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Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Analysis of Retinal Structure and Electrophysiological Function in Visual Snow Syndrome: An Exploratory Case Series Nathaniel J. Zaroban, MD, Sachin Kedar, MD, David Anderson, PhD, Amrita-Amanda D. Vuppala, MD Background: Visual snow (VS) is a rare but distressing phenomenon of persistent granular or pixelated visual distortions that may occur in isolation or as a component of visual snow syndrome (VSS). The current understanding of VS pathogenesis, including the role of retinal involvement structurally and functionally, is limited. The objective of this study is to investigate retinal structural and electrophysiological abnormalities in VS. Methods: This retrospective case series included 8 subjects (7 with VSS and 1 with isolated VS). Patients with other ocular and neurologic diseases were excluded. Data were assessed from automated perimetry, optical coherence tomography (OCT), visual evoked potential (VEP), and full-field electroretinography (ffERG) testing. The VEP and ffERG data of visual snow subjects were compared with ageand sex-matched control subjects for statistical significance. Results: The mean age of the cohort was 29.4 years (SD = ±5.3) with 50% gender split. The mean age of VS onset was 24.2 years (SD = ±3.8). All subjects had normal visual acuity, color vision, brain MRI, automated perimetry, OCT parameters (peripapillary retinal nerve fiber layer and macular ganglion cell layer thickness), and P100 and N135 wave pattern on VEP. Compared with controls, VS subjects had a greater mean b-wave amplitude in response to light-adapted 3.0 stimuli (t test; P = 0.035 right eye and P = 0.072 left eye), greater mean lightadapted 3.0 flicker amplitude (t test; P = 0.028 right University of Nebraska Medical Center (NZ), University of Nebraska College of Medicine, Omaha, Nebraska; Department of Ophthalmology (SK), Emory University School of Medicine, Atlanta, Georgia; University of Nebraska Medical Center (DA), Truhlsen Eye Institute, Omaha, Nebraska; and Department of Ophthalmology and Visual Sciences (A-AV), Medical College of Wisconsin, Milwaukee, Wisconsin. 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 Sachin Kedar, MD, Department of Ophthalmology, 1365 B Clifton Road NE, Atlanta, GA 30322; E-mail: sachin.kedar@emory.edu Zaroban et al: J Neuro-Ophthalmol 2023; 43: 227-231 eye P = 0.166 left eye) and greater b-wave amplitude in response to dark-adapted 10.0 stimuli (t test; P = 0.102 right eye; P = 0.017 left eye) on ERG. Conclusions: Patients with VS and VSS have normal retinal structure, but abnormal electrophysiology compared with control subjects. The increased b-wave and flicker amplitudes observed with ffERG suggest increased responsiveness of the rod and cone photoreceptors and may contribute to VS pathophysiology. Journal of Neuro-Ophthalmology 2023;43:227–231 doi: 10.1097/WNO.0000000000001757 © 2022 by North American Neuro-Ophthalmology Society V isual snow (VS) is a rare but distressing phenomenon of persistent granular or pixelated visual distortions (1). VS affects men and women equally. It most often presents suddenly in the second and third decades of life (2). Patients with VS often describe seeing static homogenously throughout their visual field similar to the appearance of a poorly tuned analog television (3). Although VS patients have reported differences in the characteristics of their symptoms, such as frequency of flickering or size of pixilation, most agree that their symptoms are continuously present and fail to change in character (4). VS often presents in the context of visual snow syndrome (VSS) (3). The International Classification of Headache Disorders (ICHD) diagnostic criteria for VSS requires the presence of VS with 2 additional visual symptoms (Table 1). Ophthalmologic examination such as visual acuity, visual fields, color vision, and neurologic imaging are all typically normal, making VSS a difficult clinical diagnosis (5,6). The pathophysiology of VS is poorly understood; however, several theories have been proposed. The leading theory suggests VS is a disorder of higher-order visual processing