Visual Pathway Involvement in NMDA Receptor Encephalitis: A Clinical, Optical Coherence Tomography, and 18-Fluorodeoxyglucose PET/CT Approach

Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Visual Pathway Involvement in NMDA Receptor Encephalitis: A Clinical, Optical Coherence Tomography, and 18-Fluorodeoxyglucose PET/CT Approach Grigorios Kalaitzidis, MD, Angeliki Filippatou, MD, Nicholas Fioravante, Bsc, Alissa Rothman, MD, Elias S. Sotirchos, MD, Eleni Vasileiou, MD, Henrik Ehrhardt, MBBCh, MSc, Agustina Quiroga, BA, Nicole Pellegrini, BA, Olwen C. Murphy, MD, Hussein Moussa, MD, Dimitrios C. Ladakis, MD, Jeffrey Lambe, MD, Kathryn C. Fitzgerald, ScD, Lilja Solnes, MD, Arun Venkatesan, MD, PhD, Peter A. Calabresi, MD, Shiv Saidha, MBBCh, John C. Probasco, MD E. S. Sotirchos has served on scientific advisory boards for Viela Bio, Alexion, and Genentech, and has received speaker fees from Viela Bio and Biogen. A. Venkatesan has received grants from the NIH, Howard Hughes Medical Institute, National Multiple Sclerosis Society, and the Maryland Stem Cell Research Foundation. P. A. Calabresi has received consulting fees from Disarm and Biogen and is PI on grants to JHU from Biogen and Annexon. S. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology, and has served on scientific advisory boards for Biogen, Genzyme, Genentech Corporation, EMD Serono, and Celgene. Saidha is the PI of investigator-initiated studies funded by Genentech and Biogen, was the site investigator of a trial sponsored by MedDay Pharmaceuticals and received support from the Race to Erase MS foundation. Saidha has consulted for Carl Zeiss Meditec, and has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer. J. C. Probasco serves on the editorial board, is an Associate Editor of The Neurohospitalist, and is the Editor-in-Chief of NEJM Journal Watch Neurology. The remaining authors report no disclosures. Methods: In this cross-sectional study, patients diagnosed with anti-NMDAR encephalitis per consensus criteria underwent postrecovery visual acuity (VA) testing and optical coherence tomography (OCT) with automated retinal layer segmentation. Clinical data and acute-phase brain 18F-fluorodeoxyglucose (FDG) PET/CT (performed within 90 days of symptom onset, assessed qualitatively and semiquantitatively) were retrospectively analyzed. VA and OCT measures were compared between anti-NMDAR and age, sex, and race-matched healthy controls (HC). When available, FDG-PET/CT metabolism patterns were analyzed for correlations with VA, and OCT measures. Results: A total of 16 anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study. Anti-NMDAR exhibited lower low-contrast VA (2.5% contrast: 24.4 letters [95% CI; 28.5 to 20.3]; P = 0.04, 1.25% contrast: 26.8 letters [95%CI; 212 to 21.7]; P = 0.01) compared with HC, but no differences were found on OCT-derived retinal layer thicknesses. Acutephase FDG-PET/CT medial occipital cortex metabolism did not correlate with follow-up low-contrast VA or ganglion cell/ inner plexiform layer thickness (GCIPL) (n = 7, 2.5% contrast: r = 20.31; P = 0.50, 1.25% contrast: r = 20.34; P = 0.45, GCIPL: r = 20.04; P = 0.94). Conclusions: Although the visual system seems to be involved in anti-NMDAR encephalitis, no retinal structural or occipital cortex functional abnormalities seem to be responsible for the visual dysfunction. When detected acutely, occipital lobe hypometabolism in anti-NMDAR encephalitis does not seem to associate with subsequent retrograde trans-synaptic degenerative phenomena, potentially reflecting reversible neuronal/synaptic dysfunction in the acute phase of the illness rather than neuronal degeneration. 