Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 2: Hyperkinetic movement disorders

Mitesh Chandarana; Heli Shah; Soaham Desai

doi:10.4103/AOMD.AOMD_51_21

REVIEW ARTICLES

Year : 2022 | Volume : 5 | Issue : 1 | Page : 23-37

Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 2: Hyperkinetic movement disorders

Mitesh Chandarana¹, Heli Shah², Soaham Desai³
¹ Department of Neurology, Medisquare Hospital, Ahmedabad, Gujarat, India
² Department of Neurology, Sterling Hospital, Ahmedabad, Gujarat, India
³ Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat, India

Date of Submission	15-Oct-2021
Date of Decision	12-Dec-2021
Date of Acceptance	09-Jan-2022
Date of Web Publication	25-Apr-2022

Correspondence Address:
Dr. Soaham Desai
Consultant Neurologist and Head, Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_51_21

Abstract

Movement disorders are relatively sparse amongst COVID-19 patients. However, in the setting of large number of COVID-19 cases, relatively rare acute to subacute onset, para-infectious or post-infectious movement disorders such as myoclonus and myoclonus-ataxia with or without opsoclonus have increasingly become more evident. Our objective of writing this paper is to summarize the available evidence documenting new onset hyperkinetic movement disorders associated with COVID-19. Myoclonus is the most frequently reported movement disorder associated with COVID-19 alone or in combination with ataxia and tremors. Apart from isolated myoclonus, myoclonus with ataxia, opsoclonus myoclonus ataxia syndrome have been reported post COVID. Isolated cerebellar ataxia is the other most commonly described movement disorder post COVID. Tremors, Chorea and dystonia are rarely described hyperkinetic movement disorders in association with COVID. Treatments being offered for hyperkinetic movement disorders consists of symptomatic treatment with benzodiazepine, anti-seizure drugs, immunomodulatory treatment with steroids, intravenous immunoglobulin and rehabilitative therapies. In this review we summarize the neurological features, investigations, treatments, and outcomes of all the published cases of hyperkinetic movement disorders associated with COVID-19.

Keywords: COVID-19, hyperkinetic movement disorders, hypokinetic movement disorders, neuroimaging, Parkinson’s disease, parkinsonism, SARS-CoV-2

How to cite this article:
Chandarana M, Shah H, Desai S. Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 2: Hyperkinetic movement disorders. Ann Mov Disord 2022;5:23-37

How to cite this URL:
Chandarana M, Shah H, Desai S. Spectrum of de novo movement disorders in the setting of COVID-19 infection: Part 2: Hyperkinetic movement disorders. Ann Mov Disord [serial online] 2022 [cited 2023 Mar 21];5:23-37. Available from: https://www.aomd.in/text.asp?2022/5/1/23/343846

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in December 2019 in Wuhan, China, has caused a global pandemic called the coronavirus disease 2019 (COVID-19). Apart from typical symptoms such as fever, cough, shortness of breath, myalgia, and fatigue, neurological symptoms involving the central and peripheral nervous system have been reported since the beginning of the pandemic.^[1] The pandemic has highlighted the existence of a wide range of neurological manifestations and has raised the question of the neuropathogenicity of coronaviruses.^[2] In the first of this two-part review of COVID-19-associated movement disorders, we have reviewed the pathogenesis and hypokinetic movement disorders associated with COVID. In the second part, we will review the hyperkinetic movement disorders associated with COVID.

Movement disorders are rare among COVID-19 patients. However, in the setting of large number of COVID-19 cases, relatively rare acute-to-subacute onset para or postinfectious movement disorders, such as myoclonus and myoclonus–ataxia with or without opsoclonus have become increasingly evident.^[3]

