Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome

Background: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. Methods: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. Results: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. Conclusion: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Postinfectious SARS-CoV-2 Opsoclonus-MyoclonusAtaxia Syndrome Jodi L. Nelson, DO, Gregory M. Blume, MD, Saurabh K. Bansal, MD, Jacqueline R. Kaufman, APN, Florence R. Woods, APN, Xiaojun Zhang, MD, Jorge C. Kattah, MD Background: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis–fastigial nucleus—premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. Methods: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2–specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. Results: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixaDepartment of Neurology (JN, GB, FW, XZ, and JK), University of Illinois College of Medicine Peoria, Illinois Neurologic Institute, OSF St. Francis Medical Center, Peoria, Illinois; Department of Neurology (JK and FW), Illinois Neurologic Institute OSF St. Francis Medical Center, Peoria, Illinois; and Department of Internal Medicine (SB), University of Illinois College of Medicine Peoria, OSF St. Francis Medical Center, Peoria, Illinois. 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 full text and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Jorge Kattah, MD, Department of Neurology, University of Illinois College of Medicine Peoria, St. Francis Medical Center. 530 NE Glen Oak Avenue, Peoria, IL; E-mail: [e-mail] Nelson et al: J Neuro-Ophthalmol 2022; 42: 251-255 tion block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. Conclusion: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis. Journal of Neuro-Ophthalmology 2022;42:251–255 doi: 10.1097/WNO.0000000000001498 © 2021 by North American Neuro-Ophthalmology Society T he opsoclonus-myoclonus-ataxia syndrome (OMAS) is the result of diverse etiologies with a common mechanism responsible for the ocular, trunk, and limb movements. The underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication (1–4). A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis–fastigial nucleus (FN) —premotor saccade burst neuron circuit in the brainstem (5). Therefore, the management will focus on immunosuppression, searching for a possible underlying malignancy or infectious etiology, and modulation of GABAA hypersensitivity with benzodiazepines. CASE A 57-year-old woman without a significant medical history presented with a day of speech changes and persistent 251 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution jerking movements in late February 2021. Of note, her son and husband had SARS-CoV-2 pneumonia with a positive SARS-CoV-2 nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) test, obtained at the local city public testing facility and performed at our institution in January 2021, after a family trip to Georgia. On January 2, 2021, she had a negative SARS-CoV-2 nasopharyngeal RT-PCR test, with no family history of ataxia or abnormal movements. Review of systems was negative for night sweats, unintentional weight loss, fevers, rashes, respiratory complaints, or change in olfaction or taste. Her recent mammogram was normal. On examination, she had a nonrhythmic truncal titubation (see Video 1, Supplemental Digital Content, http://links. lww.com/WNO/A551), hyperekplexia, pronounced limb and truncal ataxia, intention tremor, and dysdiadochokinesis. Cranial nerves, strength, sensation to pinprick, vibration, and proprioception were intact with symmetric deep tendon reflexes without pathological reflexes. On hospital Day 4, before steroids were started, her MOCA score was 25/30 (23 for delayed recall, 21 for copying, and 21 for floor of the hospital). Her eye examination showed unsteady visual fixation with macrosaccadic oscillations (see Video 2 Section 1, Supplemental Digital Content, http://links.lww.com/ WNO/A552) recorded the day after her first dose of 1 G of intravenous methylprednisolone (i.v. MP) and convergenceinduced brief ocular flutter (see Video 3, Supplemental Digital Content, http://links.lww.com/WNO/A553) recorded the following day after 2 days of 1 G i.v. MP. Cerebrospinal fluid (CSF) testing was clear, colorless fluid with 1 nucleated cell and 1 red blood cell, normal protein (35.5 mg/dL), and glucose (57 ng/dL). Her CSF neuronal specific enolase (NSE) was elevated at 34 ng/dL (normal ,15 ng/dL). Gram stain was negative for organisms. Cytology was negative for malignancy. Flow cytometry was negative for abnormal lymphoid population. AMPA-A, amphiphysin, antiglial nuclear, antineuronal nuclear type 1–3, CASPR2-Immunoglobulin G (IgG), CRMP-5, DPPX, GABABR, GAD65, Glial fibrillary acidic protein, glycine R, IgLON5, LGI1-IgG, mGlur1, Neuronal Intermediate Filament, n-methyl-D-Aspartate receptor, and Purkinje cell cytoplasmic antibodies were negative (Mayo Clinic Laboratory). Oligoclonal bands were absent. On admission, she had a second negative SARS-CoV-2 nasopharyngeal RT-PCR test, but she had positive serum testing: IgG to SARS-CoV-2 6.9 S/C (normal ,1/4 S/C), lactic acid 3.8, and CRP 0.75 (normal ,0.5 mg/dL). Normal Serum testing for GQ1b antibodies and the Mayo Clinc PAVAL panel were negative. Negative nasopharyngeal testing was found for SARS-CoV-2 RT-PCR (tested twice), influenza, parainfluenza, RSV, mycoplasma, bordetella pertussis, bordetella parapertussis, chlamydia pneumoniae, rhino/enterovirus, metapneumovirus, and adenovirus. A chest x-ray on admission showed patchy opacities, but no ground glass opacities, in the right lung representing pneumonia. 