in the visual accessory cortices adjacent to the primary visual cortex in the posterior occipital lobe (5,7,8). Another theory suggests a potential role for excitotoxicity in 227 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. International classification of headache disorders diagnostic criteria for visual snow syndrome (3) A B i ii iii iv C D Dynamic, continuous, tiny dots across the entire visual field, persisting for .3 mo Additional visual symptoms of at least 2 of the following 4 types: Palinopsia Enhanced entoptic phenomena Photophobia Impaired night vision (nyctalopia) Symptoms are not consistent with typical migraine visual aura Symptoms are not better accounted for by another disorder VS via hyperexcitability and subsequent loss of visual evoked potential (VEP) habituation to repeated visual stimuli in the primary and secondary visual cortices (9). Finally, thalamocortical dysrhythmia, an improper communication of sensory information between the thalamus and its cortical projections, has also been suspected as a mechanism to induce visual snow (2,3,10,11). This thalamocortical dysrhythmia has been implicated in migraine and tinnitus, both commonly reported comorbidities in VS. The neurosensory retina, a structural and functional outpost of the brain, is a potential source of VS pathophysiology (2,6,12,13). Better understanding of retinal function in VS may uncover explanations for asynchronous neural communication and hyperexcitability in downstream regions of the visual pathway. In this exploratory small case series, we aimed to assess for patterns of retinal electrophysiological dysfunction in VS patients demonstrating heterogenous symptomatology. We hypothesized that significant differences in full-field electroretinography (ffERG) measurements would exist between VS subjects and controls. METHODS A retrospective case series was conducted at the University of Nebraska Medical Center (UNMC). Study procedures were approved by the UNMC Institutional Review Board. Patients referred to the Nebraska Medicine Truhlsen Eye Institute (TEI) electroretinography (ERG) lab for electrophysiologic evaluation of abnormal visual symptoms between 2019 and 2021 were reviewed. Eleven subjects were identified as VS suspects. These subjects’ electronic medical records were accessed via Nebraska Medicine’s EPIC and Zeiss Forum database systems to determine their visual symptomatology. Subjects were included in this study if their visual symptomatology was consistent with VSS (Table 1) or isolated VS, and they had no other more likely diagnoses. Subjects that did not meet these criteria or had other ocular pathologies were excluded. Of the 11 initial suspects, 3 were excluded because it was felt their symptoms were more likely caused by migraine 228 with persistent aura. Eight subjects were included (7 with VSS and 1 with isolated VS). We collected demographic data including subjects’ age, sex, race, and ethnicity. Neurologic, psychiatric, medical, surgical, medication, family, and social histories were reviewed. Best-corrected visual acuity, stereo-acuity, and color vision assessments were recorded. We reviewed brain imaging performed while subjects were symptomatic to ensure there were no structural abnormalities that could explain visual disturbances. All 8 subjects underwent automated perimetry testing using a Humphrey Field Analyzer as part of their clinical evaluation. Measures of Visual Field Index (VFI), mean deviation (MD), and fovea threshold (FT) were recorded using the proprietary software included with the instrument. Mean and SD were calculated for each measure. The Humphrey visual fields (HVFs) of each subject were independently evaluated by 2 experienced, masked neuroophthalmologists and were determined to be normal, abnormal, or indeterminate (if the reliability indices were poor). Spectral-domain optical coherence tomography (SD-OCT) testing data were available for all 8 subjects (7 subjects measured using a Heidelberg Spectralis and 1 subject using a Cirrus HD-OCT). Measures of average peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) thickness were recorded using the proprietary software recorded with each respective