SARS-CoV-2 Parainfectious Optic Neuropathy: 3 Case Reports and a Review of the Literature

Background: Parainfectious optic neuritis is an inflammatory reaction that occurs shortly after an infection without direct invasion by a pathogen. The clinical profile depends on the infectious organism. Cases of SARS-CoV-2 parainfectious optic neuritis have been reported in the literature, but there are no reviews that have applied strict inclusion criteria to more definitively establish the clinical profile associated with SARS-CoV-2. Methods: We present 3 new cases of SARS-CoV-2 parainfectious optic neuritis. We also review the literature for definite cases by selecting only those with unambiguous clinical features and MRI findings of optic neuritis, positive SARS-CoV-2 polymerase chain reaction or serology, and the absence of myelin oligodendrocyte-glycoprotein or aquaporin-4 antibodies or other diseases associated with optic neuritis. Results: We report 2 cases of monophasic, unilateral SARS-CoV-2 parainfectious optic neuritis with optic disc edema and nadir visual acuities of finger counting. We report 1 case of mild SARS-CoV-2 parainfectious optic neuritis that featured cotton wool spots, peripapillary wrinkles and hemorrhages, and recurrence after an initial steroid taper. We identified 6 cases of unambiguous SARS-CoV-2 parainfectious optic neuritis from the literature. Combining our case series with the case reports in the literature, the average age was 42.8 years, 3/9 had bilateral disease, 6/8 had optic disc edema, 8/9 had nadir visual acuity of finger counting or worse, and all recovered visual acuity to 20/40 or better after therapy with steroids. Conclusions: SARS-CoV-2 parainfectious optic neuritis has a clinical profile that is atypical for idiopathic optic neuritis but fairly typical of parainfectious forms of optic neuritis with a severely reduced nadir visual acuity, high likelihood of bilaterality, high incidence of optic disc edema, and prompt and significant response to corticosteroids. Further study with long-term follow-up and epidemiologic investigation will be needed to further characterize this clinical entity.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD SARS-CoV-2 Parainfectious Optic Neuropathy: 3 Case Reports and a Review of the Literature Jeffrey A. Gluckstein, MD, Bart K. Chwalisz, MD, Aubrey L. Gilbert, MD, PhD, Marc A. Bouffard, MD Background: Parainfectious optic neuritis is an inflammatory reaction that occurs shortly after an infection without direct invasion by a pathogen. The clinical profile depends on the infectious organism. Cases of SARS-CoV-2 parainfectious optic neuritis have been reported in the literature, but there are no reviews that have applied strict inclusion criteria to more definitively establish the clinical profile associated with SARS-CoV-2. Methods: We present 3 new cases of SARS-CoV-2 parainfectious optic neuritis. We also review the literature for definite cases by selecting only those with unambiguous clinical features and MRI findings of optic neuritis, positive SARS-CoV-2 polymerase chain reaction or serology, and the absence of myelin oligodendrocyte-glycoprotein or aquaporin-4 antibodies or other diseases associated with optic neuritis. Results: We report 2 cases of monophasic, unilateral SARSCoV-2 parainfectious optic neuritis with optic disc edema and nadir visual acuities of finger counting. We report 1 case of mild SARS-CoV-2 parainfectious optic neuritis that featured cotton wool spots, peripapillary wrinkles and hemorrhages, and recurrence after an initial steroid taper. We identified 6 cases of unambiguous SARS-CoV-2 parainfectious optic neuritis from the literature. Combining our case series with the case reports in the literature, the average age was 42.8 years, 3/9 had bilateral disease, 6/ 8 had optic disc edema, 8/9 had nadir visual acuity of finger counting or worse, and all recovered visual acuity to 20/40 or better after therapy with steroids. Conclusions: SARS-CoV-2 parainfectious optic neuritis has a clinical profile that is atypical for idiopathic optic neuritis but fairly typical of parainfectious forms of optic neuritis with a severely reduced nadir visual acuity, high likelihood of bilaterality, high incidence of optic disc edema, and prompt and significant response to corticosteroids. Further study Neuro-ophthalmology (JAG, BKC, MAB), Massachusetts Eye and Ear, Boston, Massachusetts; Neurology (BKC), Massachusetts General Hospital, Boston, Massachusetts; Ophthalmology and NeuroOphthalmology (ALG), Kaiser Permanente Vallejo Medical Center, Vallejo, California; and Neuro-Ophthalmology (MAB), Beth Israel Deaconess Medical Center, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Marc A. Bouffard, MD, Shapiro Eye Clinic, 98 Binney Street, Boston, MA 02215; E-mail: mbouffar@ bidmc.harvard.edu Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 with long-term follow-up and epidemiologic investigation will be needed to further characterize this clinical entity. Journal of Neuro-Ophthalmology 2023;43:491–498 doi: 10.1097/WNO.0000000000001822 © 2023 by North American Neuro-Ophthalmology Society P arainfectious optic neuritis occurs during or shortly after infection without direct optic nerve invasion by the pathogen and is presumed to reflect autoimmunity. It has been reported more commonly in children than adults and is more commonly bilateral or associated with optic disc edema than typical idiopathic optic neuritis (1,2). Infections frequently trigger optic neuritis associated with aquaporin-4 antibody (AQP4) (3) and myelin oligodendrocyte-glycoprotein (MOG) antibodies (4), but existing large case series on parainfectious optic neuritis predate regular testing for these antibodies (1,2). Like other viral infections, SARS-CoV-2 can trigger flares of MOG-associated disease (5), but our clinical experience also included isolated cases with atypical clinical features. To better characterize SARS-CoV-2 parainfectious optic neuritis with negative AQP4 and MOG antibodies, we describe 3 new cases and review the existing case reports. Recognition of the phenotype of SARS-CoV-2 parainfectious optic neuritis may distinguish it from other causes of optic neuritis or SARS-CoV-2 parainfectious phenomena such as papillophlebitis, intracranial hypertension, and MOG-associated disease (6). Previous reviews of SARSCoV-2 parainfectious optic neuritis do not apply strict clinical, laboratory, or imaging criteria to identify definitive SARS-CoV-2 infection or optic neuritis, nor do they consistently report testing for AQP4 or MOG (7,8). METHODS We screened the English language literature for articles describing optic neuritis associated with SARS-CoV-2 491 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution infection using the search terms “COVID” AND “optic neur*” in PubMed and COVID optic neuropathy or COVID optic neuritis on Google Scholar on March 12, 2022. Cases were initially screened by title and abstract, then reviewed in detail. Cases were included in the final analysis if they satisfied all of the following criteria: 1. SARS-CoV-2 infection occurring within the 8 weeks preceding clinical optic neuritis based on either: a. Positive SARS-CoV-2 polymerase chain reaction (PCR) OR b. Positive antibodies to SARS-CoV-2 without previous vaccination against SARS-CoV-2 AND i. A clinical history of SARS-CoV-2 exposure OR ii. COVID-19 based on constitutional or respiratory symptoms of SARS-CoV-2 infection. 2. Unilateral or bilateral optic neuritis based on acute to subacute vision loss with neurogenic features (dyschromatopsia, abnormal disc appearance, afferent pupillary defect, and neurogenic field loss). 3. Negative MOG and AQP4 antibody testing from the serum or cerebrospinal fluid (CSF). 4. MRI findings consistent with optic neuritis. Cases were excluded from the study if any of the following were present: 1. A more likely alternative diagnosis. 2. Complicating optic nerve pathology. 3. A previous attack of optic neuritis. 4. A previous diagnosis of a disease associated with optic neuritis. We chose a strict set of inclusion criteria with the addition of imaging to avoid including speculative optic neuritis or non–SARS-CoV-2-associated optic neuritis. The results of ophthalmic examinations, the presence of additional neurological or ophthalmic symptoms, the results of diagnostic tests, and treatments were extracted from the publications. This study was approved by the Mass General Brigham Institutional Review Board. RESULTS Case Reports Patient 1 A 40-year-old man with no significant medical history was evaluated for 5 days of mildly painful vision loss affecting the superior field in the right eye (OD) in early January 2021 (Fig. 1). He had not received SARS-CoV-2 vaccination. Two household contacts had PCR-confirmed SARSCoV-2 infections 14 days before presentation, and he was quarantined with them, although he did not have symptomatic COVID-19. 