CASE 1

A 43-year-old man who was receiving regular rituximab for follicular lymphoma was admitted for COVID-19 pneumonia. He received 2 doses of the Pfizer-BioNTech mRNA vaccine 3 months prior but had no demonstrable anti-spike antibodies. Remdesivir, dexamethasone, and baricitinib were given for worsening pneumonia. On Day 11 of illness, he developed disproportionate anxiety and progressive apraxia. From Day 23, dystonic limb posturing, craniofacial dyskinesias, tongue and jaw myoclonus, mild confusion and echolalia appeared (Supplementary Video 1 in the online-only Data Supplement). On Day 27, he had a generalized tonic‒clonic seizure and respiratory failure requiring mechanical ventilation. He was sedated and paralyzed with fentanyl, propofol and atracurium due to high ventilatory requirements. Despite paralysis, he developed multifocal, irregular, positive myoclonus of the limbs and abdominal muscles. He also had intermittent saccadic intrusions that progressed to recurrent bouts of ocular flutter. Slow, semirhythmic, asynchronous myorhythmia of the face, tongue, hands and feet was noted. Serial sampling of cerebrospinal fluid (CSF) was unremarkable; in particular, severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR) and antibodies were negative. Laboratory evaluation showed B-cell depletion, but work-up for alternative causes yielded no results (Table 1). On magnetic resonance imaging (MRI) of the brain, a small diffusion-weighted hyperintensity without corresponding restricted diffusion was observed in the right basal ganglia. The electroencephalogram showed continuous generalized theta-delta slowing. The patient was given intravenous immunoglobulin. The seizure was treated with levetiracetam, sodium valproate, phenytoin and midazolam infusion. Pulsed methylprednisolone was stopped after 2 days due to nosocomial infections. In view of persistent viral PCR positivity in endotracheal aspirates and serum on Day 30, he received casirivimab/imdevimab on Day 31. He was also administered intravenous tocilizumab on Day 32 and underwent 5 sessions of plasma exchange from Day 39 for presumed dysimmune encephalopathy. His movement disorders started abating from Day 45, and he was extubated on Day 55, with improvement in his mental state. Formal neuropsychiatric assessment on Day 101 revealed mild reductions in attention, inhibitory control, verbal fluency and verbal working memory. A fluorodeoxyglucose positron emission tomography (FDG PET) scan of the brain 3 months following recovery showed mild frontal, temporal and parietal lobe hypometabolism.

CASE 2

An unvaccinated 19-year-old man with severe autism, well-controlled generalized epilepsy and morbid obesity was admitted for COVID-19 pneumonia. He was intubated for hypoxemia and required high doses of sedatives and paralytic agents (fentanyl, propofol, and atracurium) to support ventilation. He received remdesivir and dexamethasone. On Day 16 of illness, despite paralysis, he was noted to have multifocal myoclonus of his limbs, slow, semirhythmic, asynchronous myorhythmia of the craniofacial and limb muscles and intermittent ocular flutter (Supplementary Video 2 in the online-only Data Supplement). These movements were remarkably similar to those in Case 1. In addition, he had transient episodic tonic downward gaze deviations. Laboratory evaluation was unremarkable (Table 1). Brain MRI was normal. He was treated with levetiracetam and sodium valproate, and from Day 17, received intravenous immunoglobulin. His involuntary movements resolved on Day 20, and he was extubated on Day 22, without residual neurological deficits.

We describe two patients with severe COVID-19 pneumonia and encephalopathy who showed stereotypical cranial and limb movements consisting of repetitive, semirhythmic, asynchronous, nonjerky contraction of the craniofacial and distal limb muscles, which were best characterized as slow myorhythmia. The patients also displayed multifocal, jerky positive myoclonus. The semirhythmicity, slow frequency (usually 1–4 Hz), slow velocity, and involvement of a limited number of limb or craniofacial muscles distinguish myorhythmia from myoclonus. Myorhythmia is resonant of Whipple’s disease; however, our patients only had saccadic intrusions and ocular flutter without pendular convergence nystagmus or vertical gaze abnormalities. Myorhythmia with Parkinsonism, which resolved with corticosteroids, was reported in COVID-19-associated acute necrotizing encephalopathy [5]. Other causes of myorhythmia include brainstem or thalamic lesions, stroke, autoimmune encephalitis, and infections such as Listeria encephalitis, which were excluded in our patients.

In both patients, there was no radiologic-anatomic correlate for the movement disorders and encephalopathy. We could not perform electrophysiological studies, but the myorhythmia and ocular flutter in both patients and the tonic downward gaze deviation in Case 2 suggested brainstem localization [2,4]. The PET scan in Case 1 reflected the patient’s residual neurocognitive deficits.

