Coupland S, Hodge W, Lorello GR, Korluk J, Pan YI, Freedman MS, Zackan DH, Kardon RH. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol. 2006;59:963-969. 9. Wollstein G, Kagemann L, Bilonick RA, Ishikawa H, Folio LS, Gabriele ML, Ungar AK, Dukes IS, Fujimoto JG, Schuman JS. Retinal nerve fibre layer and visual function loss in glaucoma: the tipping point. Br J Ophthalmol. 2012;97:1088. 10. Danesh-Meyer HV, Papchenko T, Savino PJ, Law A, Evans J, Gamble GD. In vivo retinal nerve fiber layer thickness measured by optical coherence tomography predicts visual recovery after surgery for parachiasmal tumors. Invest Ophthalmol Vis Sci. 2008;49:1879-1885. Costello: J Neuro-Ophthalmol 2017; 37: 13-16 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.