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). Journal of Neuro-Ophthalmology 2023;43:220–226 doi: 10.1097/WNO.0000000000001696 © 2022 by North American Neuro-Ophthalmology Society Background: Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function. Division of Neuroimmunology and Neurological Infections (GK, AF, NF, AR, ESS, EV, HE, AQ, NP, OCM, HM, DL, JL, KCF, AV, PAC, SS, JCP), Department of Neurology; Russell H. Morgan Department of Radiology and Radiological Sciences (LS); and Division of Advanced Clinical Neurology (JCP), Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Supported by the National Institute of Neurological Disorders and Stroke under the grant R01NS082347. Address correspondence to John C. Probasco, MD, Division of Neuroimmunology and Neurological Infections, Division of Advanced Clinical Neurology, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287; E-mail: [e-mail] 220 A utoimmune encephalitis (AE) constitutes a discrete subgroup of acute encephalitis, characterized by autoantibodyKalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution mediated or other pathogenic immunological mechanisms. AE presents clinically with subacute onset of progressive deficits in working memory, alteration of mental status, seizures, and/or new psychiatric symptomatology, typically accompanied by paraclinical features supportive of central nervous system inflammation (electroencephalogram [EEG], MRI, 18F-fluorodeoxyglucose [FDG] PET, and/or cerebrospinal fluid [CSF] analysis) (1). Distinct neuronal autoantibodies are associated with distinct syndromes of AE, serving as clinically relevant diagnostic biomarkers. Antigenic targets of AE-associated autoantibodies include intracellular and neuronal surface proteins, ionchannels, and receptors (2). Anti-NMDA receptor (NMDAR) encephalitis, the most common AE syndrome, has been reported to be associated with postrecovery visual dysfunction (2). However, optical coherence tomography (OCT) has not demonstrated retinal layer thinning, suggesting that no retinal structural abnormalities could explain the visual dysfunction observed in anti-NMDAR, and that different parts of the visual pathway may be involved (3). However, FDG-PET performed in the acute phase of illness has revealed a pattern of occipital lobe hypometabolism that may be characteristic for anti-NMDAR compared with other AE syndromes and may be more profound among anti-NMDAR patients with the greatest disability (4). In the current study, we sought to assess patients with anti-NMDAR encephalitis for evidence of visual dysfunction during outpatient follow-up and the relationship of such visual dysfunction with OCT-identified retinal structure and FDG-PET/CT occipital lobe metabolism during the acute phase of illness. Finally, we assessed whether acute-phase occipital lobe hypometabolism is associated with subsequent retrograde trans-synaptic degeneration of retinal ganglion cells, as assessed by OCT (5). METHODS Standard Protocol Approvals, Registrations, and Patient Consents Johns Hopkins University Institutional Review Board approval was obtained for the study. Written informed consent was obtained from all participants before study enrolment. Study Participants and Clinical Data In this cross-sectional study, patients with anti-NMDAR encephalitis were prospectively recruited from the Johns Hopkins Encephalitis Center outpatient clinic and were invited to undergo OCT and visual function testing. AntiNMDAR patients were diagnosed according to the consensus clinical criteria, and they were all defined by the detection of serum and/or CSF anti-NMDAR autoantibodies by commercially available assays (Athena Diagnostics, Worcester, MA; Mayo Clinic Laboratories, Rochester, MN) (1). AntiKalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 NMDAR patients were matched to healthy controls (HC) according to age, sex, and race, in a ratio of 1:2. Matched HC were identified from an ongoing prospective observational OCT study at our center, and consisted of Johns Hopkins University staff and patients’ spouses. After review of medical records, the following data were collected: demographic information; co-morbidities; diagnosis of co-existing neoplasm(s); diagnostic test results, including antibody assay results; modified Rankin Scale (mRS) scores, representing neurological disability; and availability of FDG-PET/CT within 90 days of symptom onset. Visual Function Monocular and binocular, habitual-corrected visual acuity (VA) was tested using standardized retro-illuminated eye charts (Precision Vision, La Salle, IL). High-contrast VA (100%) and low-contrast VA (2.5% and 1.25%) were assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (at 4 m) and low-contrast Sloan Letter charts (at 2 m), respectively. High-contrast letter-acuity (HCLA) and lowcontrast letter-acuity (LCLA) scores were determined by the total number of letters correctly identified on each level of contrast. The maximum score of detectable letters for each chart was 70 (corresponding to a 20/10 Snellen VA). Optical Coherence Tomography Spectral-domain OCT (Cirrus HD-OCT, Model 5000, software version 11.5; Carl Zeiss Meditec, Dublin, CA) was used for retinal imaging, as previously described (6). Two types of scans were acquired from each participant: Peripapillary scans, using the Optic Disc Cube 200 · 200 protocol, and macular volume scans, using the Macular Cube 512 · 128 protocol. Scans were acquired by experienced technicians, and only scans meeting the OSCAR-IB quality control criteria were included in analyses (7). For peripapillary scans, average peripapillary retinal nerve fiber layer (pRNFL) thickness was estimated using the incorporated software provided by the Cirrus HD-OCT device. For macular scans, automated macular segmentation was performed, as described elsewhere (8). For each macular layer, the average thickness was obtained within a foveacentered annulus, with an internal diameter of 1 mm and an external diameter of 5 mm. Segmented macular volume scans underwent qualitative assessment in a blinded manner, for the assurance of segmentation accuracy and the recording of retinal pathology (G.K., A.Q.). Brain Fluorodeoxyglucose-PET/CT For patients with available FDG-PET/CT performed within 90 days of symptom onset (acute-phase), a review was performed by a board-certified nuclear medicine radiologist (L.S.) using the commercially available 221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution database, CortexID (GE Healthcare, Waukesha, WI) as described elsewhere (4). Briefly, standard CortexID brain regions of interest (ROI) (visual cortex-representing the medial occipital lobe, occipital lobe-representing the lateral occipital lobe, caudate, cerebellum, frontal lobe, parietal lobe, and temporal lobe) were qualitatively assessed as normal, hypometabolic, or hypermetabolic after visual inspection. In addition, ROIs were semiquantitatively assessed using the calculated regional average Z-scores using the CortexID database of HC. Because CortexID expresses these Z-scores in hypometabolism, these were corrected to a hypermetabolism scale by multiplying by 21. Thus, corrected regional Z-scores greater than 2.00 or less than 22.00 (i.e., ±2 SD from the mean of HC for each ROI) were designated as hypermetabolic or hypometabolic, respectively. Visual Function Testing, Optical Coherence Tomography, and Fluorodeoxyglucose-PET/CT Timeline VA testing and OCT were performed at the same follow-up date, at least 1 year after the acute clinical episode. The specific timing allowed us to: i) search for characteristic patterns of retinal damage in the context of visual dysfunction, ii) seek for evidence of subsequent retrograde trans-synaptic degeneration of retinal ganglion cells following acute occipital hypometabolism (5), iii) limit the effect of cognitive dysfunction on VA. Statistical Methods For the comparison of VA and OCT measures between anti-NMDAR and matched HC, mixed-effects linear regression models with subject-specific random intercepts adjusted for age, sex, and race were fitted, accounting for within-subject, intereye correlations. Spearman correlation was used to examine the correlation of medial (visual cortex) and lateral occipital lobe PET Z-scores with VA scores and OCT layer thicknesses. For FDG-PET Z-score analyses, left and right hemisphere scores were averaged. Likewise, for Spearman correlation between PET Z-scores and VA, as well as OCT, binocular VA and average OCT layer thicknesses were used. Statistical analyses were completed using Stata version 16 (StataCorp, College Station, TX). P-value for significance was defined as ,0.05. Data Availability Anonymized data used in this study will be made available on reasonable request and the proper data sharing agreements in place. RESULTS Sixteen anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study (Table 1). Thirteen antiNMDAR (81%) had mRS # 2 at the time of VA (Table 1). Visual Function and Optical Coherence Tomography Measures in Anti-NMDA Receptor Compared