492 Ophthalmic examination revealed visual acuities of finger counting at 2 feet OD and 20/25 in the left eye (OS), a right relative afferent pupillary defect (rAPD), and subjective dyschromatopsia OD. The right optic nerve was edematous without pallor or hemorrhages. SARS-CoV-2 IgM and IgG antibodies were positive. Serum MOG and AQP4 antibodies were negative. Orbital MRI showed 1 cm of contrast enhancement of the right optic nerve head and anterior optic nerve. Brain MRI showed several nonspecific white matter lesions without contrast enhancement. He received intravenous methylprednisolone 1 g daily for 3 days, resulting in reduced pain with eye movements and improved visual acuity to 20/200 OD. Visual field testing showed a dense superior defect extending centrally and nasally. He received an oral prednisone taper with weekly dose decrements to 60 mg, 40 mg, 20 mg, and 15 mg. Lumbar puncture demonstrated 6 white blood cell (WBC) (72% lymphocytes) in Tube 1 and 3 WBC (72% lymphocytes) in Tube 4, total protein 49 mg/dL, a normal CSF IgG index, and negative oligoclonal banding. After 4 weeks of prednisone, his eye pain had resolved, and his examination had improved to 20/25 OD, 8/8 Ishihara color plates in both eyes (OU), and a persistent rAPD. He had mild nasal disc edema, and Humphrey visual fields showed no defects. MRI C and T spine revealed a small, nonenhancing T2 hyperintensity in the anterior cord from C2 to C3 without myelopathy (Fig. 2). At 5-month follow-up, he reported no pain and normal afferent visual function. Examination revealed acuities of 20/20-2 OD and 20/15 OS, a trace right rAPD, 8/8 color plates OU, and resolved disc edema. Humphrey visual fields were normal. The average retinal nerve fiber layer thickness was 96 mm OD and 116 mm OS with ganglion cell complex thicknesses of 66 mm OD and 88 mm OS. Repeat examination 8 months after presentation remained stable. Patient 2 A 41-year-old woman, vaccinated against SARS-CoV-2 in April 2021, presented for painful vision loss OD in January 2022. She reported pain OD, followed 2–3 days later by ipsilateral vision loss. Examination revealed visual acuities of counting fingers at 3 feet OD and 20/20 OS, a right rAPD, and a central scotoma to confrontation. Mildly hyperemic optic disc edema was observed OD with otherwisenormal fundi. She had no additional neurologic symptoms and a normal neurologic examination. Orbital MRI revealed abnormal T2 signal and enhancement of the intracanalicular right optic nerve without nerve sheath enhancement or fat stranding. Brain MRI was normal. Spinal imaging and lumbar puncture were deferred. Serum AQP4 and MOG antibodies, anti-nuclear antigen, nuclear antibody panel, antineutrophilic cytoplasmic antigen, and testing for syphilis, sarcoid, and tuberculosis were negative. She was admitted and reported an isolated sore throat. PCR for SARS-CoV-2 was positive. She received Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Clinical course and fundus photographs for Patient 1. RNFL, peripapillary retinal nerve fiber layer thickness. intravenous methylprednisolone 1 g/day for 3 days, then oral prednisone tapered according to the Optic Neuritis Treatment Trial (ONTT). Her pain resolved 2 days after steroid initiation, and her visual acuity improved to 20/70 after 3 days. Ten weeks after symptom onset, visual acuity had improved to 20/40 with some central points of depression on automated visual field testing. Her optic disc appearance had normalized. Patient 3 A 44-year-old woman with a history of psoriasis, vaccinated against SARS-CoV-2 in March 2021, presented for evaluation of painful vision loss OS in July 2021. Symptoms began contemporaneously with her son developing a cough. PCR tests for SARS-CoV-2 were positive in both the patient and her son, although she had no COVID-19 symptoms. After 4 days, she developed patchy visual field loss OS. Initial examination revealed acuities of 20/30 OD and 20/50 OS, rAPD and dyschromatopsia OS, a normal right optic nerve, and mild, 270-degree disc edema with hyperemia OS with an otherwise-normal funduscopic examination. Orbital MRI revealed enhancement of the intraorbital left optic nerve sparing the optic nerve sheath and orbital fat. MRI of the brain and cervical spine was normal. Lumbar puncture demonstrated 0 WBC, 36 RBC, protein 23, glucose 66, and negative oligoclonal bands. Serum AQP4 and MOG antibodies were negative. She received intravenous methylprednisolone 1 g/day for 5 days then oral prednisone at 40 mg daily with a taper by 10 mg every 3 days thereafter, resulting in substantial but incomplete improvement of her eye pain. One day after transitioning to oral prednisone, the examination revealed acuities of 20/20 OD and 20/25 OS, 8/8 Ishihara color plates OU with mild red desaturation OS, patchy loss OS on Humphrey visual field, and a rAPD OS. Mild disc elevation OS was noted with mild FIG. 2. Clinical course and ancillary studies for Patient 2. Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 493 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 20/20 OS, red desaturation remained mild, and disc edema remained stable. The peripapillary wrinkles, heme, and cotton wool spots had resolved. Roughly 4 days after stopping prednisone, painful eye movements recurred and vision worsened OS. Examination revealed stable afferent visual function, worsened disc edema, and recurrent obscuration of a single vessel at the nasal disc with several new small foci of peripapillary heme. computed tomography of the chest did not reveal evidence of sarcoid. Prednisone was resumed at a dose of 60 mg by mouth daily with a taper of 10 mg per week until reaching 20 mg daily, followed by a reduction of 5 mg each week. Pain with eye movements resolved entirely within 4 weeks. Her optic disc appearance normalized within 6 weeks. She was followed for 12 months without any further relapses. Literature Review Screening articles based on title yielded 42 articles. Six articles describing 6 patients with SARS-CoV-2 parainfectious optic neuritis with negative MOG and AQP4 antibodies were selected for final analysis as described in the methods. The 3 cases we report were included in our final analysis. Most patients reported vision loss within 2 weeks of COVID-19 symptoms (mean 1.3 weeks, range of 2 days–4 weeks) (Table 1) (5,9–13). Three cases were not symptomatic with COVID-19, and the remainder exhibited a mild illness. Two of the 3 patients we report were previously vaccinated. Four of 6 reported previously were diagnosed before the advent of vaccination; vaccination status was not reported in the remaining 2 patients. Three of 9 were male. Nadir acuity in 8 of 9 cases was count fingers or worse in the more-affected eye. CSF oligoclonal bands were absent in the 5 cases tested (Table 2) (5,9–13). Eye pain was present in 8/8 cases where this symptom was queried. All patients were treated with high-dose intravenous methylprednisolone for 3–5 days, and 8 of 9 received an oral steroid taper. All had a prompt and profound response to steroids. The worst final documented visual acuity was 20/40. DISCUSSION FIG. 3. Fluorescein angiogram in the affected eye at 43 seconds (A), at 6 minutes 35 seconds (B), and corresponding Optos image on day of fluorescein angiography (C). hyperemia, subtle temporal peripapillary wrinkles, a single small cotton-wool spot along the superior temporal arcade, and several subtle flecks of new peripapillary heme in the nerve fiber layer. Fluorescein angiography 3 days later revealed only optic disc leakage OS, and photos documented resolution of heme and cotton wool (Fig. 3). Six days later, on prednisone 30 mg daily, eye pain OS was present only in extreme left gaze, acuity had improved to 494 Our newly reported cases of SARS-CoV-2 parainfectious optic neuritis highlight several clinical features atypical to idiopathic optic neuritis as described in the ONTT, which is usually associated with subacute, painful, monophasic vision loss to a nadir acuity better than 20/200 and a normal funduscopic examination without disc edema or hemorrhages in the retinal nerve fiber layer (14). Cases 1 and 2 featured a nadir visual acuity of count fingers or worse, optic disc edema, and a prompt response to steroids. Case 3 featured an early relapsing course responsive to steroids, optic disc edema, peripapillary wrinkles, heme, and cotton wool spots. Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 Citation Age (yrs) Sex Initial Visual Acuity Laterality Timing After COVID-19 Fundus Findings Visual Field Findings Jossy (8) Deane (9) 16 21 M F 20/20; LP 20/20, HM Left Left 2 wk No symptoms—incidental positive PCR NR NR Micieli (10) 31 M CF @ 4’; 20/20 Right 2d Case 1 40 M CF at 2’, 20/25 Right Case 2 41 F CF @ 3 ft, 20/20 Right Case 3 44 F 20/30, 20/50 Left No symptoms—9 d after COVID-19 symptoms in 2 household contact No symptoms before neuritis—positive PCR and sore throat during admission No symptoms—optic neuritis concomitant with cough in a household contact Normal 360° disc elevation with obscuration of the vessels leaving the disc and tortuous vessels OS Mild right optic disc edema Disc edema OS Sainath (11) 56 F CF; CF Bilateral 2 wk Novi (12) Caudill (13) 64 72 F F HM, HM