Although direct etiology cannot be concluded, the temporal association, similarity to other reported cases of these 2 contemporaneous patients, and exclusion of alternative etiologies (Table 1) suggest COVID-19 encephalopathy as the likely cause of the movement disorders [2,3,5,6]. While both patients required mechanical ventilation, they did not have prolonged untreated hypoxia or liver or renal failure that could have resulted in cortical myoclonus. High doses of analgesics and sedatives may be confounders, but the movement disorder in Case 1 preceded their initiation and persisted in Case 2 despite their cessation. The borderline anti-thyroid peroxidase antibodies were likely a nonspecific reflection of inflammation rather than Hashimoto encephalopathy.

Various mechanisms have been postulated for the neurological manifestations in COVID-19, including cerebral hypoxia, direct viral invasion, and cytokine-mediated immune response to infection [1-3,5,6]. The lack of viral particles and antibody response in the CSF of Case 1, as well as the time course, laboratory profile, and response to immunomodulatory treatments, suggested a parainfectious, dysimmune etiology. The depletion of B cells in Case 1 makes an antibody-mediated process unlikely. We suspected an immunopathology centered on innate immunity, T-cells and cytokine storm. The latter can disrupt the blood‒brain barrier and trigger microglial activation and T-cell infiltration. Of note, Case 1’s sequentially escalating immunotherapy included tocilizumab, an interleukin-6 inhibitor, although it is uncertain to which treatment he eventually responded. Histopathological findings in a postmortem study of COVID-19 patients showed activation of microglia and infiltration of cytotoxic T-lymphocytes mostly confined to the brainstem and cerebellum, the likely sites of pathology in our patients [7]. In conclusion, we report slow myorhythmia as part of the spectrum of hyperkinetic movement disorders associated with COVID-19.

Supplementary Material

Video 1.

Segment 1: Limb dystonia – involuntary episodic dystonic posturing starting on Day 23, with right arm extended, left arm flexed, head turned to right, fingers extended and legs extended. Segment 2: Craniofacial dyskinesia – involuntary grimacing. Segment 3: Episodic tongue and jaw myoclonus, observed on Day 24, approximately 1.5 Hz. Segment 4: Apraxia – difficulty executing motor tasks, such as touching his nose with his fingers, and mimicking actions, including brushing teeth, opening and closing eyes, protruding tongue, and smiling. These were not due to weakness, cerebellar or sensory ataxia, or dysphasia. Segment 5: Speech abnormalities – staccato speech in the absence of other cerebellar signs. Echolalia – patient echoing instructions to open and close hands. Segment 6: Ocular signs – following intubation on Day 27, transient saccadic intrusions, intermittently progressing to short bursts of ocular flutter, were noted. Segment 7: Limb and abdominal myoclonus – jerky, multifocal and asynchronous, starting from Day 29. Segment 8: Craniofacial myorhythmia – slow, rhythmic, nonjerky, asynchronous movements; frequency of approximately 0.5 Hz. Segment 9: Distal limb myorhythmia – slow, rhythmic, nonjerky, varying amplitudes; approximately 0.35 Hz. Slow episodic plantarflexion of both feet. Slow episodic flexion of the wrist, similar in appearance to asterixis, could be induced by holding the fingers and slightly extending the wrist. Segment 10: Day 60 of illness. No movement disorders; patient expressing residual anxiety symptoms.

Video 2.

Segment 1: Limb myoclonus – multifocal, asynchronous. Segment 2: Craniofacial myorhythmia – slow, nonjerky, irregular, and asynchronous eyebrow elevation and eye closure; frequency 0.2 to 0.4 Hz. Segment 3: Tongue and jaw myorhythmia, frequency 0.4 to 0.6 Hz. Segment 4: Hand myorhythmia, frequency 0.12 Hz, often induced by holding the fingers and wrists in an extended position. Foot myorhythmia manifesting as gentle plantarflexion of the ankles. Segment 5: Transient saccadic intrusions occasionally progressing to short bursts of ocular flutter, observed on Day 16. Segment 6: Transient episodic tonic downward gaze deviation.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author contributions

Conceptualization: Rebecca Hui Min Hoe, Fan Yang, Siew Kit Shuit, Thirugnanam Umapathi. Data curation: Rebecca Hui Min Hoe, Fan Yang, Siew Kit Shuit, Thirugnanam Umapathi. Formal analysis: Rebecca Hui Min Hoe, Fan Yang, Siew Kit Shuit, Thirugnanam Umapathi. Writing—original draft: Rebecca Hui Min Hoe, Fan Yang, Siew Kit Shuit, Thirugnanam Umapathi. Writing—review & editing: Rebecca Hui Min Hoe, Glenn Khai Wern Yong, Ser Hon Puah, Jennifer Sye Jin Ting, Mucheli Sharavan Sadasiv, Thirugnanam Umapathi.

Acknowledgments

We thank Professor Louis Tan and Dr. Yeo Tianrong at Department of Neurology, National Neuroscience Institute (Tan Tock Seng Hospital Campus), for their critical review and comment on the videos and manuscript. We would also like to acknowledge the many health care workers involved in the care of these two patients.

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