Review Article - (2022) Volume 5, Issue 4
As the list of neurological sequelae of Severe Acute Respiratory Syndrome Coronavirus 2. (SARS-CoV-2) infection continues to expand; the number of recorded cases of post-acute Coronavirus Disease (COVID-19) movement disorders is on the rise. The possibility of a functional origin of these abnormal movements has been largely overlooked. Here we present a review of recent literature exploring para-and post-infectious movement disorders in COVID-19 patients.
COVID-19 • Movement Disorders • CNS
Coronaviruses (CoV), so named for their crown or spike-like cell surface proteins, were first discovered in the 1960s and include 4 subgroups: alpha, beta, gamma, and delta. Presently, there are a total of 7 coronaviruses known to affect humans: 229E, HKU1, NetherLand 63 (NL63), OC43, MERS-CoV, SARS-CoV-1, and SARS-CoV-2 [1]. The beta coronaviruses Middle East Respiratory Syndrome Coronavirus (MERSCoV), SARS-CoV1, and SARS-CoV-2 can cause severe illness in humans. Neurological manifestations associated with CoV infection were described well prior to the 2020 SARS-CoV-2 pandemic. Historically, notable CoV outbreaks include the 2003 Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) outbreak in Asia and 2015 MERS-CoV outbreak in Saudi Arabia. Documented neurological manifestations following infection with SARS-CoV1 and MERS-CoV include alterations in consciousness, headache, affective disorders, ataxia, seizures, generalized pain, and persistent anosmia [2,3]. Managing neurological disease in COVID-19 patients has proven exceedingly difficult. While hypoxia or ischemiarelated Central Nervous System (CNS) damage has been proposed as a potential trigger, the presence of anti-neuronal antibodies in the serum and Cerebrospinal Fluid (CSF) of COVID-19 patients in combination with the absence of hypoxia induced CNS damage on postmortem studies suggests the existence of alternative mechanisms of injury.
Aside from hematogenous dissemination, the prevailing theory is that neurotropism results in direct damage to the peripheral or CNS with invasion mediated by Angiotensin-Converting Enzyme 2 (ACE-2) receptors on the surface of cells that comprise neuronal tissue. Support for this theory comes, in part, from the discovery that olfactory epithelium expresses concentrations of ACE-2 receptors like that found in lung tissue. This could suggest a means of direct entry into the brain/ CNS. A recent study of COVID-19 patients with otherwise unexplained neurological symptoms revealed elevated levels of autoantibodies in CSF, suggesting that autoimmunity may play a role in neuronal damage [4]. A recent presentation at the American Academy of Neurology 2022 annual meeting titled “Cognitive Symptoms After Mild SARS-CoV-2 Infection Associated with Higher Levels of CSF Immune Activation and Immunovascular Markers'' suggests that SARS-CoV-2 induced immune activation may persist well after the acute illness and, thus, could cause persistent neurological symptoms. Several possible autoantigens have been described including Heat Shock Protein (HSP)A5, HSP 90-beta (HSP90AB1), titin, Ryanodine Receptor 2 (RYR2) [5]. Another study stratifying COVID-19 patients found increased incidence of thrombotic or neurological complications in patients with autoantibodies compared to those without [6]. Still, some studies have found no evidence of CNS viral invasion [7,8]. While postmortem brain biopsies of COVID-19 patients have shown evidence of hypoxic injury, no histopathological changes or cytoplasmic staining could be ascribed to the virus [9]. Although the specific neurobiology underlying neuronal injury remains undetermined it is likely that an interplay of mechanisms, including both innate and adaptive immune responses, contribute to neuronal damage.
So-called “long COVID” is a term used to describe new, recurrent, or persistent health problems experienced 4 or more weeks following infection [10]. While there is still much to learn about this phenomenon, it appears to follow both asymptomatic and symptomatic infection. Commonly reported neurological symptoms include tiredness, difficulty thinking or concentrating, “pins-and-needles” feeling, sleep problems, dizziness, mood changes, and changes in smell or taste. Proposed mechanisms include autoimmune conditions and multisystem inflammatory syndrome. Because some of these symptoms parallel those that can occur after any hospitalization, it is often difficult to discern their cause. Neurological issues occurring as a consequence of systemic complications (e.g. stroke, intracerebral hemorrhage, critical illness polyneuropathy, headache, encephalitis, cognitive impairment), COVID-19 related or otherwise, are well-documented [11,12]. However, disorders of movement in COVID-19 patients have received little attention. Commonly reported abnormal movements include ataxia, myoclonus, and tremor [13-17]. Abnormal movements such as these are often observed in neurodegenerative processes such as alzheimer’s disease, frontotemporal dementia, or corticobasal degeneration. Unlike the aforementioned, a pathological basis for abnormal movements remains to be found in COVID-19 patients. While hypoxia and/or metabolic disturbances are commonplace in COVID-19 patients and could explain many acute neurological manifestations (e.g. post-anoxic myoclonus or “lance adams syndrome), these transient changes are unlikely to explain persistent or late-onset abnormal movements. The discovery of anti-neuronal antibodies to components of the basal ganglia, a region of the brain integral in control of voluntary movement, suggest that alternative mechanisms of injury exist [18]. One study even showed a bilateral decrease in presynaptic dopamine uptake on Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) in a patient with new onset hypokinesia and rigidity [19]. Further, patterns of neuronal loss inconsistent with hypoxia have been observed in many areas of the brain of COVID patients [20], effectively excluding ischemia as a potential explanation. While a causal relationship remains to be established, several case reports have described the appearance of Parkinson's disease following COVID-19 infection [21- 23]. Of course, this could be a simple matter of coincidence in that the onset of Parkinson’s disease tends to occur within a similar age range to that of patients most adversely affected by COVID-19. It could also be that infection serves as a potentiating, rather than causal, factor in the evolution of Parkinson’s disease, like what has been observed with pesticide exposure [24]. Nevertheless, these findings suggest the possibility of a causal relationship between SARS-CoV-2 infection and movement disorders.