instrument. The mean and SD were calculated for each of these measurements. The subject whose mGCL thickness was measured using the Cirrus HD-OCT and another subject, whose mGCL was not measured, were not included in the mean. The OCTs of each subject were independently evaluated by 2 experienced, masked neuro-ophthalmologists and were determined to be normal, abnormal, or borderline. ffERG was performed using the Diagnosys Colordome and corresponding proprietary Diagnosys software program (Diagnosys Espion V6 Series 0-238 Software V6.64.21724.14; Diagnosys LLC, Lowell, MA). All electrophysiology studies were performed using the International Society for Clinical TABLE 2. Mean automated perimetry measurements in visual snow subjects Mean (±SD) VFI OD (%) VFI OS (%) MD OD (dB) MD OS (dB) FT OD (dB) FT OS (dB) 99.500 (0.707) 99.375 (0.696) 20.379 (1.184) 20.469 (1.056) 37.000 (1.500) 37.125 (1.536) n = 8 for all values. FT, fovea threshold; MD, mean deviation; OD, right eye; OS, left eye; VFI, visual field index. Zaroban et al: J Neuro-Ophthalmol 2023; 43: 227-231 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Mean optical coherence tomography retinal thickness measurements in visual snow subjects Mean (±SD) pRNFL OD (mm) pRNFL OS (mm) mGCL OD (mm) mGCL OS (mm) 103.250 (4.548) 102.500 (4.690) 34.500 (0.957) 34.500 (1.708) OD, right eye; OS, left eye; mGCL, macular ganglion cell layer, n = 6; pRNFL, peripapillary retinal nerve fiber layer, n = 8. Electrophysiology of Vision (ISCEV) standard protocol published by ISCEV (14,15). ERG a-wave and b-wave electrical potential amplitudes and latencies were recorded in response to light adapted-3.0, light adapted-3.0 flicker, dark adapted-0.01, dark adapted-3.0, and dark adapted-10.0 visual stimuli protocols. P100 and N135 VEP amplitude and latency were measured using occipital scalp electrodes following visual stimulation with a CRT Pattern Stimulator. VS subject ffERG and VEP data were compared with age- and sex-matched control subjects from our research registry. All 8 subjects were successfully matched. Statistical Analysis A 2-tailed, unequal variance, independent two-sample t test (95% CI) was performed for each of the ERG and VEP measurements comparing between VSS and control subjects. The same statistical tests were repeated after values greater than 2 SDs of the mean were removed and are reported in Supplemental Digital Content (See Tables 1 and 2, http://links.lww.com/WNO/A647 and http://links. lww.com/WNO/A648). There were no values greater than 3 SDs of the mean. RESULTS Of the 8 subjects included in this study, 7 satisfied the criteria for VSS and 1 subject satisfied only the criteria for isolated VS. Four subjects were assigned male sex at birth and 4 subjects were assigned female. The mean age was 29.4 years (SD = ±5.3 years). Racially, all 8 subjects were white. All subjects demonstrated normal visual acuity (LogMAR right eye = 0.006) (SD = ±0.076); LogMAR left eye = 0.019 (SD = ±0.082) and color vision. The mean stereo-acuity was 67.5 arc-seconds (SD = ±53.8 arc-seconds; n = 8). All 8 (100%) subjects had normal brain MRI while symptomatic. Six (75%) subjects had a previous and/or concurrent psychiatric disorder diagnosis, with the most common being depression (50%) and anxiety (50%). Mean age of VS onset was 24.2 years (SD = ±3.8 years; n = 6). One subject reported experiencing VS as long as they could recall, and another had no record of age at symptom onset. Six (75%) subjects also suffered from migraine headaches, but only 1 (12.5%) reported experiencing tinnitus. There were no other identifiable trends in past medical, pharmacologic, or social histories in this subject population. Automated perimetry parameters (mean VFI, MD, and FT) were normal (Table 2). Furthermore, all subjects’ HVFs were determined to be reliable and were independently interpreted as normal by both neuro-ophthalmologists. OCT parameters (mean pRNFL and mGCL thicknesses) were also normal (Table 3). All subjects’ OCT data were interpreted as normal by both neuro-ophthalmologists. Two-sample t test comparisons of VEP parameters (P100 and N135 amplitudes and latencies) showed no significant differences between VS