Corresponding Ganglion Cell Atrophy in Patients With Postgeniculate Homonymous Visual Field Loss

A 67-year-old man developed jaw claudication followed by loss of vision in the left eye caused by anterior ischemic optic neuropathy (AION). An erythrocyte sedimentation rate was normal, but C-reactive protein was slightly elevated. Although the patient had no evidence of a right optic neuropathy, magnetic resonance imaging (MRI) revealed bilateral optic nerve sheath enhancement. A temporal artery biopsy was consistent with active giant cell arteritis (GCA). Our case demonstrates that bilateral optic nerve sheath enhancement on MRI can be seen in the setting of unilateral AION. This unique combination of clinical and imaging findings has not been reported previously and extends the clinical spectrum of presentation of GCA.

Original Contribution Corresponding Ganglion Cell Atrophy in Patients With Postgeniculate Homonymous Visual Field Loss Jamie R. Mitchell, MD, Cristiano Oliveira, MD, Apostolos J. Tsiouris, MD, Marc J. Dinkin, MD Background: The goal of our study was to look for the presence of homonymous ganglion cell layer-inner plexiform layer complex (GCL-IPL) thinning using spectraldomain optical coherence tomography (SD-OCT) in patients with a history of adult-onset injury to the postgeniculate pathways with rigorous radiological exclusion of geniculate and pregeniculate pathology. Methods: We performed a retrospective review of twentytwo patients (ages 24-75 y, 6 men, 16 women) with homonymous visual field (VF) defects secondary to postgeniculate injury examining the GCL-IPL with SD-OCT. An additional fifteen patients (ages 28-85 y, 5 men, 10 women) with no visual pathway pathology served as controls. Using segmentation analysis software applied to the macular scan, a normalized asymmetry score was calculated for each eye comparing GCL-IPL thickness ipsilateral vs contralateral to the patient's brain lesions. Results: We found that 15 of the twenty-two subjects had a relative thinning of the GCL-IPL ipsilateral to the postgeniculate lesion in both eyes (represented by a positive normalized asymmetry score in both eyes), whereas a similar pattern of right/left asymmetry was found in 4 controls (P = 0.0498). The magnitude of asymmetry was much greater in subjects compared with controls (P = 0.0004). There was no association between the degree of GCL-IPL thinning and the mean deviation on automated VF testing. A moderate correlation (R = 0.782, P = 0.004) between the magnitude of thinning and latency from onset of retrogeniculate injury was observed only after excluding patients beyond a cutoff point of 150 months. Departments of Ophthalmology (JM, CO, MD), Radiology (AJT), and Neurology (MD), Weill Cornell Medical College, New York, New York. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Marc J. Dinkin, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY 10021. E-mail: [e-mail] Mitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 Conclusions: This data provides compelling new evidence of retrograde transsynaptic degeneration causing retinal ganglion cell loss after postgeniculate visual pathway injury. Journal of Neuro-Ophthalmology 2015;35:353-359 doi: 10.1097/WNO.0000000000000268 © 2015 by North American Neuro-Ophthalmology Society C ircumpapillary retinal nerve fiber layer (RNFL) atrophy, as measured by time domain optical coherence tomography (TD-OCT) and spectral domain OCT (SDOCT) is known to occur following pregeniculate optic tract lesions in humans (1). Athough retrograde transsynaptic degeneration (RTSD) within parts of the central nervous system has been demonstrated in animal models (2) and humans (3,4), its occurrence in the visual pathways has been controversial. RTSD has been documented in nonhuman primates after lesions to the primary visual cortex (5-7), and clinical atrophy of the optic nerve and retinal nerve fibers on funduscopy has been reported in cases of injury to the postgeniculate visual pathways occurring either congenitally or at a very early age (8,9). RTSD of the visual system has been shown histologically in a patient with a congenital occipital malformation status post occipital lobectomy more than 40 years before (10) and is the likely cause of bilateral optic nerve cupping in patients with periventricular leukomalacia as a result of ischemic degeneration of the occipital radiations in children with perinatal hypoxic injury (11). Decreased signal responses of the parvocellular retinal ganglion cells using pattern electroretinography (PERG) have been recorded in patients with postgeniculate homonymous hemianopia suggestive of RTSD (12). But a follow-up PERG study using different temporal and spatial frequencies found no significant difference between the ganglion cell response to hemifield visual stimuli on the