Reduced Peripapillary and Macular Vessel Density in Unilateral Postgeniculate Lesions With Retrograde Transsynaptic Degeneration

Background: Retrograde transsynaptic degeneration (RTSD) of the retinal ganglion cells and retinal nerve fiber layer after postgeniculate injury has been well documented, but to the best of our knowledge, associated retinal microvascular changes have not been examined. The purpose of our study was to assess vessel density (VD) at macular and peripapillary regions in patients with RTSD. Methods: Cross-sectional study including 16 patients with homonymous visual field defects secondary to unilateral postgeniculate visual pathway injury and 18 age-matched controls. All participants were examined with AngioVue optical coherence tomography angiography to measure the peripapillary vessel density and macular vessel density (pVD/mVD) as well as the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell complex (GCC) thicknesses. The pRNFL and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses also were evaluated using Cirrus OCT. A normalized asymmetry score (NAS) was calculated for GCIPL and GCC thickness, and mVD. Results: Average pRNFL and macular GCIPL/GCC thicknesses were significantly thinner in both eyes of patients compared with control eyes (all P ≤ 0.05). Eight patients (50%), who showed a RTSD of the GCIPL map, had a relative thinning of the GCIPL/GCC ipsilateral to the brain lesion in both eyes (represented by a positive GCIPL-NAS/GCC-NAS). The mean pVD and mVD also were significantly reduced in patients (all P ≤ 0.05). There was a strong correlation between GCIPL-NAS/GCC-NAS and mVD-NAS index in both eyes (all r > 0.7, P = 0.001). Furthermore, there was a similar spatial pattern of damage for the macular GCC thickness and VD values. Conclusions: We demonstrated a significant VD decrease in peripapillary and macular areas of patients with RTSD because of postgeniculate lesions. The structural and microvascular asymmetry indexes were significantly correlated. These findings provide new insights regarding transsynaptic degeneration of the visual system.

Original Contribution Reduced Peripapillary and Macular Vessel Density in Unilateral Postgeniculate Lesions With Retrograde Transsynaptic Degeneration Laia Jaumandreu, MD, PhD, Veronica Sánchez-Gutiérrez, MD, Francisco J. MuñozNegrete, MD, PhD, Victoria de Juan, PhD, Gema Rebolleda, MD, PhD Background: Retrograde transsynaptic degeneration (RTSD) of the retinal ganglion cells and retinal nerve fiber layer after postgeniculate injury has been well documented, but to the best of our knowledge, associated retinal microvascular changes have not been examined. The purpose of our study was to assess vessel density (VD) at macular and peripapillary regions in patients with RTSD. Methods: Cross-sectional study including 16 patients with homonymous visual field defects secondary to unilateral postgeniculate visual pathway injury and 18 age-matched controls. All participants were examined with AngioVue optical coherence tomography angiography to measure the peripapillary vessel density and macular vessel density (pVD/mVD) as well as the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell complex (GCC) thicknesses. The pRNFL and macular ganglion cell–inner plexiform layer (GCIPL) thicknesses also were evaluated using Cirrus OCT. A normalized asymmetry score (NAS) was calculated for GCIPL and GCC thickness, and mVD. Results: Average pRNFL and macular GCIPL/GCC thicknesses were significantly thinner in both eyes of patients compared with control eyes (all P # 0.05). Eight patients (50%), who showed a RTSD of the GCIPL map, had a relative thinning of the GCIPL/GCC ipsilateral to the brain lesion in both eyes (represented by a positive GCIPL-NAS/GCC-NAS). The mean pVD and mVD also were significantly reduced in patients (all P # 0.05). There was a strong correlation between GCIPL-NAS/GCC-NAS and mVD-NAS index in both eyes (all r . 0.7, P = 0.001). Furthermore, there was a similar spatial pattern of damage for the macular GCC thickness and VD values. Ophthalmology Service, University Hospital Ramón y Cajal, School of Medicine and Health Science, University of Alcalá (IRYCIS), Madrid, Spain. 