252 MRI of the brain with and without contrast on hospital Day 2 showed modest caudate nuclei hyperintensities in T2 fluid-attenuated inversion recovery sequence and Diffusion weighted imaging but without restricted diffusion. A 30min EEG on hospital Day 2 and an overnight EEG from Days 3 to 4 were negative for seizures or epileptiform discharges. Neuropsychological evaluation on Day 3 (before starting Solu-MEDROL) showed symmetrically impaired fine motor dexterity speed bimanually. Her encephalopathy manifested as slower mental processing speed, particularly in performing visual construction tasks with a heavier executive demand, mental flexibility, visual memory, or noncontextual verbal encoding. We treated her with 1000 mg i.v. Solu-MEDROL for 5 days and clonazepam 0.25 mg twice a day and 0.5 mg at night. She improved after the second dose of Solu-MEDROL. She was able to ambulate more steadily, and her ocular flutter was only present with convergence, whereas before it was also present with vertical and horizontal saccadic eye movements. We discharged her on Day 5 with an oral steroid taper. Ten days after discharge, she had residual, albeit improved, limb and trunk ataxia, and the family noted that occasional eye movements present behind closed eyelids, which were also present previously, have resolved. We recorded the eye movements using the Otometrics Chartr-200 goggles with the head fixed (Trustrup, Denmark). She had normal eye movements and steady fixation in response to visual targets; however, she had intermittent bursts of multidirectional, fast, large amplitude saccades without an intersaccadic interval, characteristic for opsoclonus, exclusively with fixation block (Fig. 1; see Video 2 section 2, Supplemental Digital Content, http://links.lww.com/WNO/A552). These oscillations persisted throughout the 5-minute recording. We did not see these movements with eyelid closure at a quick glance. This was concerning for suboptimal response to steroids; therefore, we initiated further workup and administered a 750-mg rituximab infusion. CT scans of chest, abdomen, and pelvis did not show cancerous lesions but showed pulmonary ground-glass opacities in the right lower lung that appeared improved from her CXR showing a larger opacity limited to the right lower lung 19 days earlier. Serums such as Antinuclear antibodies, Extractable nuclear antigen antibodies, CA125, and Carcinoembrionic antigen were negative. She showed significant improvement 2 weeks after the rituximab infusion. The examination and video recording 4 weeks after the symptom onset and hospitalization were normal; the patient returned to work. DISCUSSION The striking myoclonus and hyperekplexia represent a dramatic, but potentially curable, neurological syndrome. In our patient, the initial eye abnormalities were more severe before the first bedside eye movement video (recorded after the first high-dose steroids on Day 4). Nelson et al: J Neuro-Ophthalmol 2022; 42: 251-255 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Video-oculography recording of primary eye position with fixation block. Note a burst of conjugate, nonrhythmic, 40-degree amplitude saccades without an intersaccadic interval (A), with a frequency of 7 Hz and a vertical component. There are also oscillations with an intersaccadic interval and 1 square-wave jerk. Macrosaccadic oscillations (MSOs) were present primarily during vertical saccade refixations (see Video 2, first section, Supplemental Digital Content, http://links.lww.com/ WNO/A552). Whereas the etiology of OMAS in children and older adults is paraneoplastic, in younger adults, it is often postinfectious. Regardless of age, brain MRI may be normal. Opsoclonus does not occur in natural or experimental lesions in primates (1). In addition, neuropathological examination in paraneoplastic opsoclonus typically lacks definitive macroscopic or microscopic abnormalities (1,2). In particular, the pause cells, initially proposed as the principal OMAS cells— group target, showed no microscopic abnormalities (3). However, 1 patient with paraneoplastic opsoclonus had sparse gliosis and mild lymphocytic infiltrates in the FN and inspired the first OMAS computer model (2). The current theoretical mechanisms to explain the ocular oscillations in these patients involve simultaneous neuron dysfunction in the brainstem and cerebellum (1,4,5). The brainstem circuitry theoretically involves omnipause neuron (OPN) inability to regulate postinhibitory rebound (PIR) from oscillating excitatory (Excitatory burst Neuron [EBN]) and inhibitory burst neuron (IBN) circuits in the pons (6–8). Disruption of this mechanism causes back-to-back saccades without intersaccadic intervals (Fig. 1). Although not documented with videonystagmography in this case, convergence/ divergence refixations (known to suppress OPN) (7,9) caused transient ocular oscillations in our patient. They likely represent ocular flutter and thus support a brainstem role as well (see Video 3, Supplemental Digital Content, http://links. lww.com/WNO/A553), recorded on Day 5 of admission and the second day of high-dose steroids (7). In addition to altered membrane excitability in the