subjects and their respective controls (Table 4). No significant differences were observed after removal of values outside 2 SDs of the mean (See Supplemental Digital Content, Table 1, http://links.lww.com/WNO/A647). Two-sample t test comparisons of ffERG parameters between VS subjects and controls is reported in Table 5. The same comparisons, with values outside 2 SDs of the mean removed, are reported in Supplemental Digital Content (See Table 2, http://links.lww.com/WNO/A648). VS subjects had a greater mean b-wave amplitude in response to light-adapted 3.0 ERG stimuli compared with their respective control subjects that was significant in the right eye (P = 0.030), but nonsignificant in the left (P = 0.318; Table 5). With outlier removal, this difference remained significant in the right eye (P = 0.035) and approached significance in the left eye (P = 0.072; See Supplemental Digital TABLE 4. Two-sample t-tests comparing visual evoked potential P100 and N135 wave parameters in visual snow subjects vs controls VEP Wave P100 Measure Amplitude (mV) Latency (ms) N135 Amplitude (mV) Latency (ms) OD/OS VS Mean (±SD) Control Mean (±SD) P OD OS OD OS OD OS OD OS 11.831 (4.025) 10.710 (4.136) 107.250 (8.743) 105.750 (3.562) 214.168 (5.641) 213.980 (4.640) 149.875 (6.508) 149.125 (9.266) 14.347 (7.322) 13.358 (10.159) 105.375 (7.245) 105.750 (6.778) 216.840 (7.009) 216.030 (7.591) 145.875 (12.201) 147.500 (10.571) 0.443 0.538 0.669 1.000 0.446 0.554 0.461 0.764 n = 8 for all values. OD, right eye; OS, left eye; VEP, visual evoked potential; VS, visual snow. Zaroban et al: J Neuro-Ophthalmol 2023; 43: 227-231 229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 5. Two-sample t-tests comparing mean full-field electroretinography parameters of visual snow subjects vs controls ERG Stimuli Wave Light-adapted 3.0 A Measure Amplitude (mV) Latency (ms) B Amplitude (mV) Latency (ms) Flicker Flicker Amplitude (mV) Latency (ms) Dark-adapted 0.01 A Amplitude (mV) Latency (ms) B Amplitude (mV) Latency (ms) Dark-adapted 3.0 A Amplitude (mV) Latency (ms) B Amplitude (mV) Latency (ms) Dark-adapted 10.0 A Amplitude (mV) OD/OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS Latency (ms) OD OS B Amplitude (mV) OD OS Latency (ms) OD OS VS Mean (±SD) Control Mean (±SD) P 229.695 (15.095) 239.764 (15.056) 13.000 (1.000) 13.000 (1.225) 171.675 (54.896) 169.650 (61.547) 29.250 (0.829) 29.375 (0.992) 136.325 (36.790) 137.704 (40.769) 25.500 (0.866) 26.125 (1.452) 211.268 (4.948) 211.370 (7.379) 17.250 (3.419) 18.625 (0.696) 313.625 (148.609) 315.838 (109.310) 91.375 (12.609) 90.000 (13.398) 2254.750 (94.795) 2271.213 (94.799) 14.750 (0.661) 14.875 (0.599) 428.038 (180.879) 456.550 (157.045) 61.750 (32.240) 51.875 (3.480) 2299.520 (125.887) n=5 2301.200 (129.471) n=5 12.200 (0.400) n=5 12.000 (0.632) n=5 191.925 (110.350) n=6 183.538 (73.262) n=6 41.167 (2.609) n=6 41.000 (2.236) n=6 232.718 (6.836) 240.876 (13.540) 13.125 (1.364) 13.875 (0.781) 114.353 (21.935) 135.870 (60.473) 29.500 (0.500) 30.250 (1.392) 92.406 (26.740) 113.483 (46.036) 26.625 (2.058) 27.125 (2.571) 213.420 (10.703) 216.563 (19.113) 20.125 (5.904) 18.375 (7.449) 314.975 (120.349) 308.938 (126.799) 85.000 (33.941) 95.750 (17.570) 2206.725 (38.179) 2245.150 (86.182) 15.000 (0.707) 15.125 (0.599) 332.088 (77.208) 397.075 (156.493) 49.250 (1.854) 50.125 (1.053) 2230.738 (42.103) 0.640 0.887 0.848 0.137 0.030 0.318 0.508 0.199 0.024 0.564 0.214 0.389 0.640 0.519 0.288 0.932 0.985 0.915 0.653 0.503 0.244 0.599 0.506 0.448 0.227 0.490 0.340 0.237 0.343 2268.613 (82.445) 0.666 12.125 (0.781) 0.837 12.250 (0.661) 0.551 79.205 (45.142) 0.073 96.179 (77.936) 0.073 39.125 (2.315) 0.192 39.125 (2.315) 0.186 Bold indicates P , 0.05. Italics indicate P , 0.10. n = 8 for all values unless otherwise noted. ERG, electroretinography; OD, right eye; OS, left eye; VS, visual snow. Content, Table 2, http://links.lww.com/WNO/A648). VS subjects had a significantly greater mean light-adapted 3.0 flicker wave amplitude than their respective controls in the right eye (P = 0.024), but not the left eye (P = 0.564; Table 5). With outlier removal, this difference remained significant in the right eye (P = 0.028) and trended closer