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 HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Laia Jaumandreu, MD, PhD, Ophthalmology Service, University Hospital Ramón y Cajal, School of Medicine and Health Science, University of Alcalá (IRYCIS), Madrid, Spain; E-mail: [e-mail] 462 Conclusions: We demonstrated a significant VD decrease in peripapillary and macular areas of patients with RTSD because of postgeniculate lesions. The structural and microvascular asymmetry indexes were significantly correlated. These findings provide new insights regarding transsynaptic degeneration of the visual system. Journal of Neuro-Ophthalmology 2019;39:462–469 doi: 10.1097/WNO.0000000000000794 © 2019 by North American Neuro-Ophthalmology Society R etrograde transsynaptic degeneration (RTSD) of the visual pathway, first observed in animal studies (1,2), has been demonstrated in clinical studies including patients with congenital lesions (3) and acquired postgeniculate brain injury. However, it is not present in all patients (4,5). Both retinal nerve fiber layer (RNFL) (6–12) and ganglion cell complex (GCC) (13) or ganglion cell–inner plexiform layer (GCIPL) (9,10,14–18) thinning, detectable by optical coherence tomography (OCT), have been observed in eyes with RTSD phenomenon, but the ganglion cell analysis seems to be more sensitive than RNFL evaluation (4,13,14). Optical coherence tomography angiography (OCT-A) is a novel diagnostic technique that offers an additional approach for visualizing retinal microvasculature by detecting motion contrast from flowing blood. It uses a fast, noninvasive technology capable of giving structural and microvasculature information (19). It has been shown that there is decreased optic disc perfusión and peripapillary capillary density on OCT-A in patients with glaucoma and other chronic optic neuropathies (20). Hijashijama et al (21) reported a decrease in the peripapillary retinal perfusion that correlated with the visual field defects (VFDs) due to chiasmal compression. To the best of our knowledge, retinal microvascular changes due to RTSD from postgeniculate lesions have not Jaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution been studied. We hypothesized that patients with RNFL and GCC/GCIPL damage due to RTSD have a decrease of the vessel density (VD) at corresponding areas of visual field (VF) loss as measured by OCT-A. The purpose of our study was to examine the peripapillary and macular VD by OCT-A in patients with homonymous VFDs secondary to unilateral postgeniculate visual pathway lesions and assess for any correlation with RNFL and GCC/GCIPL thicknesses. METHODS Participants Thirty-two eyes of 16 patients with homonymous VFDs secondary to unilateral retrogeniculate visual pathway lesions and 36 eyes of 18 healthy age-matched controls were recruited from June to December 2017. To be included in the study, patients had to have a reliable homonymous VFD by automated perimetry (Swedish Interactive Threshold Algorithm standard 24–2 strategy, Humphrey Visual Field Analyzer Carl Zeiss Meditec, Dublin, CA), due to a neurological injury located within the postgeniculate portion of the visual pathway and diagnosed at least 10 months before the beginning of the study. Patients with other ocular or neurological pathology that could produce a VFD or OCT charges were excluded. Subjects unable to cooperate with the imaging protocol, with extreme refractive errors or media opacities altering the OCT were also excluded from the analysis. Neuroimaging was carefully reviewed to exclude other lesions involving either the optic tract or lateral geniculate nucleus. Healthy control eyes were defined as follows: bestcorrected visual acuity better than or equal to 20/20; intraocular pressure less than 21 mm Hg; normal-appearing optic discs; no evidence of retinal pathology or optic neuropathy; normal automated VFs (Humphrey SITA 242); and no history of visual pathway pathology or