Methods

We performed an electronic search of PubMed and Google Scholar from August 1, 2019, to August 31, 2021, using the following keywords: “COVID-19,” “SARS-CoV-2,” “Myoclonus,” “Ataxia,” “Tremor,” “Opsoclonus–myoclonus–ataxia (OMAS),” “Opsoclonus,” “Dystonia,” “Chorea,” “Tics,” and “Stereotypies”. In addition, we searched for specific articles by cross-referencing the selected studies with relevant journal websites. We initially found a total of 318 articles using this search strategy. We included studies reporting COVID-19-associated hyperkinetic movement disorders, which included the management and outcomes of such cases. We included peer-reviewed studies, including cohort studies, case-control studies, and case reports, and original articles describing COVID-19-associated hyperkinetic movement disorders. After removing duplicates and irrelevant studies, 309 studies were identified. The titles and abstracts of the remaining 309 studies were screened for inclusion by three reviewers (MC, HS, SD). We excluded the studies with 1) prior history of movement disorders that worsened during or after COVID-19 infection, 2) duplicate publications, 3) studies published in non-English languages or those that were not accessible, and 4) studies with insufficient clinical or laboratory/imaging data. This yielded 80 articles whose full text was accessed and reviewed. After a detailed review of these articles and after excluding articles with incomplete details or contentious or analogous descriptions, a total of 70 articles were finally included in this review [Figure 1].

Figure 1: Search methodology for the review

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The hyperkinetic movement disorders associated with COVID are listed in [Table 1]. [Table 2] provides a summary of the neurological features, investigations, treatments, and outcomes of all the published cases of hyperkinetic movement disorders associated with COVID-19.

Table 1: The spectrum of hyperkinetic movement disorders associated with COVID-19 infection (published reports)

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Table 2: Summary of the neurological features, investigations, treatments, and outcomes of published cases of hyperkinetic movement disorders associated with COVID-19 infection

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Myoclonus and COVID-19

There were 34 published cases of isolated myoclonus [Table 2]; all patients developed myoclonus after COVID-19 infection. Most cases were reported from Europe and the United States (except for one case from Morocco). Majority of the patients in the published cases had generalized or multifocal myoclonus (32/34 patients; 94.1%), while only two patients had diaphragmatic myoclonus.^[7] Negative myoclonus was reported in four patients.^[4],[10] The most commonly associated neurological symptoms were cognitive dysfunction (3/34) and encephalopathy (2/34). Neuroimaging [computed tomography/magnetic resonance imaging (MRI)] data were available for 26 patients. The results were normal in majority of the patients, except for corpus callosum microbleeds in two patients,^[8] T2 hyperintensity in the right temporal lobe in one patient,^[5] and cortical and brainstem ischemic lesions in one patient.^[10] Electroencephalogram (EEG) data were available for 16 patients, out of which eight had abnormal EEG results. The most common abnormal EEG finding was mild-to-moderate diffuse cerebral dysfunction (present in all eight patients) and bi-frontal sharp waves in one patient.^[5] Electromyography in three cases suggested a cortical, subcortical, or cortical–subcortical physiological classification for multifocal myoclonus.^[8],[9] Somatosensory evoked potential results were available in one case of diaphragmatic myoclonus,^[7] which were normal.

Treatment strategies varied across cases and consisted of symptomatic treatment of myoclonus with broad-spectrum antiseizure medications such as valproate, levetiracetam, clonazepam, anesthetic agents, and immunotherapy [steroids, intravenous immunoglobulin (IVIG), or plasmapheresis] directed at postinfectious/immune-mediated mechanisms. Treatment options were not available for two patients but were available for 32 patients, out of which 87.5% (28/32) patients reported improvement or resolution of myoclonus within 2 months. Four patients died during the course of the hospitalization.^[5],[6],[12]

Myoclonus–ataxia (without opsoclonus) and COVID-19

Thirty-three patients had myoclonus–ataxia, of which 14 mat the criteria for OMAS. Nineteen patients with myoclonus–ataxia (without opsoclonus) had either multifocal or generalized myoclonus with limbs and/or gait ataxia ([Table 2]). The commonly associated neurological symptoms were encephalopathy/mental confusion (7/19 patients), cognitive decline (6/19 patients), voice tremor (6/19 patients), and hand or head tremor (4/19 patients). Neuroimaging results were available for all patients, among which 17 had normal brain imaging results. One patient had diffuse pachymeningeal enhancement^[5] and one patient had multifocal bilaterally asymmetric non-enhancing T2-weighted and f-attenuated inversion recovery hyperintense lesions in the fronto-parieto-occipital subcortical regions, thalami, and brainstem; these findings were consistent with acute disseminated encephalomyelitis (ADEM).^[27] EEG data were available for 11 patients, of which mild-to-moderate diffuse background slowing without epileptiform discharges was observed in six patients, while five had normal EEG readings.