With Healthy Controls Visual function measures and OCT-measured retinal layer thicknesses are summarized and compared between antiNMDAR and HC in Table 2. Anti-NMDAR patients had lower LCLA compared with HC, at 2.5% contrast (24.4 letters [95% CI; 28.5 to 20.3] P = 0.04; see Supplemental Digital Content 1, Figure, http://links.lww.com/WNO/A624) and 1.25% contrast (26.8 letters [95% CI; 212.0 to 21.7]; P = 0.01; see Supplemental Digital Content 1, Figure, http://links.lww. com/WNO/A624). No difference was noted in HCLA between anti-NMDAR patients and HC. Even though anti-NMDAR patients exhibited worse low-contrast VA compared with HC, no differences were noted for any of the OCT measured retinal layer thicknesses (Table 2, see Supplemental Digital Content 2, Figure, http://links.lww.com/WNO/A625). TABLE 1. Demographic and clinical characteristics of participants Participants, n (eyes) Age in years, mean (SD) Female sex, n (%) Race, n (%) Caucasian American African American Other New cancer diagnosis, n (%) Ovarian Teratoma Diffuse large B cell lymphoma Melanoma mRS # 2 at the time of VA, n (%) Anti-NMDAR HC 16 (32 eyes) 30.6 (12.2) 13 (81%) 32 (64 eyes) 30 (11.1) 26 (81%) 9 (56%) 4 (25%) 3 (19%) 6 (38%) 4 (25%) 1 (6%) 1 (6%) 13 (81%) 18 (56%) 8 (25%) 6 (19%) HC, healthy control; mRS, modified Rankin Scale; NMDAR, NMDA receptor; VA, visual acuity. 222 Kalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Summary and comparison of letter acuity scores and optical coherence tomography retinal layer thicknesses Anti-NMDAR vs HC Letter-acuity scores, median (IQR) 100% contrast 2.5% contrast 1.25% contrast OCT measures, mm, mean (SD) GCIPL INL ONL AMT pRNFL Anti-NMDAR HC Beta (95% CI)* P* 56.5 (53–61.5) 29 (22–35) 12.5 (4–22) 60 (56–64) 34 (26.5–37) 22 (14.5–27.5) 22.6 (26.4 to 1.2) 24.4 (28.5 to 20.3) 26.8 (212.0 to 21.7) 0.18 0.037 0.010 74.6 (6.1) 44.6 (1.9) 66.2 (3.6) 307.6 (11.3) 90.2 (12.2) 75.5 (3.8) 44.1 (2.0) 67.1 (5.4) 309.4 (10.8) 94.1 (9.0) 20.8 (23.5 to 1.8) 0.5 (20.6 to 1.6) 20.9 (23.7 to 1.9) 21.7 (27.7 to 4.3) 23.9 (29.4 to 1.5) 0.54 0.36 0.52 0.58 0.16 Statistically significant results are in bold. *Mixed-effects linear regression models adjusted for age, sex, and race were used in analyses. Beta coefficients represent differences in number of correct letters and micrometers between the groups compared, for letter-acuity scores and OCT measures, respectively. AMT, average macular thickness; GCIPL, Ganglion cell/inner plexiform layer; HC, healthy control; INL, inner nuclear layer; IQR, interquartile range; NMDAR, NMDA receptor; ONL, outer nuclear layer; pRNFL, peripapillary retinal nerve fiber layer. Fluorodeoxyglucose-PET/CT and Its Association With Visual Function For anti-NMDAR patients with available acute-phase PETFDG/CT scans (n = 7), ROI z-scores and number of patients with occipital lobe hypometabolism, and the timeline of FDG-PET/CT, OCT, and VA, are summarized in Table 3. Of note, anti-NMDAR patients demonstrated marked lateral and medial occipital hypometabolism relative to other ROIs. No correlation was noted between acute-phase occipital lobe FDG-PET/CT Z scores and postrecovery letter-acuity scores in the anti-NMDAR patients (Fig. 1). In detail, no correlation was found between medial occipital lobe metab- olism and 100% contrast VA (r = 20.36; P = 0.43; Fig. 1A), 2.5% contrast VA (r = 20.31; P = 0.50; Fig. 1B), or 1.25% contrast VA (r = 20.34; P = 0.45; Fig. 1C). Similarly, no correlation was found between lateral occipital lobe metabolism and 100%, 2.5%, or 1.25% contrast VA (Fig. 1D–F). Fluorodeoxyglucose-PET/CT Association With Optical Coherence Tomography No correlation was found between acute-phase occipital lobe PET Z-scores and GCIPL thickness at a time when retrograde trans-synaptic degeneration-mediated GCIPL thinning would be evident (Fig. 2). TABLE 3. Summary of regional FDG-PET/CT metabolism within 3 months of symptom onset for NMDA receptor, and FDG-PET/CT, VA, and OCT timeline Region N (patients) PET2FDG/CT Z2scores, median (IQR) Lateral occipital lobe Visual cortex (medial occipital cortex) Parietal lobe Temporal lobe Frontal lobe Caudate Cerebellum N of abnormal cortical metabolism on semi-quantitative assessment (patients) Occipital lobe (medial and/or lateral) hypometabolism Time between FDG2PET/CT and onset, days (range) Time between FDG2PET/CT and VA/OCT, days (range) Time between VA/OCT and onset, days (range) Anti-NMDAR 7 22.7 (23.3 to 20.8) 22.5 (24.1 to 21.1) 21.0 (22.9 to 20.2) 21.1 (21.6 to 0.2) 21.4 (22.4 to 0.2) 21.0 (23.0 to 2.0) 20.0 (20.9 to 1.8) 5 (71%) 26 (15–52) 620 (491–705) 635.5 (71–3,860) FDG, fluorodeoxyglucose; IQR, interquartile range; NMDAR, NMDA receptor; OCT, optical coherence tomography; VA, visual acuity. Kalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Relationships between follow-up letter-acuity scores and acute onset FDG-PET/CT medial and lateral occipital lobe Zscores in anti-NMDAR. Two-way scatter plots depicting the lack of an association between acute-phase medial occipital lobe FDG-PET/CT Z-scores and letter-acuity scores for anti-NMDAR at all contrasts (A. 100% contrast, B. 2.5% contrast, and C. 1.25% contrast), and the lack of an association between acute-phase lateral occipital lobe FDG-PET/CT Z-scores and letteracuity scores at all contrasts (D. 100% contrast, E. 2.5% contrast, and F. 1.25% contrast). Spearman correlation coefficients and relative P-values are also reported. The vertical, dashed, gold line represents the tipping point in hypometabolism—when FDG-PET/CT Z-scores are lower than 22, the ROI is considered to be hypometabolic. FDG indicates fluorodeoxyglucose; NMDAR, NMDA receptor. CONCLUSIONS In this study, we aimed to assess the presence of visual dysfunction and characterize the parts of the visual pathway involved in anti-NMDAR encephalitis. Even though postrecovery LCLA was lower in anti-NMDAR patients, we did not find any retinal structural abnormalities on OCT, nor any correlations of acute-phase occipital cortex metabolism on FDG-PET/CT with subsequent visual dysfunction. Occipital lobe metabolism within 3 months of symptom onset did not correlate 224 with follow-up GCIPL thickness at a time point when retrograde trans-synaptic degeneration would theoretically have been expected to have occurred. Visual dysfunction following anti-NMDAR encephalitis has been previously described (3,9,10). When assessing visual function in our study, only low-contrast VA was lower in anti-NMDAR patients compared with HC in the postrecovery period. Despite the observation that 81% of anti-NMDAR patients had realized a good neurologic disability outcome by the time of VA and OCT assessment, it is possible that low-contrast VA Kalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Relationships between follow-up GCIPL thickness and acute-onset medial and lateral occipital lobe FDG-PET/ CT Z-scores in anti-NMDAR. Two-way scatter plots depicting the lack of an association between acute-phase occipital lobe FDG-PET/CT Z-scores (A. medial, B. lateral occipital lobe) with GCIPL thickness. Spearman correlation coefficients and relative P-values are also reported. The vertical, dashed, gold line represents the tipping point in hypometabolism—when FDG-PET/CT Z-scores are lower than 22 the ROI is considered to be hypometabolic. FDG indicates fluorodeoxyglucose; GCIPL, Ganglion cell/inner plexiform layer; NMDAR, NMDA receptor; ROI, regions of interest. impairment was simply a function of persistent cognitive impairment, because mRS is a poor marker of neurobehavioral outcomes (11). Besides cognitive impairment, 2 parts of the visual system could explain postrecovery visual dysfunction in patients with anti-NMDAR encephalitis. First, the anterior visual pathway spanning from the retina to the thalamic lateral geniculate nucleus. Consistent with prior observations, we found no differences in OCT retinal thicknesses between anti-NMDAR and HC, suggesting that no structurally damaging process is responsible for the noted residual visual dysfunction (3). However, considering that various types of contrast-modulating retinal neurons express NMDAR, and that anti-NMDAR autoantibodies lead to a selective decrease in anti-NMDAR currents by internalization of the receptor, but without Kalaitzidis et al: J Neuro-Ophthalmol 2023; 43: 220-226 affecting synapse numbers, functional retinal changes as a cause of visual dysfunction cannot be ruled out (12–14). The second potential target is the posterior