Post-viral myoclonus is perhaps the most well-documented of known virally triggered movement disorders and was described well prior to SARS-CoV-2 [25-32]. While opsoclonus-myoclonus syndrome is common, all forms of myoclonus (i.e. focal, segmental, and generalized) have been described following viral infection. It can occur following a variety if viral infections including various arboviruses, Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV), Human T-Lymphotropic Virus Type 1 (HTLV-1), and measles virus. [33] published a case series of 3 patients with myoclonus affecting the face, neck, shoulders, and upper extremities with exaggerated startle response. The acute onset of this myoclonus and its similarity to previously describe virally triggered myoclonus, as well as its presumed response to immunotherapy, led these investigators to hypothesize that a para-infectious immune-mediated mechanism could be responsible. Unfortunately, Electromyography (EMG) was not performed in any of the 3 patients and no nasopharyngeal swab was performed in 2 of 3. Further, we were unable to identify a single case report or series of COVID-19 patients where EMG was used to localize myoclonus. [34] reported a case of a 54-year-old man with continuous flexion movements of the head that began shortly following SARS-CoV-2 infection. He continued to experience unexplained jerky movements well after convalescence. Similarly, [35] reported a case of a 52-year-old patient who developed persistent generalized jerking movements and disequilibrium following infection. The report states that the patient tested positive for SARS-CoV-2 a week before onset of these symptoms. There are several other case reports describing post COVID-19 myoclonus [31-44]. While movement disorders are generally considered a rare neurological manifestation of COVID-19, their prevalence appears to be increasing. One study of 550 patients referred to a tertiary care center for movement disorders found a 60% increase in incidence of Functional Movement Disorders (FMD) during the pandemic [41].
An internal sensation of tremors or vibrations and external tremors continue to be reported by patients suffering from so-called “long-COVID.” While their origin remains a mystery, proposed theories include autonomic nervous system dysfunction and peripheral nerve damage. One 50-yearold female described her experience for Becker’s Hospital Review “It feels like someone put something on my bed and it’s vibrating. My body is moving inside, it’s jolting” Interestingly, [42] discovered an association between both self-reported COVID-19 infection and positive serology with persistent physical symptoms [43]. This has led some to suspect a functional origin of these complaints, perhaps occurring because of increased fear and anxiety related to prolonged isolation [44]. Case reports from early in the pandemic have described the onset of abnormal movements (e.g. repetitive head flexion, jerking of limbs) in patients with severe anxiety and depression determined by self-reported questionnaires [45, 46]. Of course, the possibility of coexisting functional and organic symptoms (e.g. “long-COVID” patients with a history of essential tremor prior to infection) should not be overlooked. That said, our opinion remains steadfast that functional disorders should remain diagnoses of exclusion. Whether functional or organic in origin, these sensations and abnormal movements can have significant impact on patient well-being [47]. Further investigation is paramount in effective identification and treatment of these abnormal movements.
Reports of movement disorders following COVID-19 infection are increasing. While the pathophysiology underlying these abnormal movements remains uncertain, the proportion of patients suffering from functional symptoms appears to be increasing.
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Citation: Grossman JT. Post-acute COVID-19 Movement Disorders: Organic or Functional?. Neurol Neurorehabilit. 2022, 4(3), 25-27
Received: 16-Jun-2022, Manuscript No. NNR-22-66750; Editor assigned: 19-Jun-2022, Pre QC No. NNR-22-66750 (PQ); Reviewed: 29-Jun-2022, QC No. NNR-22-66750 (Q); Revised: 05-Jul-2022, Manuscript No. NNR-22-66750(R); Published: 07-Jul-2022, DOI: 10.37532/22.4.3.25-28
Copyright: ©2022 Grossman JT, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