toward significance in the left eye (P = 0.116). The difference in mean b-wave amplitude in response to dark-adapted 10.0 ERG 230 stimuli between VS subjects and controls trended toward significance in both eyes (right eye P = 0.073; left eye P = 0.073; Table 5). With outlier removal, this difference remained insignificant in the right eye (P = 0.102), but became significant in the left eye (P = 0.017; See Supplemental Digital Content, Table 2, http://links.lww.com/WNO/A648). There were no other significant differences in ffERG measures between the 2 groups. Zaroban et al: J Neuro-Ophthalmol 2023; 43: 227-231 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution CONCLUSIONS In this exploratory small case series, we demonstrate possible abnormalities of retinal signal processing in patients with VS. Our study cohort compares favorably with previous large studies of patients with VS, with respect to patient characteristics and examination findings (3). In accordance with past reports, visual acuity, stereo-acuity, color vision, HVF perimetry, and neurologic imaging in our subjects were all normal (5,6). The prevalence of comorbid migraine headaches in this group (75%) further strengthens the previously known association between VS and migraine and encourages further investigation of the potential pathophysiologic overlap between the 2 (2,16). The high prevalence of comorbid psychiatric diagnoses (75%) in these subjects is also well-reported in other studies (6,17). These findings prove this subject population an appropriate representation of VS and thus an effective model to assess retinal structure and function in this disease. We did not find any retinal structural abnormalities on SDOCT imaging, in accordance with previous reports in VS patients (6,12,13). We found no significant differences in the VEP parameters between VS subjects and the controls in this study. Several previous papers have reported normal VEP measures in VS patients (2,5,10,13). However, increased VEP N145 wave latency and decreased P100 wave amplitude have been found in the past (8). Other VEP abnormalities described in VS patients include loss of habituation and decreased threshold for visual cortex excitability (9). These abnormal findings, accompanied with other evidence of increased secondary visual cortex volume and hyperactivity in VS patients, do seem to suggest involvement of the occipital visual cortices in VS pathology (5,7). We acknowledge that our exploratory study lacks adequate power to detect small differences in VEP between normal and VS patients because of small sample size. Case reports of ffERG studies in VS patients are sparse, but have all been reported as normal thus far (2,6,12,13). To our knowledge, ffERG data recorded from VS patients have not yet been pooled and directly compared with matched control subjects. The current VS subjects’ significantly or nearly-significantly heightened b-wave amplitudes in response to light-adapted 3.0, light-adapted 3.0 flicker, and dark-adapted 10.0 ERG stimuli (compared with their respective controls) suggest possible rod and cone photoreceptor pathway hyper-responsiveness in these subjects (14). Thus, our results provide novel information and may implicate aberrant retinal function in VS pathogenesis. Our study has several significant limitations that stem from the very small sample size and retrospective design, given the exploratory nature of the study. But, based on the findings of this exploratory case series, we conclude that larger and more highly powered ffERG studies of VS patients are necessary and warranted to further delineate the retinal pathophysiology involved and how it contributes to VS symptomatology. Zaroban et al: J Neuro-Ophthalmol 2023; 43: 227-231 STATEMENT OF AUTHORSHIP Conception and design: S. Kedar, D. Anderson, A.-A. Vuppala; Acquisition of data: N. Zaroban, D. Anderson; Analysis and interpretation of data: N. Zaroban, S. Kedar, D. Anderson, A.-A. Vuppala. Drafting the manuscript: N. Zaroban, S. Kedar, D. Anderson, A.-A. Vuppala; Revising the manuscript for intellectual content: N. Zaroban, S. Kedar, D. Anderson, A.-A. Vuppala. 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