blind or intact side (13). Magnetic resonance imaging studies showing T2 hyperintensity within the lateral geniculate 353 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution nucleus (LGN) in cases of congenital occipital injury have also supported a concept of retrograde degeneration (14). TD-OCT has demonstrated retinal nerve fiber layers (RNFL) thinning in 2 cases of congenital occipital injury (15), offering a quantitative correlate to the optic atrophy observed on funduscopy in similar long-standing cases (8,9). Jindahra et al (16) also showed RNFL thinning using TD-OCT in 7 patients with congenital homonymous visual field defects (VFD). All of these findings supported the concept that RTSD was a phenomenon that occurred in patients with congenital or long-standing postgeniculate injury (17). However, Jindahra et al (16) also demonstrated for the first time RTSD using TD-OCT in 19 patients with acquired homonymous VFD. In a follow-up study by the same authors (18), the time course of RTSD was examined in a crosssectional analysis of 38 patients who had postgeniculate lesions of different durations and a longitudinal analysis of 11 patients who were followed serially from the time of diagnosis of their retrogeniculate injury. The results demonstrated a logarithmic relationship between age-adjusted RNFL thickness and time duration since injury, with the maximum rate of atrophy occurring in the first 1-2 years, consistent with previous pathology studies in primates (6). RTSD of the RNFL also has been demonstrated after cerebral infarctions both within and outside of the striate cortex (19) and in multiple sclerosis patients with evidence of atrophy in their visual cortex (20). The enhanced resolution of SD-OCT has enabled analysis of the ganglion cell layer-inner plexiform layer complex (GCL-IPL) in the macula using segmentation software. The aim of our study was to search for the presence of homonymous GCL-IPL thinning in patients with a history of adult-onset injury to the postgeniculate pathways with rigorous radiological exclusion of geniculate and pregeniculate pathology. METHODS Medical records from November 2010 to April 2014 were searched for the diagnostic codes homonymous hemianopia, homonymous VFD, or quadrantanopia. The 201 matches were screened for patients who had undergone Cirrus SDOCT (software version 6.5.0.772; Carl Zeiss Meditec, Dublin, CA) scans of the optic nerve and macula, which resulted in 39 subjects. Eleven subjects were excluded due to lack of available neuroimaging or the presence of optic nerve or retinal pathology. Neuroimaging of the remaining 28 subjects was reviewed independently by a neuroradiologist (A.J.T.) and a neuroophthalmologist (M.J.D.) to exclude lesions involving either the optic tract and/or LGN (found in 6 cases). The medical records of the remaining 22 subjects were reviewed for the following: date of VFD was first noted by the patient, OCT data (date of the scan, RNFL and GCL-IPL values), automated visual field data (type of VFD, date when first diagnosed, and mean deviation), and the date and location of 354 brain lesion identified on neuroimaging. Fifteen subjects with no visual pathway pathology served as controls. GCL ANALYSIS Using segmentation analysis software applied to the macular scan, a GCL-IPL asymmetry score was calculated for each eye. This was calculated as follows: 1) subtracting the combined thickness of the 2 sextants ipsilateral to the brain lesion (presumably affected side) from the combined thickness of the 2 contralateral (presumably normal) sextants, 2) the result obtained was divided by the combined thickness of the 2 contralateral sextants to create a normalized asymmetry score (NAS) for each eye. Thus, a positive NAS reflected a greater GCL-IPL thickness on the side of the macula contralateral to the brain lesion, and a negative score would reflect a greater thickness on the side ipsilateral to the brain lesion (Fig. 1). Two patients with bilateral lesions were included. We chose to analyze the longer standing lesion in both cases because this was more likely to be associated with RTSD (16,19). As the controls had no brain lesions, the NAS was calculated by subtracting the 2 left sextants from the 2 right sextants and dividing by the combined thickness of the 2 right sextants. Thus, a positive NAS indicated a thinner GCL-IPL on the left and a negative NAS indicated a thinner GCL-IPL on the right. RNFL Analysis RNFL was analyzed using the same protocol as in Jindahara et al (16). Specifically, we looked at the ratio of the RNFL thickness in the eye contralateral to the brain lesion (crossing fiber defect eye)/RNFL thickness ipsilateral to the lesion (noncrossing fiber defect eye). A ratio of 1 indicated no interocular difference. A ratio.1 implied greater loss of noncrossing RNFL