intraocular surgery (other than uneventful cataract extraction). The research protocol followed the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Ramon y Cajal University Hospital, Madrid, Spain. Written informed consent was obtained from each patient before enrollment. All eligible participants underwent a comprehensive ophthalmologic evaluation including refraction, anterior and posterior segment biomicroscopy, tonometry (Goldmann tonometer; Haag-Streit AG, Koeniz, Switzerland), axial length measured using IOL Master (Carl Zeiss Meditec), and at least 2 reliable automated conventional perimetry tests of both eyes with Humphrey Visual Field Analyzer (Carl Zeiss Meditec). Spectral domain OCT using 2 OCT devices and OCT-A imaging were performed on the same day and by the same operator (V.d.J.). Peripapillary retinal nerve fiber layer (pRNFL) and periJaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 papillary vascular parameters, as well as macular GCC thicknesses and macular vascular parameters were analyzed by AngioVue OCT (Optovue, Inc, Fremont, CA version 2017.1.0.134). pRNFL and GCIPL thicknesses were obtained using GCA software provided by Cirrus OCT (Carl Zeiss Meditec AG, Jena, Germany) (Fig. 1). At least 2 scans for each protocol were taken, and the image with the best quality was chosen. All scans were individually reviewed by one investigator (V.d.J.) for signal strength, segmentation error, misalignment, poor fixation, or motion artifact. Poor-quality images were discarded. The AngioVue OCT-A (Optovue, Inc) is an angiographic platform implemented on the existing SD-OCT platform that provides structural and vascular measurements. Vascular information is optimized for the SplitSpectrum Amplitude-Decorrelation Angiography algorithm (22). VD percentages were automatically calculated by measuring the percentage of vascular areas with blood flow on en face angiograms. Normalized Asymmetry Score In a right homonymous hemianopia due to left brain injury, the nasal fibers of the right eye and temporal fibers of the left eye are “presumably affected” (left hemimaculas); and the temporal fibers of the right eye and nasal fibers of the left eye are “unaffected” (right hemimaculas); thus, damage is reflected in the hemimacula ipsilateral to the brain injury. A GCC-normalized asymmetry score (GCC-NAS) and GCIPL-normalized asymmetry score (GCIPL-NAS) were calculated for each eye by subtracting the combined thickness of the 2 ipsilateral quadrants or sectors, respectively (presumably affected side), from the combined thickness of the 2 contralateral quadrants or sectors (presumably normal side) and dividing this result by the combined thickness of the 2 contralateral quadrants or sectors (Fig. 2) (10). Therefore, a positive GCC-NAS/GCIPL-NAS indicates a lower GCC/GCIPL thickness on the affected hemimacula, and a negative score reflects just the opposite. In a similar way, we calculated the mVD-NAS to compare both hemimacular VDs (mVD-NAS) (Fig. 2). For this index, a positive mVD-NAS points a lower VD on the presumably affected hemimacula. As the healthy control subjects had no brain injury, the right eye was assumed as the eye with nasal hemianopia (ipsilateral to the brain lesion) and the left eye as the eye with temporal hemianopia (contralateral to the brain lesion). Observable Retrograde Transsynaptic Degeneration Two neuro-ophthalmologists reviewed the Cirrus OCT images to detect the thinning pattern of RNFL or GCIPL consistent with RTSD, named as “observable RTSD” following the same criteria as Mitchell et al (10). 