Antiaquaporin 4-Related Optic Neuritis and Myelitis Post-COVID-19 Infection

Coronavirus disease 2019 (COVID-19) causes severe acute respiratory syndrome and is a novel disease first reported in December 2019 (1). Common symptoms associated with COVID-19 are cough, fatigue, dyspnea, and fever (1).

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Antiaquaporin 4-Related Optic Neuritis and Myelitis Post-COVID-19 Infection Pouriska B. Kivanany, PhD, Subahari Raviskanthan, MBBS, Peter W. Mortensen, MD, Andrew G. Lee, MD C oronavirus disease 2019 (COVID-19) causes severe acute respiratory syndrome and is a novel disease first reported in December 2019 (1). Common symptoms associated with COVID-19 are cough, fatigue, dyspnea, and fever (1). Over the past year, multiple postinfectious sequelae have been reported, with multisystem involvement (1). Similar to other coronaviruses, it is speculated that COVID-19 may enter the central nervous system (CNS) through transsynaptic pathways causing neurologic manifestations, such as neuromyelitis optica (NMO) (2,3). To date, there have only been 2 cases of antiaquaporin 4 (AQP4)associated transverse myelitis in a presumed patient with COVID-19 (2,3). We report a case of anti-AQP4–related optic neuritis post-COVID infection; to the best of our knowledge, this is the only such case in the English language ophthalmic literature. A 35-year-old Hispanic woman presented to the emergency department (ED) with progressive headaches, fevers, neck stiffness, nausea, vomiting, and binocular diplopia. Her headaches were not positional. She had no respiratory symptoms or vision loss. Her medical history was significant for COVID-19 infection 6 weeks before, confirmed with polymerase chain reaction. Her only medication was aspirin/paracetamol/caffeine tablets as needed. She had 3 to 4 standard alcoholic drinks weekly and denied tobacco and drug use. Her body mass index was 29.4 kg/m2. Her vital signs were within normal limits, and she was afebrile. Neurological examination at this time was significant for esotropia in primary gaze. The ductions and versions were consistent with a left abducens nerve palsy. Saccadic velocities were not documented. Laboratory investigations were significant for a white blood count of 13.46k/mL (normal 4.50–11.00k/mL) with immature granulocytes on blood film. Sedimentation rate and C-reactive protein Ophthalmology Department, Capital and Coast District Health Board, Wellington, New Zealand. The authors report no conflicts of interest. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street 450, Houston, TX 77030; E-mail: aglee@ houstonmethodist.org Kivanany et al: J Neuro-Ophthalmol 2022; 42: e571-e573 were within normal limits. MRI of the brain and orbits with contrast and venogram showed empty sella and bilateral papilledema (Fig. 1). There was no venous sinus thrombosis. Lumbar puncture (LP) revealed a white blood cell count of 171/cells/ mm3 (CMM) (normal 0–5/CMM) with 94% lymphocytes. Cerebrospinal protein, glucose, Gram stain, bacterial and fungal culture, and viral workup were negative. The opening pressure was 31 cm H2O, and oligoclonal bands were not detected. The patient reported symptomatic improvement in the headache post-LP, and her abducens nerve palsy resolved. The patient was empirically treated with intravenous acyclovir, cefepime, and vancomycin, as well as acetazolamide 500 mg by mouth twice a day for intracranial hypertension in the setting of aseptic meningitis until the Gram stain and viral CSF results returned negative. She was discharged home after 4 days. She represented 10 days later because of worsening headaches and new vision loss in the right eye and painful eye movements. On neuro-ophthalmic examination, her visual acuity was light perception in the right eye and 20/ 40 in the left eye. Her pupils were isocoric with a relative afferent pupillary defect in the right eye. Motility was full in both eyes. Slitlamp biomicroscopy and intraocular pressures were normal. Dilated fundus examination revealed Grade 3 disc edema in the right eye and Grade 2 in the left eye. Upper-limb neurological examination revealed a left Hoffman sign, bilateral hyperreflexia at brachioradialis reflexes, with no motor or sensory abnormalities. In the lower limbs, she had normal tone, with nonsustained clonus bilaterally, and hyperreflexic ankle jerks bilaterally. She had a sensory level at T12. There was no bowel or bladder involvement. In retrospect, she reported unsteady gait and lower-limb weakness at the time of her initial ED presentation. MRI showed right optic nerve enhancement and nonenhancing central cord abnormality at T4 extending to T7-T8 (Fig. 2). AQP4 antibodies subsequently returned positive with a titer of 1:1,000, consistent with a diagnosis of NMO. The patient was treated with 5 days intravenous methylprednisolone and 5 cycles of plasma exchange subsequently