visual pathway, from the lateral geniculate nucleus to the visual cortex. Concerning the visual cortex, a pattern of occipital lobe hypometabolism with frontotemporal hypermetabolism has been reported for anti-NMDAR patients, with the antero-posterior gradient correlating with severity of disease, and treatment and recovery leading to its normalization (15,16). In addition, occipital hypometabolism has been reported to be more evident in antiNMDAR patients compared with other types of AE (4). In our study, patients with anti-NMDAR encephalitis were again noted to have significant occipital lobe hypometabolism, more so than for other ROIs. Despite the occipital lobe hypometabolism, no association was noted with postrecovery VA in anti-NMDAR. Retrograde neuronal degeneration, a well-studied phenomenon, represents neuronal apoptosis following axonal injury. Subsequent apoptosis of the next in chain neurons providing afferent input to the neurons undergoing retrograde degeneration describes the phenomenon of retrograde trans-synaptic degeneration (17). OCT may be an invaluable tool for studying retrograde transsynaptic degeneration in the visual pathway (5,17). In retrograde trans-synaptic degeneration of the visual system, lesions in the neurons of the visual cortex can lead to retinal ganglion cell degeneration, which can be captured on OCT as GCIPL thinning. In our study, FDG-PET/ CT occipital lobe hypometabolism did not associate with OCT measured GCIPL thickness, suggesting the absence of retrograde trans-synaptic degeneration mechanisms in anti-NMDAR encephalitis. Anti-NMDAR autoantibodies target neuronal surface proteins and thus potentially lead to reversible functional changes. Functional, short-lasting abnormalities of the visual cortex rather than degenerating mechanisms could explain why FDG-PET/CT occipital hypometabolism did not associate with follow-up OCT measured GCIPL thickness, emphasizing the potential role of immunotherapies in reversing observed dysfunction during the acute-phase of illness. Our study is limited in several aspects. First, our observations were derived from a relatively small, heterogenous group of patients evaluated at a tertiary, subspecialty clinic. However, anti-NMDAR encephalitis is a rare disease, with a prevalence as low as 0.6 cases per 100,000 per year (18). Also, patients included in the study were recruited in a single center, and underwent scanning on the same OCT and PET devices, limiting measurement bias. Second, our study is limited by the cross-sectional design. The lack of longitudinal OCT data limited our ability to study dynamic changes of OCT retinal thicknesses and the association of OCT measures with FDGPET/CT occipital metabolism throughout time. Finally, our study is limited by the retrospective nature of our data. 225 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution In conclusion, anti-NMDAR patients exhibit visual dysfunction without structural retinal damage. Although occipital hypometabolism could explain visual dysfunction in patients with anti-NMDAR encephalitis, we did not find such an association when comparing acute-phase occipital metabolism with postacute visual acuity and OCT. Future prospective studies with the addition of acute-phase OCT and VA assessment (if possible), postacute FDG-PET/CT assessments at time of postacute OCT and VA assessment, electroretinography, and visual evoked potentials may further clarify visual dysfunction in anti-NMDAR encephalitis. STATEMENT OF AUTHORSHIP Conception and design: G. Kalaitzidis, A. Filippatou, A. Venkatesan, P. A. Calabresi, S. Saidha, J. C. Probasco; Acquisition of data: G. Kalaitzidis, A. Filippatou, N. Fioravante, A. Rothman, E. S. Sotirchos, E. Vasileiou, H. Ehrhardt, A. Quiroga, N. Pellegrini, O. C. Murphy, H. Moussa, D. Ladakis, J. Lambe, L. Solnes; Analysis and interpretation of data: G. Kalaitzidis, A. Filippatou, K. C. Fitzgerald, A. Venkatesan, P. A. Calabresi, S. Saidha, John C. Probasco. Drafting the manuscript: G. Kalaitzidis, J. C. Probasco, A. Venkatesan, P. A. Calabresi, S. Saidha; Revising the manuscript for intellectual content: G. Kalaitzidis, J. C. Probasco, A. Venkatesan, P. A. Calabresi, S. 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