fibers and a ratio,1 indicated greater loss of crossing RNFL fibers. We calculated the ratio for each clock-hour in both eyes because we would expect there to be greater loss of crossing fibers from the contralateral eye (ratio,1), which are located nasally and temporally (band optic atrophy) and greater loss of noncrossing fibers (superiorly and inferiorly) in the ipsilateral eye. For controls, the ratio of the right eye to the left eye was used and plotted for each clock-hour. Determination of "Readily Observable RTSD" For both RNFL and GCL, we assessed whether RTSD was readily observable based on a simple observation of the regions of thinning according to the Cirrus OCT's current standards. We defined "readily observable RTSD" for RNFL analysis, as the presence of RNFL thinning (within the 0%- 1% interval for the distribution of normal; red on the OCT reports) in the temporal and nasal sectors in the eye contralateral to the lesion and within the superior, inferior, and temporal regions in the ipsilateral eye. We defined "readily observable RTSD" for GCL analysis as the presence of GCL thinning within at least 1 homonymous sextant in both eyes Mitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A normalized asymmetry score (NAS) is calculated for each eye by subtracting the 2 sextants (blue arrows) ipsilateral to the patients' left-sided brain lesion from the 2 contralateral sextants (red arrows) and divided by the 2 contralateral sextants. Asymmetry corresponding to the lesion is not seen in both eyes in this example. GCL-IPL, ganglion cell layer-inner plexiform layer complex. ipsilateral to the lesion without any homonymous thinning in either of the 2 contralateral sextants in either eye. RESULTS The median age of the 22 patients was 50.5 years (range: 24-75 y), and the median age of controls was 60 years (range: 28-85 y). Seven (32%) had homonymous hemianopia, 14 (64%) had homonymous quadrantanopia, and 1 (4%) had a homonymous scotoma that straddled the horizontal meridian. Eighteen of the 22 VFDs (82%) were congruous, whereas 4 (18%) were incongruous. The etiologies of the field defects varied (Table 1). Fifteen (68%) of the 22 subjects had positive NAS in both eyes. This is compared with 5 of 15 controls (33%) who had a NAS in the same direction in both eyes (Fig. 2). Of the 7 subjects who did not show positive NAS in both eyes, 1 subject (4%) had no asymmetry in either eye. Three subjects (14%) had a positive NAS in 1 eye and no asymmetry in the other eye, and 3 (14%) had 1 eye with a positive NAS and 1 eye with a negative NAS. None of the subjects demonstrated a negative NAS in both eyes, whereas 4 of 15 controls had a negative NAS in both eyes (P = 0.0207 by Fisher exact test). Five of the 7 patients who did not show a positive NAS in both eyes had developed visual field loss within 1 year. TABLE 1. Etiology of homonymous visual field loss Etiology of Visual Field Defect Infarct Hemorrhagic stroke AVM hemorrhage Glioblastoma Epilepsy mapping surgery Tuberculosis (acute)/hemorrhage with encephalomalacia (chronic) Infarct (acute)/chronic infarct with encephalomalacia (chronic) Multiple sclerosis Meningioma Inflammatory lesion of unclear etiology Pleomorphic xanthoastrocytoma Number of Number With Thinner GCL Ipsilateral to Patients Brain Lesion OU Duration of Brain Injury, mo 3 3 3 4 2 1 1 1 3 2 1 1 1.5, 119, 208 1, 9.6, 19 9, 60, 384 3.5, 6, 12, 18 156, 156 132 (old), 41 (new) 1 1 (Thinner ipsilateral to side of encephalomalacia) 1 2 1 1 Unknown (old), 1 month (new) 86 36, 57 40 60 1 2 1 1 Bold indicates patients with positive normalized asymmetry score. AVM, arteriovenous malformation; GCL, ganglion cell layer. Mitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 355 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Positive normalized asymmetry score (NAS) values reflect ganglion cell layer-inner plexiform layer complex (GCLIPL) thinning ipsilateral to a post-geniculate lesion in eyes of 22 patients. B. In control eyes, a positive NAS reflects left-sided thinning and a negative NAS reflects right-sided thinning. Analysis of the control group showed that 18 of 30 eyes (60%) had a negative NAS and 12 of 30 eyes (40%) had a positive NAS. There were 5 controls (33%) where the sign of the NAS was the same in both eyes. The average magnitude (absolute value) of the NAS in the patient cohort was 0.113 (±0.114 SD). This was significantly higher than the control group (P = 0.0004) whose average NAS magnitude was 0.034 (±0.012 SD). The difference in NAS magnitude was also significant when comparing the 15 subjects with a positive NAS in both eyes (mean: 0.149 ± 0.012 SD) to the 5 controls whose NAS was in the same direction in both eyes (mean: 0.029 ± 0.017 SD) (P = 0.0044). In patients with homonymous field defects, a correlation was found between