463 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A. Automated visual fields and axial T2 brain MRI of a patient with a right homonymous hemianopia due to a stroke. B. Shown for the left eye with a nasal hemianopia (eye ipsilateral to the stroke) are color-coded thicknesses for peripapillary RNFL and corresponding color-coded map of peripapillary vessel density. C. Color-coded thickness maps for macular GCIPL and GCC thicknesses, and for macular superficial layer vessel density. There is GCC and GCIPL thinning and decreased macular vessel density (VD) in the temporal hemimacula (darker blue). GCC, ganglion cell complex; GCIPL, ganglion cell– inner plexiform layer; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. Statistical Analysis The Kolmogorov–Smirnov test was used to verify the normality of the data distribution. For quantitative comparisons between groups, we used the Student t test for independent samples for parametric variables. Chi-square tests were used to evaluate categorical variables. Pearson correlation coefficients were calculated to assess the relation between continuous variables. Statistical analyses were performed using SPSS statistical software for Windows (version 20.0, IBM-SPSS, Chicago, IL). The level of statistical significance was set at P , 0.05. RESULTS This study initially enrolled 20 patients, but 4 were excluded because of poor quality of OCT images (nystag464 mus [n = 2] and media opacities [n = 2]). The analyzed sample eventually included 16 patients (32 eyes) and 18 age-matched healthy subjects (36 eyes). Table 1 (See Supplemental Digital Content, Table E1, http://links. lww.com/WNO/A373) summarizes the demographics and clinical characteristics of both groups. There was no significant difference in age, sex, axial length, or refractive error between groups. The etiology and duration of homonymous VFD are shown in Table 2 (See Supplemental Digital Content, Table E2, http://links.lww.com/WNO/ A374). Overall, the mean time lapsed from initial diagnosis was 7.1 ± 5.9 years. Eleven patients (68.75%) had homonymous hemianopia, and 5 (31.25%) had homonymous quadrantanopia. The VF defect was symmetrical in most patients (93.7%). Jaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. The GCC, GCIPL, and mVD normalized asymmetry scores (NASs) were calculated for both eyes in a patient with a right homonymous hemianopia due to a left-sided brain lesion. We subtract the combined thickness of the 2 presumably affected sectors, from the combined thickness of the 2 unaffected sectors, dividing the result by the combined thickness of the 2 unaffected sectors. All scores (GCC-NAS, GCIPL-NAS, and mVD-NAS) were positive in both eyes, indicating that damage was more pronounced on the left hemimacula, ipsilateral to the brain damage. GCC, ganglion cell complex; GCIPL, ganglion cell–inner plexiform layer; mVD, macular vessel density; NAS, normalized asymmetry score. A comparison of pRNFL thickness provided by Cirrus and Optovue, OCT, and peripapillary vessel density (pVD) values by AngioVue OCT between eyes of patients and eyes of control subjects are shown in Supplemental Digital Content (see Table E1, http:// links.lww.com/WNO/A373). This table also displays differences in macular GCC thickness, GCIPL thickness, and macular VD, between eyes of patients and eyes of controls. The pattern of distribution for pRNFL and pVD damage and GCC thickness and macular vessel density (mVD) values is shown in Figure 3. It can be observed that while the pattern of distribution for pRNFL and pVD damage was not exactly the same, in the case of GCC thickness and mVD, there was a similar spatial distribution of damage. Figure 4 shows the asymmetry indexes for macular GCC, GCIPL, and VD in affected eyes and controls. We found 16 eyes (8 patients: 50%) who had an “observable RTSD” for GCIPL. All these patients had a positive GCIPL/GCC-NAS in both eyes. From these 16 eyes, all eyes with nasal hemianopia, and 5 with temporal hemianopia eyes had a positive mVD-NAS (Fig. 4, left column). The remaining 8 patients (50%) showed a positive GCCNAS in one eye and negative in the other, with similar findings in VD-NAS, and a GCIPL-NAS that tended to zero independently of the sign (in 7 of the 8 cases, the TABLE 1. Demographic and clinical characteristics in patients with homonymous visual field defects secondary to retrogeniculate visual pathway lesions and healthy controls Sex (male/%) Age (years ± SD) MD (mean ± SD) Diabetes mellitus, n (%) Hypertension, n (%) Dyslipidemia, n (%) Mean axial length Patients (n = 16) Controls (n = 18) P value 11 (68.8) 