CLINICAL/SCIENTIFIC NOTES COVID-19 presenting with ophthalmoparesis from cranial nerve palsy

Marc Dinkin, MD, Virginia Gao, MD, PhD, Joshua Kahan, MBBS, PhD, Sarah Bobker, MD, Correspondence Marialaura Simonetto, MD, Paul Wechsler, MD, Jasmin Harpe, MD, Christine Greer, MD, Gregory Mints, MD, Dr. Dinkin Gayle Salama, MD, Apostolos John Tsiouris, MD, and Dana Leifer, MD [email protected] ® 2020;95:221-223. doi:10.1212/WNL.0000000000009700

Neurologic complications of COVID-19 are not well described. We report 2 patients who were RELATED ARTICLE diagnosed with COVID-19 after presenting with and ophthalmoparesis. Editorial Cranial neuropathies and COVID-19: Neurotropism Case 1 and autoimmunity A 36-year-old man with a history of infantile presented with left , diplopia, and Page 195 bilateral distal leg paresthesias. He reported subjective fever, cough, and myalgias which had developed 4 days earlier and resolved before presentation. Examination was notable for left MORE ONLINE , mild ptosis, and limited depression and adduction, consistent with a partial left oculomotor palsy. Abduction was limited bilaterally consistent with bilateral abducens palsies COVID-19 Resources (figure, A). Lower extremity hyporeflexia and hypesthesia, and gait ataxia were noted. WBC was For the latest articles, 2.9 × 103/μL with an absolute lymphocyte count of 0.9 × 103/μL. Nasal swab for SARS-CoV-2 invited commentaries, and PCR was positive. MRI revealed enhancement, T2-hyperintensity, and enlargement of the left blogs from physicians (figure, B–D). Chest radiograph was unremarkable. The next day, there was around the world worsening left ptosis, complete loss of depression and horizontal eye movements on the left and NPub.org/COVID19 loss of abduction on the right. The patient received IV immunoglobulin (2g/kg over 3 days) to treat presumed Miller Fisher syndrome and hydroxychloroquine for COVID-19 (600 mg twice a day for 1 day, followed by 400 mg daily for 4 days). Deficits improved partially before discharge 3 days after admission. A ganglioside antibody panel was negative.

Case 2 A 71-year-old woman with hypertension presented with painless diplopia on waking 2 days before and could not abduct her right eye (figure, E). Visual acuity, , and funduscopy were normal. She reported cough and fever for several days. She was sent to the emergency de- partment, where she was febrile and hypoxemic. WBC was 9.2 × 103/μL with an absolute lymphocyte count of 0.5 × 103/μL. Lumbar puncture was normal with opening pressure of 16 cm H2O. MRI showed enhancement of the sheaths and posterior Tenon capsules (figure, F and G). Chest radiograph revealed bilateral airspace opacities (figure H), and nasal PCR for SARS-CoV-2 was positive. Her COVID-19 pneumonia was treated with hydroxychloroquine (dosing as above). Her abduction palsy did not improve significantly before discharge on room air after a 6-day admission. She reported gradual improvement of diplopia when contacted by phone 2 weeks after discharge.

Discussion We describe 2 patients who developed cranial neuropathies within days of respiratory symptoms related to SARS-CoV-2 infection and were found to have abnormal perineural or cranial nerve findings on MRI. To reduce the risk of transmission, workup was limited to the essential studies needed to determine management.

From the Department of Neurology (M.D., V.G., J.K., S.B., M.S., P.W., J.H., D.L.), Department of (M.D., C.G.), Department of Medicine (G.M.) and Department of Radiology (G.S., A.J.T.), Weill Cornell Medical College, New York.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Copyright © 2020 American Academy of Neurology 221 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Figure Eye movements and radiologic findings in 2 patients with COVID-19 and ophthalmoparesis