EBN/IBN circuit and PIR, disinhibition of the FN causes increased nonrhythmic eye oscillations. In humans, lesions of the FN cause saccade hypermetria (1,7,10); our patient had similar saccades (see Video 2, Section 1, Supplemental Digital Content, http://links.lww.com/WNO/A552). In a study, serum from 3 of 7 patients with opsoclonus had anti–Purkinje cell antibodies with punctate staining in the cerebellar molecular layer, presumably directed against the Nelson et al: J Neuro-Ophthalmol 2022; 42: 251-255 parallel fiber–Purkinje cell synapse (11). Moreover, PET scan hypermetabolism of cerebellar nuclei supports the potential role of deep cerebellar nuclei (12). A recent simulation model (5) based on opsoclonus related to anabolic steroids, which modulate GABAA receptors, implies mistimed neuronal activity in the brainstem and cerebellum in the pathogenesis of opsoclonus. This may explain the findings in our patient (5,13). In their mathematical model, the steroids increased the sensitivity of GABAA receptor, leading to increased GABA inhibition of neurons in the FN and OPN. FN inhibition did not allow saccades to stop on target. Delayed OPN reactivation caused a return movement with no saccadic interval driven by PIR. The varying degree of FN and OPN inhibition leads to a continuum of movements, including MSO, ocular flutter, and opsoclonus; our patient had these same eye movements. This suggests a simultaneous brainstem– cerebellar mechanism [2, (5) 11, 12]. As a potential example, using abnormal eye movements in OMAS, one could draw an analogous explanation for the head and truncal tremor in our patient with a similar etiology. Irregular oscillations of motoneurons innervating the trunk and neck may originate in the cerebellum, particularly the regions of the FN that control movement of axial musculature (5,14) (see Video 1, Supplemental Digital Content, http://links.lww.com/WNO/A551). In our case, elevation of NSE (a neuronal lesion marker) and the absence of white matter changes on MRI (15) suggest Purkinje cell, cerebellar deep nuclei, and pontine neurons rather than cerebellar outflow tracts as the cause of the abnormal eye movement and the symmetric limb and truncal ataxia. Of note, elevated NSE did not preclude full recovery of function after treatment. In general, alteration of function in OMAS responds well to the management, and this may be predicted by the fact that PET CT has shown cerebellar deep nuclei hyperactivity and not hypoactivity as one would expect with irreversible injury. The waveform of the oscillations in these patients includes large amplitude back-to-back saccades and, as seen in this case, MSO and flutter (16). The oscillations remained with eyelid closure, as noted by the patient’s family. In a previous instance, they occurred during REM sleep (17). In some cases, they developed in lateral gaze (18) and in some instances triggered by position changes (19). Interestingly, we recorded overt opsoclonus with fixation block 10 days after the symptom onset (Fig. 1); this suggests that PIR may be fixation-suppressed which is similar to previous studies that showed persistent opsoclonus with eye closure (1,3). Therefore, vision may be important in restoring or hasting the proper timing of neuronal activation in the EBN/IBN/OPN circuit. Treatment typically includes combinations of steroids, Intravenous Immunoglobulin (IVIG), and plasma exchange. However, others used azathioprine, rituximab, and mycophenolate mofetil successfully (20,21). We chose 253 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution rituximab in our case because it has a longer half-life than IVIG. Rituximab improved opsoclonus-myoclonus syndrome in children with or without neuroblastoma (22). The mechanism may be through CD202 B-cell population normalization; however, an exact explanation is unclear. Although there are minimal data on adults, we could apply the pediatric experience to adults. Our patient’s VOG 2 weeks later showed steady fixation in all testing conditions, possibly reflecting the beneficial effect of rituximab on the presumed postviral OMAS antibody. The paraneoplastic syndrome often precedes diagnosis of cancer and improves at a slower pace after tumor resection or cancer-specific treatment (3). Idiopathic/nonparaneoplastic etiologies seem to be monophasic with hastened recovery after immunotherapy, as in our case (23). Our case highlights a SARS-CoV-2 para/postinfectious OMAS in the setting of subclinical pneumonia. Recent reports suggest that OMAS may be an infrequent post– SARS-CoV-2 neurological syndrome (24–27). The bilateral caudate hyperintensities on MRI, high NSE, and encephalopathy suggest additional CNS targets (28,29). CSF may be normal in patients with OMAS (22,25,29), however; to the best of our knowledge, NSE was not tested. We add to previous post–SARS-CoV-2 OMAS reports with serial, clinical, oculomotor, and immunological findings before and after rituximab-associated remission. Serum immunological testing is valuable when confronting unexplained neurological abnormalities in patients exposed to SARSCoV-2 and negative nasopharyngeal RT-PCR testing. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Nelson and Jorge C Kattah; b. Acquisition of data: J. Nelson, G. Blume, S. Bansal, J. Kaufman, F. Woods, X. Zhang, and J. Kattah; c. Analysis and interpretation of data: J. 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