50.6 ± 17 213.8 ± 6 0 (0) 5 (31.2) 3 (18.7) 23.8 ± 0.8 8 (44%) 48.8 ± 15.5 21.1 ± 1.3 1 (5.5) 2 (11.1) 3 (16.7) 23.4 ± 0.9 0.229† 0.743* 0.000* 0.34† 0.15† 0.87† 0.29* *Independent t test. † 2 x test. Jaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 465 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Etiology, duration, and ganglion cell complex (GCC)/ganglion cell–inner plexiform layer (GCIPL) damage associated in patients with homonymous visual field defects Etiology ICH AV malformation Trauma Stroke Intracranial tumor* Number (%) 4 6 1 2 3 (25) (37.5) (6.25) (12.5) (18.7) GCC/GCIPL Damage (%) 4 3 0 0 1 VD Decrease (%) (100) (50) (0) (0) (33.3) 3 2 0 0 1 (75) (33.3) (0) (0) (33.3) Time Form Injury (yrs) VF Defect (Hemianopia/Quadrantanopia) 14 ± 1.4 5.9 ± 4 15 17.5 1.3 ± 0.4 3/1 2/4 1/0 2/0 3/0 *meningioma, low-grade glioma, gangliocytoma. AV, arteriovenous; VD, vessel density; VF, visual field; ICH, spontaneous intracranial hemorrhage. GCIPL-NAS was #0.05) indicating very little asymmetry (Fig. 4, middle column). The average magnitude of the GCC-NAS and GCIPLNAS was significantly greater in eyes of patients with VF defects than in eyes of controls (all P , 0.05). In control eyes, the mean mVD at the nasal sectors was significantly higher than at the temporal ones (107.5 ± 7.5 vs 100.1 ± 7.4; P = 0.000). The Supplemental Digital Content (see Table E2, http://links.lww.com/WNO/A374) displays the correlations among structural and microvascular parameters provided by AngioVue OCT. We observed a strong direct correlation between the GCC-NAS and mVD-NAS indexes in both eyes (r = 0.7, P = 0.001; and r = 0.8, P , 0.001 for eyes with nasal and temporal hemianopia, respectively) (left column) and between the GCIPL-NAS and mVD-NAS (r = 0.7, P = 0.005; and r = 0.8, P , 0.001) (See Supplemental Digital Content, Fig. E1, http://links.lww.com/WNO/ A372). We did not find any significant relationship between GCC-NAS, GCIPL-NAS, or mVD-NAS, and the time elapsed since onset of brain injury, even after excluding 4 patients evaluated beyond 150 months from injury. DISCUSSION We demonstrated that patients with homonymous VF defects due to retrogeniculate visual pathway and RTSD showed not only a significant RNFL thinning and homonymous damage of macular GCC/GCIPL but also a concordant decrease of VD in peripapillary and macular areas. Jindahra et al (6) initially showed RTSD in the human retina following acquired occipital lesions by using OCT. They found a thinning of the superior and inferior fibers in the eye with nasal hemianopia (ipsilateral to the brain lesion or “noncrossing fiber defect eye”) and thinning predominantly of the nasal and temporal side of the disc in the eye with temporal hemianopia (contralateral to the lesion or “crossing fiber defect eye”). Several authors also 466 have demonstrated RTSD in the macular area with GCIPL analysis (9,10,14–18) and GCC analysis (16) corresponding to the pattern of VF loss. Our study supports these findings. In addition, we found a statistically significant decrease in the mean average pVD in both eyes compared with controls (P = 0.000), although the pattern of distribution for pRNFL and pVD damage by quadrants was not exactly the same. The highest difference was found in the temporal and superior quadrants in eyes with a nasal hemianopia, and in the nasal quadrant in eyes with temporal hemianopia and a significant reduction of mVD in patients compared with controls that followed a similar spatial distribution of damage to the macular GCC thinning (Fig. 3B). Mitchell et al (10) studied the GCIPL thickness of 22 patients with homonymous VF loss. They found a relative GCIPL thinning ipsilateral to the brain lesion in both eyes in 15 patients (68%) by using the NAS index. In line with Mitchell’s study, we found 50% of subjects with observable RTSD for GCIPL map. All these patients had homonymous GCC/GCIPL thinning corresponding to the pathway projection of the postgeniculate lesion and had a positive GCC-NAS in both eyes. Furthermore, we obtained similar findings when analyzing vascular parameters. A