Motility examination of patient 1 (A) revealed limitation of left eye adduction (A.a) and depression (A.d). A subtle left eye was observed in primary gaze (A.b), which worsened in left gaze (A.c). Enhancement of the left oculomotor nerve (arrows) can be seen on coronal (B) and axial (C) T1 fat-saturated postcontrast MRI. Enlargement and hyperintense signal of the left oculomotor nerve is demonstrated (arrows) on axial T2 fat-saturated MRI sequence (D). Motility examination of patient 2 (E) revealed 40% abduction of the right eye consistent with a right abducens palsy (E.a), and an in primary gaze (E.b). Enhancement of the perineural sheaths without involvement of the optic nerve substance was seen in the right eye (arrows) and left eyes (arrowhead) on axial T1 fat-saturated postcontrast MR sequence (F). Enhancement of Tenon’s capsule was seen OD (arrows) and OS (arrowhead) on axial T1 fat-saturated postcontrast MRI (G). Chest x-ray revealed multifocal pneumonia (H).

In a retrospective review of 214 patients with COVID-19 in although radiologic evidence of involvement was Wuhan, China, 36.5% had neurologic symptoms,1 which were lacking,thepresenceofopticnervesheathenhancementofthe more common in patients with severe disease. Most were involved eye could reflect viral leptomeningeal invasion, al- nonspecific symptoms common in viral infections such as though these findings are nonspecific.7 Given her risk factors and headache and dizziness, but 5.7% presented with acute cere- the painless nature of the diplopia, the differential includes an brovascular disease. The occurrence of hypogeusia and an- ischemic process. In both cases, neurologic symptoms could be osmia suggests olfactory bulb involvement, which has been unrelated to SARS-CoV-2 infection. Nonetheless, in the setting proposed as a mechanism of entry into the nervous system.2 of the COVID-19 pandemic, the occurrence of cranial neurop- COVID-19 encephalitis with positive SARS-CoV-2 PCR in athies should prompt consideration of SARS-CoV-2 infection in the CSF3 and acute necrotizing brainstem encephalopathy4 patients with even mild symptoms and signs of COVID-19. have been reported. CNS manifestations were more prevalent Hydroxychloroquine was used in both cases per institutional fi in patients with lymphopenia,1 as seen in our patients. CNS practice, although whether clinical bene t was conferred is not entry of SARS-CoV-2 may depend on viral interaction with known. Further studies are needed to understand the natural fi membrane-bound ACE2 receptor,5 which is expressed not history and prognostic signi cance of cranial neuropathies in only in nasal and oral mucosa but also in the nervous system,2 SARS-CoV-2 infection and to determine the best treatment. and SARS-CoV-2 appears to have a 10- to 20-fold higher Study funding ffi 5 a nity than SARS-CoV for the ACE2 receptor. Notably, No targeted funding reported. neither patient had a history of ACE inhibitor use. Disclosure The combination of ophthalmoparesis, leg paresthesia, and The authors report no relevant disclosures. Go to Neurology. areflexia in our first case suggested an acute demyelinating in- org/N for full disclosures. flammatory polyneuropathy secondary to a virus-mediated im- mune response, similar to other reports.6 However, the Publication history occurrence of neurologic symptoms within a few days of disease Received by Neurology April 4, 2020. Accepted in final form onset led to consideration of direct infection. In our second case, April 23, 2020.

222 Neurology | Volume 95, Number 5 | August 4, 2020 Neurology.org/N Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Appendix Authors Appendix (continued)