LP, LP Bilateral Bilateral 4 wk 1.5 wk Average or summary 42.8 3/9 male CF or worse in 8/9 3/9 bilateral Average 1.3 wk after exposure or symptoms 1+ R disc edema Initial disc edema and hyperemia OS. Later peripapillary wrinkles, cotton wool spots, and peripapillary heme on recurrence with optic disc leakage on fluorescein angiography Normal NR Slight disc edema OD, trace disc edema OS 6/8 disc edema Central scotoma OD at 2 mo Superior defect involving fovea OD, normal OS NR Patchy, nonspecific defects with mildly reduced total sensitivity Paracentral scotomas OU on recovery Diffuse depression NR — Original Contribution CF, count fingers; HM, hand motion; LP, light perception; NR, not reported; OD, right eye; OS, left eye; PCR, polymerase chain reaction. 495 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Demographic characteristics, initial examination, and ophthalmic studies in patients with SARS-CoV-2 parainfectious optic neuropathy Lumbar Puncture Findings Citation MRI Findings Jossy (8) Increased signal in the intraorbital and intracanalicular left optic nerve. Normal MRI brain and spine Nonenhancing T2 FLAIR subcortical white-matter hyperintensities mainly in the frontal lobes. Enhancement of the left optic nerve Enhancement of the intraorbital right optic nerve and optic nerve sheath. T2 FLAIR hyperintensity of the lateral pons without enhancement Anterior optic nerve enhancement. Nonspecific cerebral white matter disease. T2 hyperintensity without enhancement in the anterior spinal cord at C2-3 5 wk after presentation T2 hyperintensity and enhancement of the right optic nerve. No parenchymal changes Enhancement of the intraorbital left optic nerve without nerve sheath enhancement or orbital fat stranding. Normal MRI brain Increased T2 signal in the intraorbital optic nerves OD . OS Bland Novi (12) MRI orbits bilateral optic nerve enhancement, MRI brain with multiple enhancing lesions, MRI spine with T7-8 lesion. Lymphocytic pleocytosis WBC 22, 95% T cells, CD4:CD8+ 7:1, protein 45.2 mg/dL Caudill (13) MRI of the head negative. Bilateral intraorbital nerve enhancement OD . OS LP bland. Opening pressure 27.5 cm CSF Deane (9) Micieli (10) Case 1 Case 2 Case 3 Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 Sainath (11) Treatment Final Acuity Timing of Final Follow-up IVMP · 3 d, then 1 mg/kg oral prednisone 11 d, 3 d taper IVMP and remdesivir NR; 20/32 2 mo Normal 1 mo NR IVMP · 5 d followed by prednisone orally 1 mg/kg daily 20/20; 20/20 3 mo Bland IVMP · 5 d, then oral prednisone taper 20/20, 20/15 5 mo NR IVMP · 3 d then PO taper 20/40, 20/20 10 wk Bland IVMP · 5 d, then oral prednisone taper, repeat oral taper after recurrence IVMP · 3 d, then oral methylprednisolone 1 mg/kg daily · 11 d IVMP · 5 d followed by IVIg 2 g/kg in 5 d and oral prednisone 75 mg/day with subsequent taper IVMP daily for 6 d followed by an oral prednisone taper 20/20, 20/20 14 mo 20/30; 20/30 1 wk 20/30; 20/20 10 d 20/30; 20/30 3 wk Bland Bland IVMP, intravenous methylprednisolone 1 g per day; LP, light perception; NR, not reported; OD, right eye; OS, left eye; PO, by mouth. Original Contribution 496 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Radiographic findings, lumbar puncture results, treatment course, final visual acuity, and timing of final follow-up in patients with SARS-CoV-2 parainfectious optic neuropathy Original Contribution Pooled analysis of our 3 patients and the 6 previously reported patients revealed similarly atypical features. The average age was 42.8 years, over a decade older than the average age of 31.8 years reported in the ONTT (15). Vision loss was more severe than in the ONTT; only 1 of 9 cases had a nadir visual acuity better than count fingers in the more affected eye. Disc edema, where evaluated, was noted in 6 of 8 (75%) patients as compared to 35% of patients in the ONTT. SARS-CoV-2 parainfectious optic neuritis was bilateral in 3 of 9 cases, whereas bilateral disease is present in roughly 6% of cases of typical idiopathic optic neuritis (16,17). All cases of SARS-CoV-2 parainfectious optic neuritis recovered well after steroid treatment, and only 1 of 9 experienced an early relapse after steroid withdrawal. Parainfectious optic neuritis from both SARS-CoV-2 and other infections seems to exhibit features atypical to idiopathic optic neuritis. Publications by Selbst and Rappoport report that severe nadir vision loss with excellent recovery was common in cases of parainfectious optic neuritis associated with varicella, mumps, rubeola, and rubella (1), although adults rarely had a nadir acuity worse than 20/200 (2). Disc edema was present in 46/53 cases described by Selbst (1) and Rappoport (2). The literature summarizing parainfectious optic neuritis also predates regular MOG or AQP4 testing, and it is reasonable to question whether some of these cases reflect MOG-associated optic neuritis, which commonly features bilateral disease, disc edema, and steroid responsiveness, rather than true, seronegative parainfectious optic neuritis (17). The frequency with which these features were encountered in our series of MOG- and AQP4-negative patients suggests that these features may be associated with parainfectious optic neuritis. SARS-CoV-2 parainfectious optic neuritis is unlikely to reflect direct viral infection of the optic nerve. The cases we report generally occurred after symptomatic infection and responded promptly to steroid therapy, comporting with the late immune phenomena known to complicate COVID-19. Furthermore, the existing body of literature has not conclusively demonstrated pathological invasion of central nervous system tissue by SARS-CoV-2, with only a subset of studies demonstrating direct viral invasion by quantitative PCR, immunostaining, or electron microscopy (18). Only 1 case reported a positive SARS-CoV-2 PCR test from the CSF, but was accompanied by inflammatory CSF and acute demyelinating encephalomyelitis. The absence of CSF PCR in the remaining cases limits our ability to draw firm conclusions. Vaccination is unlikely to have played a causal role in SARS-CoV-2 parainfectious optic neuritis in any of the patients in our series. Patient 1 was unvaccinated, Patient 2 had received a Pfizer mRNA booster 2 months before her optic neuritis, and Patient 3 developed optic neuritis 4 months after Pfizer mRNA vaccination. Vaccination status was not uniformly reported in the literature, although 5 of Gluckstein et al: J Neuro-Ophthalmol 2023; 43: 491-498 the 6 previously published cases described patients who presented before the development of SARS-CoV-2 vaccines, and none mention vaccination within 4 weeks of optic neuritis. Although case reports temporally associating optic neuritis with antecedent vaccination have been published, previous epidemiologic studies have failed to demonstrate any significant association between vaccination and new diagnoses of optic neuritis or clinically isolated syndrome (19). Early reports on ophthalmic disease associated with COVID-19 suggested an increased incidence of cotton wool spots, microhemorrhages, retinal arterial, and vein enlargement on fundus photography.20 Only Case 3, which demonstrated an otherwise-classic clinical presentation and neuroimaging for optic neuritis, featured these funduscopic findings. Although these are uncommon funduscopic features of optic neuritis, the presence of cotton wool spots was noted in a small percentage of patients in the ONTT (15) and disc heme is a common feature of myelin oligodendrocyte glycoprotein antibody-associated disease optic neuritis (17). The unusual demographic and clinical profile of SARSCoV-2 optic neuritis without MOG and AQP4 antibodies suggests that it may be a distinct clinical entity, but may also be due to a publication bias toward more severe cases, a failure to recognize mild cases during COVID-19, or co-occurrence of a common disease and atypical optic neuritis. Epidemiologic studies, longer follow-up, and better recognition of SARS-CoV-2 parainfectious optic neuropathy may lead to a better understanding of this clinical entity. CONCLUSIONS The combination of clinical features atypical to idiopathic optic neuritis and a clinical profile similar to previous reports of parainfectious optic neuritis suggest that MOG/ AQP4-negative SARS-CoV-2 parainfectious optic neuritis may be a distinct clinical entity, rather than a coincidental co-occurrence of SARS-CoV-2 infection and idiopathic optic neuritis. STATEMENT OF AUTHORSHIP Conception and design: M. Bouffard, J. Gluckstein; Acquisition of data: M. Bouffard, J. Gluckstein, A. Gilbert, B. Chwalisz; Analysis and interpretation of data: M. Bouffard, J. Gluckstein, A. Gilbert, B. Chwalisz; Drafting the manuscript: M. Bouffard, J. Gluckstein, A. Gilbert, B. Chwalisz; Revising the manuscript for intellectual content: M. Bouffard, J. Gluckstein, A. Gilbert, B. Chwalisz; Final approval of the completed manuscript: M. Bouffard, J. Gluckstein, A. Gilbert, B. Chwalisz. REFERENCES 1. Selbst RG, Selhorst JB, Harbison JW, Myer EC. 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