key: cord-0691027-nfu8rdvh authors: Muccioli, Lorenzo; Rondelli, Francesca; Ferri, Lorenzo; Rossini, Giada; Cortelli, Pietro; Guarino, Maria title: Subcortical myoclonus in COVID‐19: comprehensive evaluation of a patient date: 2020-08-07 journal: Mov Disord Clin Pract DOI: 10.1002/mdc3.13046 sha: 8b3375a0cc67bc51e62797456830469f0c71ca43 doc_id: 691027 cord_uid: nfu8rdvh nan Myoclonus has been reported as a possible manifestation of coronavirus disease 2019 (COVID-19), yet its neurophysiology and pathogenesis were poorly investigated. [1] [2] [3] [4] We describe a middle-aged man with COVID-19 who underwent extensive examinations for his disabling myoclonus. A 58-year-old hypertensive man with a one-week history of fever and cough presented to the emergency department with dyspnea. A nasopharyngeal swab tested positive for SARS-CoV-2. The patient was admitted to the ICU after one week and placed on invasive mechanical ventilation due to respiratory distress. He was treated with hydroxychloroquine, tocilizumab and remdesivir. Respiratory status quickly improved, thus he was extubated after five days and oxygen therapy was progressively weaned off. Two days after ICU discharge, he became markedly agitated. His mental status normalized in 48 hours, however at this point he developed multifocal myoclonus elicited by action and tactile stimuli, predominant in the right proximal inferior limb muscles, preventing his ability to stand [Video 1]. Cognitive deficits were not observed. Electrolytes, renal and liver function tests were unremarkable. Cerebrospinal fluid (CSF) analysis, performed eight days after myoclonus onset, demonstrated 5 leukocytes/μL, elevated protein levels (75 mg/dL) and CSF/serum albumin ratio (13.1), and negative SARS-CoV-2 RT-PCR. Cytokine analyses revealed IL-6 at 11.6 pg/mL in CSF (29.3 pg/mL in serum, reference<5.9) and IL-8 at 38 pg/mL in CSF (11 pg/mL in serum, reference<70). A serologic panel of autoantibodies against neuronal intracellular and cell surface antigens was negative. Brain MRI showed cerebral small vessel disease of moderate severity. EEG was unremarkable. Polymyography confirmed the presence of multifocal positive myoclonus with a burst duration of 140-220 ms. Back-averaging analysis did not show EEG time-locked discharges [ Figure 1 ]. The patient was treated with clonazepam and levetiracetam, resulting in marked amelioration of the myoclonus within five days. This case report confirms that myoclonus can occur in the context of diffuse inflammation related to COVID-19. In previously published reports, myoclonus has been described as spontaneous or action-induced, multifocal or generalized, with a non-specific distribution. [1] [2] [3] [4] This article is protected by copyright. All rights reserved. In our patient, the prominent involvement of axial and proximal limb muscles, myoclonus stimulussensitivity, the absence of cortical discharges at EEG jerk-locked back-averaging and the long duration myoclonic bursts, are consistent with subcortical myoclonus, possibly secondary to brainstem involvement. Defining the underlying pathophysiology is challenging. Myoclonus may present in the context of other viral infections, with concomitant encephalopathy/encephalitis or as an isolated postinfectious phenomenon. 5-6 SARS-CoV-2 may theoretically access subcortical structures involved in myoclonus generation via invasion of the olfactory bulb. 1 In our patient, however, clinical course (including the absence of hyposmia), MRI and CSF findings argue against a direct pathogenic role of CNS viral invasion. Even though myoclonus appeared after a period of intubation, our patient did not suffer anoxic brain injury, thus excluding Lance-Adams syndrome. Myoclonus onset timing and clinical course were also not consistent with an adverse drug reaction, a mechanism suggested in the form of serotonin syndrome in two patients treated with lopinavir/ritonavir. 2, Agitation and myoclonus were preceded by severe cytokine release syndrome, a distinctive feature of COVID-19. 7 CSF analysis showed blood-brain barrier disruption, slightly elevated CSF IL-6 levels and elevated IL-8 CSF/blood ratio. These abnormalities may have been more pronounced if assessed at myoclonus onset. Interestingly, cytokine-mediated neuroinflammation induced by SARS-CoV-2 has been implicated in steroid-responsive COVID-19-associated encephalopathy. 5 In addition to marked agitation in our patient, previous reports also had clinical/instrumental findings suggestive of encephalopathy, including dysexecutive syndrome, delirium, somnolence, EEG slowing, elevated inflammatory markers, variable responses to immunotherapies and a benign clinical course, 1-4 further suggesting an immune-mediated/inflammatory pathogenesis. In conclusion, subcortical myoclonus should be considered among the neurological manifestations associated with COVID-19. The pathogenic role of cytokine-mediated neuroinflammation should be addressed in future studies. This article is protected by copyright. All rights reserved. Generalized myoclonus in COVID-19 Serotonin syndrome in two COVID-19 patients treated with lopinavir/ritonavir This article is protected by copyright. All rights reserved Mixed central and peripheral nervous system disorders in severe SARS-CoV-2 infection Delirium in COVID-19: A case series and exploration of potential mechanisms for central nervous system Hyperkinetic movement disorders associated with HIV and other viral infections Isolated" postinfectious myoclonus Cytokine release syndrome in severe COVID-19 Steroid-responsive encephalitis in Covid-19 disease We thank Prof. Paolo Tinuper for helpful discussion on the case, the neurophysiology technologists Soraia Garrossi and Rita Signorelli for their quality work during this pandemic, and Olivia J. Henry for English language editing. The authors confirm that approval of an institutional review board was not required for this work.Informed written consent for publication was obtained from the patient. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.