Author Location Contribution Author Location Contribution

Marc Dinkin, Weill Cornell Medical Designed and Christine Weill Cornell Medical Designed and MD College, NY Presbyterian conceptualized the report, Greer, MD College, NY Presbyterian conceptualized the report, Hospital acquired and interpreted Hospital acquired and interpreted the patient data, and the patient data, and drafted drafted the manuscript the manuscript for for intellectual intellectual content. content. Gregory Weill Cornell Medical Designed and Virginia Gao, Weill Cornell Medical Designed and Mints, MD College, NY Presbyterian conceptualized the report, MD, PhD College, NY Presbyterian conceptualized the report, Hospital acquired and interpreted Hospital acquired and interpreted the patient data, and drafted the patient data, and the manuscript for drafted the manuscript intellectual content. for intellectual content. Gayle Weill Cornell Medical Designed and Salama, MD College, NY Presbyterian conceptualized the report, Joshua Weill Cornell Medical Designed and Hospital acquired and interpreted Kahan, College, NY Presbyterian conceptualized the report, the patient data, and drafted MBBS, PhD Hospital acquired and interpreted the manuscript for the patient data, and drafted intellectual content. the manuscript for intellectual content. Apostolos Weill Cornell Medical Designed and John College, NY Presbyterian conceptualized the report, Sarah Weill Cornell Medical Designed and Tsiouris, MD Hospital acquired and interpreted Bobker, MD College, NY Presbyterian conceptualized the report, the patient data, and drafted Hospital acquired and interpreted the manuscript for the patient data, and drafted intellectual content. the manuscript for intellectual content. Dana Leifer, Weill Cornell Medical Designed and MD College, NY Presbyterian conceptualized the report, Marialaura Weill Cornell Medical Designed and Hospital acquired and interpreted Simonetto, College, NY Presbyterian conceptualized the report, the patient data, and drafted MD Hospital acquired and interpreted the manuscript for the patient data, and drafted intellectual content. the manuscript for intellectual content.

Paul Weill Cornell Medical Designed and References Wechsler, College, NY Presbyterian conceptualized the report, 1. Mao L, Wang M, Chen S, et al. Neurological manifestations of hospitalized patients with MD Hospital acquired and interpreted COVID-19 in Wuhan, China. JAMA Neurol. 2020;e201127. the patient data, and 2. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play drafted the manuscript a role in the respiratory failure of COVID-19 patients. J Med Virol 2020;92:552–555. for intellectual 3. Zhou L, Zhang M, Wang J, Gao J. Sars-Cov-2: underestimated damage to nervous content. system. Trav Med Infect Dis Epub 2020 Mar 24. 4. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated Jasmin Weill Cornell Medical Designed and acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology; Harpe, MD College, NY Presbyterian conceptualized the report, Epub 2020 Mar 31. Hospital acquired and interpreted 5. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the patient data, and the prefusion conformation. Science 2020;367:1260–1263. drafted the manuscript 6. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barr´e syndrome associated with SARS- for intellectual CoV-2 infection: causality or coincidence? Lancet Neurol 2020;19(5):383–384. content. 7. Gala F. Magnetic resonance imaging of optic nerve. Indian J Radiol Imaging 2015;25: 421–428.

COVID-19 and Neurologic Disease: Call for Papers!

The editors of Neurology are interested in papers that address the neurological aspects of COVID-19 infection and challenges to the management of patients with chronic neurological conditions who have, or are at risk for, the infection. Relevant papers that pass initial internal review will undergo expedited peer review and online publication. We will consider papers posted in preprint servers. Submit observational studies and clinical trials as Articles and case series and case reports under the Clinical/Scientific Notes category to https://submit.neurology.org/ today!

Neurology.org/N Neurology | Volume 95, Number 5 | August 4, 2020 223 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy Marc Dinkin, Virginia Gao, Joshua Kahan, et al. Neurology 2020;95;221-223 Published Online before print May 1, 2020 DOI 10.1212/WNL.0000000000009700

This information is current as of May 1, 2020

Updated Information & including high resolution figures, can be found at: Services http://n.neurology.org/content/95/5/221.full

References This article cites 4 articles, 1 of which you can access for free at: http://n.neurology.org/content/95/5/221.full#ref-list-1 Citations This article has been cited by 4 HighWire-hosted articles: http://n.neurology.org/content/95/5/221.full##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Neuro-ophthalmology http://n.neurology.org/cgi/collection/all_neuroophthalmology Diplopia (double vision) http://n.neurology.org/cgi/collection/diplopia_double_vision Ocular motility http://n.neurology.org/cgi/collection/ocular_motility Viral infections http://n.neurology.org/cgi/collection/viral_infections Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/about/about_the_journal#permissions Reprints Information about ordering reprints can be found online: http://n.neurology.org/subscribers/advertise

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2020 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.