strong relationship was observed in 5 of 8 patients between GCC/GCIPL thickness asymmetry and the VD asymmetry scores. In the remaining 3, the VF defects were not complete (1 patient had quadratic VF loss). Another explanation could be related to OCT-A resolution, since only when flow is within the acquisition range will there be a decorrelation signal with OCT-A. Consistent with the findings of Mitchell et al (10), we also found that the magnitude of the asymmetry indexes was significantly greater in patients who showed RTSD than in controls. In a normal macula, there is a higher ganglion cell density nasally than in equivalent temporal eccentricities (23,24). Surprisingly, we also found this difference in the superficial capillary plexus in healthy controls, with a 7% greater VD in the nasal compared with the temporal Jaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. A. A comparison of peripapillary RNFL thickness and pVD by Angiovue OCT between patients and controls. Eyes with nasal hemianopia (top and bottom left) and eyes with temporal hemianopia (top and bottom right), respectively. B. A comparison of macular GCC thickness and macular VD by Angiovue OCT between patients and controls. Eyes with nasal hemianopia (top and bottom left) and eyes with temporal hemianopia (top and bottom right), respectively. GCC, ganglion cell complex; I, inferior; N, nasal; OCT; optical coherence tomography; pVD, peripapillary vessel density; RNFL, retinal nerve fiber layer; S, superior; T, temporal; VD, vessel density. hemimacula (P , 0.001). This finding differs from previously reported “spiderweb” appearance, where the vessels are evenly distributed (22). These anatomical factors explain why in patients without RTSD and in controls, each eye has a GCC-NAS and mVD-NAS with a different sign, as well as why in patients with observable RTSD, Jaumandreu et al: J Neuro-Ophthalmol 2019; 39: 462-469 the magnitude of asymmetry of the eye with nasal hemianopia (damage in the temporal hemimacula) is always greater than in eyes with temporal hemianopia (damage in the nasal hemimacula). RTSD contrast, GCIPL-NAS is less affected by this physiological asymmetry because the temporal and nasal sectors better encompass the 467 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Ganglion cell complex normalized asymmetry score (GCC-NAS) (upper row), ganglion cell–inner plexiform layer asymmetry score (GCIPL-NAS) (middle row), and macular vessel density (mVD-NAS) (lower row) in patients with observable RTSD, no observable RTSD, and in controls. X axis represents the number assigned to each patient or control. The eye with nasal hemianopia is shown in blue and the eye with temporal hemianopia in green. RTSD, retrograde transsynaptic degeneration. totality of the hemimacula than the GCC analysis protocol (Fig. 2). RTSD does not occur in all patients, and it remains unknown how long it takes for OCT abnormalities to develop. RTSD has been reported as soon as 3.5 months after ischemic stroke (4,10,11). In our study, 8 patients did not demonstrate RTSD. Of these, only 1 patient was evaluated within 1 year after injury, and some had a dense VF defect from a brain lesion occurring beyond 5 years. There may be other factors required for RTSD to occur. The main limitation of our study is the relatively small sample size. In addition, the OCT-A technology is still in development, and the device used has some limitations including imaging artifacts due to the inability to correct for movement of the eyes. In conclusion, we have found a decrease of the peripapillary and macular retinal perfusion correlating with RNFL and GCC/GCIPL damage due to RTSD. Further longitudinal studies with larger patient cohorts are needed to assess the temporal relationship between structural and 468 microvascular damage and to elucidate the role of retinal perfusion in RTSD. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: L. Jaumandreu, V. SánchezGutiérrez, F. J. Muñoz-Negrete, V. de Juan, and G. Rebolleda; b. acquisition of data: L. 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