without significant vision improvement. She is currently being worked up for ongoing immunosuppression. Neuro-ophthalmic manifestations related to COVID-19 include optic neuritis (some of which are myelin e571 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. MRI of the brain and orbits at initial presentation. A. T1 sagittal image showing empty sella (arrow). B. T2 axial image showing flattening of the globe and optic disc edema in both eyes (arrow pointing to right eye globe flattening and disc edema). oligodendrocyte glycoprotein [MOG] associated), cranial nerve palsies, visual snow, and visual field defects (1). NMO, although not previously reported with optic neuritis, can be precipitated by viral infections, including COVID-19 (3). To be diagnosed with NMO, patients must have both optic neuritis and acute myelitis and 2 of the 3 following features: contiguous cord MRI lesion in 3 vertebral segments, brain MRI not meeting criteria for multiple sclerosis, or AQP4Immunoglobulin G seropositivity (4). Our patient met all of these criteria. It is known that COVID-19 binds to angiotensinconverting enzyme-2 (ACE2) receptors to access host cells (3). COVID-19 may be able to penetrate through the blood–brain barrier cellular architecture by using these ACE2 receptors and priming the CNS for developing NMO (3). There have been recent reports of patients developing optic neuritis as a sequela of COVID-19, with some having associated MOG antibodies (1). There are no reported cases of AQP4-IgG-associated optic neuritis; however, there are 2 cases of COVID-19-associated transverse myelitis, which presumably occurs through a similar mechanism (2,3). Postinfectious NMO has been reported in the literature, with herpes zoster being the most common associated infection. A case–control study of 19 patients with NMO screening for acute infections at the time of initial presentation/flare of symptoms found that 47% of the patients had associated evidence of acute infection, of which most were viral infections, compared with 15% of the control group (5). Given this potential association and the strong immune response that COVID-19 often produces, we suspect that secondary autoantibody production is the mechanism in which our patient’s NMO occurred. The 7-week delay between the COVID symptoms and her subsequent presentation could also be explained by a form of immune constitution reconstitution syndrome that has been hypothesized for delayed autoimmune manifestations after COVID-19, explained by an unregulated immune response after recovery from the triggering illness causing new autoimmune phenomena (6). As the spectrum of COVID-19–related complications keeps expanding, new associations will continue to be identified. Although it is not possible to prove a direct correlation between COVID-19 and outpatient’s NMO or the temporal relationship, other COVID-19 and postinfectious NMO reports make it important to consider. To the best of our knowledge, this is the first presentation of anti-AQP4–related optic neuritis and myelitis postCOVID-19. Clinicians should remain aware of FIG. 2. MRI during patient’s representation. Postcontrast T1 fat saturated showing right optic nerve enhancement in axial (A) and coronal (B) sequences (arrows). Short T1 sagittal inversion recovery sequence (C) showing a hyperintense lesion from T4–T8 (arrow). e572 Kivanany et al: J Neuro-Ophthalmol 2022; 42: e571-e573 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence postinfectious manifestations of COVID-19 and continue screening and workup of patients as the presence of antibodies may change the patient’s visual prognosis and requirement for continued immunosuppression. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; b. Acquisition of data: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; c. Analysis and interpretation of data: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Category 2: a. Drafting the manuscript: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee; b. Revising it for intellectual content: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: P. B. Kivanany, S. Raviskanthan, P. W. Mortensen, and A. G. Lee. Kivanany et al: J Neuro-Ophthalmol 2022; 42: e571-e573 REFERENCES 1. Gold DM, Galetta SL. Neuro-ophthalmologic complications of coronavirus disease 2019 (COVID-19). Neurosci Lett. 2021;742:135531. 2. Chuang TY, Miskin D. Case report: neuromyelitis optica associated with SARS-CoV-2. Pract Neurol. 2020;33:49–52. 3. Batum M, Kisabay A, Mavio glu H. Covid-19 infection-induced neuromyelitis optica: a case report. Int J Neurosci. 2020;1–7 (Online ahead of print). 4. Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm. 2015;2:e110. 5. Koga M, Takahasi T, Kawai M, Fujihara K, Kanda T. A serological analysis of viral and bacterial infections associated with neuromyelitis optica. 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