the side and degree of thinning between the 2 eyes (R = 0.786) (see Supplemental Digital Content, Figure E1A, http://links.lww.com/WNO/A160). This was even more apparent in patients whose OCT was obtained .1 years after the onset of visual field loss (R = 0.898) (see Supplemental Digital Content, Figure E1B, http://links.lww.com/WNO/A160). No correlation was found between the degree of GCLIPL asymmetry and the mean deviation or pattern deviation on automated visual field testing. When including all patients with a positive NAS in both eyes (n = 14; the time since injury was unknown for 1 356 subject), there was no statistically significant relationship between time elapsed since onset of injury (latency) and the magnitude of thinning. Based on the finding of Jindahra et al (18) that the rate of RNFL thinning in the second decade was only slightly higher than expected for age, we repeated the analysis, including only patients with a latency #150 months (n = 11), and found a moderate correlation (R = 0.782, P = 0.0004) (see Supplemental Digital Content, Figure E2, http://links.lww.com/WNO/A161). The results of the RNFL analysis suggested greater loss of crossing fibers nasally; however, only the inferotemporal sector was statistically significant (P = 0.042) by 2-tailed paired t test (see Supplemental Digital Content, Figure E3, http://links.lww.com/WNO/A162). Analysis of readily observable RTSD revealed that 10 of 22 (45.5%) patients demonstrated this finding by GCL analysis, whereas none demonstrated it by RNFL analysis (Fig. 3). DISCUSSION Our study demonstrates homonymous thinning of the macular GCL-IPL in patients with retrogeniculate lesions confirming the utility of GCL-IPL analysis in detecting RTSD. Mitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Readily observable retrograde transsynaptic degeneration (RTSD). Color-coded thickness maps for RNFL and GCL-IPL in each eye of each patient with results of automated visual fields. Boxed GCL plots indicated readily observable RTSD. AVF, automated visual fields; GCL, ganglion cell layer; RNFL, retinal nerve fiber layer. We found 2 previous case series describing RTSD of the macular GCL-IPL in patients with postgeniculate homonymous VFD (21,22). One series included 3 patients, all with complete hemianopias from large posterior cortical infarcts of greater than 1-year duration (21). The second series included 8 patients with a variety of lesions of the occipital cortex and internal capsule including infection, hemorrhage, excision, and infarct (22). The most recent lesion in this series was 1.4 years old. Our study is the largest case series describing RTSD of the macular GCL-IPL in patients with postgeniculate homonymous VFD, and it is the first to compare GCLIPL asymmetry due to RTSD with controls. Our results confirm those of Keller et al (22) that RTSD of the GCLIPL may be due to a variety of postgeniculate lesions (Table 1) and not just occipital infarction. By developing an NAS, we were able to demonstrate a significantly larger NAS in patients with postgeniculate lesions as compared with conMitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 trols. Although 15 patients had a positive NAS in both eyes, none of the patients had a negative NAS in both eyes. Not only were patients more likely to have a positive NAS in both eyes but also the magnitude of asymmetry in patients was significantly greater than that of controls (Fig. 2). Additionally, there was a correlation of the size and magnitude of the NAS between the 2 eyes of patients with postgeniculate lesions but not in controls, consistent with their homonymous nature. Our results are consistent with those of Keller et al (22) showing GCL-IPL thinning in cases of homonymous quadrantanopia, and that thinning occurred in sectors corresponding to the pathway projection of the postgeniculate lesions (Fig. 3). Unlike the 2 previous series looking at RTSD of the GCLIPL (21,22), we did not find RTSD in every patient. This is partly because, unlike previous reports, we included patients who developed a postgeniculate lesion within 1 year of 357 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution evaluation. However, there were 2 patients in our series who did not have a positive NAS in both eyes despite having visual field loss for more than 1 year. The lack of correlation in these 2 patients suggests that RTSD may not occur to the same degree in every person. Of note, the field loss in these 2 patients was a quadrantanopia, while all patients with homonymous hemianopias did demonstrate a positive NAS in both eyes. In our patients, a moderate correlation (R = 0.782, P = 0.0004) between the magnitude of thinning and time from onset of retrogeniculate injury was observed only after excluding patients beyond a latency cutoff point of 150 months (see Supplemental Digital Content, Figure E2, http://links.lww.com/WNO/A161). This is likely attributable to a plateau effect of a stabilization of GCL-IPL thinning over time (18). The positive correlation of the NAS with latency in our study suggests that RTSD continues to occur, at least in some patients, for up to 10 years. The exact biochemical changes responsible for RTSD remain unknown but the long time course suggests that there is a slow spread of a degenerative "signal" up the axon, the length of which contributes to the prolonged time course. In addition, different cell types within the GCL have variable rates of degeneration. Animal studies of neuronal dropout over time after cortical injury have demonstrated preferential degeneration of Pb (a parvocellular subtype) neurons, with relative sparing of alpha and gamma cells (23). The ratio of such projections to geniculate projections might contribute to the speed of degeneration of a given GCL neuron. Two patients had bilateral hemispheric lesions involving the postgeniculate visual pathway and were analyzed according to the older lesion, based on previous studies indicating progression of RTSD with time (18). As expected, the direction of the NAS score of both eyes corresponded to the side of the older lesion (16). We did not find a correlation between mean deviation on automated visual field testing and the magnitude of the NAS. Because a negative correlation between visual field loss and GCL thickness was demonstrated in some sectors in a previous study (24), we hypothesize that our negative results may simply reflect the greater significance of latency on GCL-IPL asymmetry, superseding any effect of visual field mean deviation in this small study. Based on our small series, we were unable to compare the sensitivity of GCL-IPL vs RNFL analysis for the detection of RTSD. However, although detection of RTSD requires a complex analysis of the RNFL (17-19), its presence with GCL-IPL color-coded thickness maps is readily apparent (Fig. 3). From a pragmatic standpoint, this is very valuable for the clinician and is exemplified by several case studies (Fig. 4). FIG. 4. A. This 24-year-old woman has a left inferior quadrantanopia after resection of a right occipital pleomorphic xanthoastrocytoma. SD-OCT shows right superior GCL-IPL thinning. B. A 63-year-old woman had a right homonymous hemianopia from a left parieto-occipital arteriovenous malformation hemorrhage 30 years before. SD-OCT shows corresponding GCL-IPL thinning on the left. C. This 46-year-old woman has a left superior quadrantanopia due to a right inferior occipital lobe lesion. OCT shows corresponding right inferior GCL-IPL thinning. GCL-IPL, ganglion cell layer-inner plexiform layer complex; SD-OCT, spectral-domain optical coherence tomography. 358 Mitchell et al: J Neuro-Ophthalmol 2015; 35: 353-359 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution There were several limitations to our study. First of all, it was a retrospective study with a small sample size. Although optic tract involvement was excluded radiologically, occult involvement could not be definitively excluded in some patients with demyelination or glioblastoma. Latency was determined based on the time at which the patient noted the VFD, which was at the time of tumor resection in some cases, although previous RTSD due to the tumor itself could not be excluded. Finally, the available segmentation software for Cirrus SD-OCT does not provide GCL-IPL quadrant or sextant analysis following a vertical and horizontal orientation; therefore, our analysis did not include the GCL-IPL complex within 30 degrees of midline. This series adds to the literature demonstrating the existence of RTSD following acquired postgeniculate lesions to the visual pathway in humans, in the form of clear-cut corresponding thinning of the GCL-IPL. Further investigation with prospective data is required to better illustrate the time course of macular GCL-IPL atrophy following postgeniculate visual pathway injury and to better elucidate the significance of this secondary degeneration, if any, on the prospects for visual rehabilitation in patients who have suffered homonymous field loss from postgeniculate injury. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design J. R. Mitchell, C. Oliveira, M. J. Dinkin; b. Acquisition of data J. R. Mitchell, C. Oliveira, M. J. Dinkin; c. Analysis and interpretation of data J. R. Mitchell, C. Oliveira, A. J. Tsouris, M. J. Dinkin. Category 2: a. Drafting the manuscript J. R. Mitchell, C. Oliveira, M. J. Dinkin; b. Revising it for intellectual content J. R. Mitchell, C. Oliveira, M. J. Dinkin. Category 3: a. Final approval of the completed manuscript J. R. Mitchell, C. Oliveira, A. J. Tsouris, M. J. Dinkin. 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