Postinfectious immune-mediated mechanisms were suspected in 15 of 19 patients, while COVID-19 encephalitis was suspected in three patients (one patient had positive autoantibody against Purkinje cells, striatal, and hippocampal neurons^[22]) and one patient had ADEM.^[27] The treatment options consisted of immunotherapy (15/19 patients) and/or symptomatic treatment (7/19 patients; valproic acid, levetiracetam, and clonazepam). Among patients who received immunotherapy, steroids were given to nine patients and IVIG was administered to 11 patients. Majority of the patients (15/19 patients) showed remarkable improvement/resolution of both myoclonus and ataxia posttreatment, except for four patients, as reported by Chaumont et al.,^[17] in which myoclonus persisted 3 weeks after discharge. There were two cases by Shetty et al.^[26] and Ghosh et al. from India,^[27] where one patient had postinfectious immune-mediated etiology and the other had myoclonus–ataxia as a part of ADEM. Both patients showed remarkable improvement following immunotherapy.

Opsoclonus–myoclonus–ataxia syndrome and COVID-19

To date, a total of 14 patients with COVID-19-related OMAS have been reported. All patients presented with symptoms a few days after COVID-19 infection [Table 2]. Among the patients with OMAS, one patient had opsoclonus and ataxia (without myoclonus), one patient had opsoclonus and myoclonus (without ataxia), and one infant presented with isolated opsoclonus without myoclonus or ataxia. All reported patients with myoclonus had generalized or multifocal myoclonus. Four patients had associated mental confusion and altered sensorium. One patient had associated asymmetric hypokinetic rigid syndrome with oculomotor abnormalities.^[28] Neuroimaging was normal for all patients. EEG data were available for six patients, of which two had diffuse nonspecific cerebral slowing. Autoimmune/paraneoplastic antibody testing results were available for seven patients, all of which were negative for any autoantibodies.

Postinfectious etiology was suspected in all cases, and immunotherapy (steroids and/or IVIG) was administered to 12 patients, along with symptomatic treatment for myoclonus in a few patients (valproic acid, levetiracetam, and clonazepam). All patients had remarkable symptomatic recovery. Two patients showed spontaneous resolution of all symptoms without any specific treatment.^[28],[35] To date, only a single case of post-COVID-19 OMAS has been reported from India by Shah and Desai et al.^[29] The patient in their study showed marked improvement within one week of starting intravenous steroids and symptomatic treatment of myoclonus.

Cerebellar ataxia and COVID-19

To date, there are 23 cases of isolated cerebellar ataxia without opsoclonus/myoclonus in the literature. Six patients presented with cerebellar ataxia with or without other neurological symptoms as presenting manifestations of COVID-19, while 17 patients presented with symptoms a few days/weeks after COVID-19 [Table 2]. The associated neurological features include confusion/disorientation (7/23 patients), lower limb areflexia (6/23 patients), vertigo/headache/vomiting (4/23 patients), ophthalmoparesis (3/23 patients), and multiple cranial nerve palsy and limb weakness (each in two patients). Neuroimaging showed acute infarcts in the vermis of cerebellum in two patients,^[40],[48] bilateral cerebellar/corpus callosum T2 and fluid-attenuated inversion recovery hyperintensities in three patients,^[36],[37] leptomeningeal enhancement in two patients,^[37],[52] and diffusion restriction in the splenium of the corpus callosum in one patient.^[41] One patient had enlargement and enhancement of the third cranial nerve on one side.^[46]

The etiology of the cerebellar ataxia syndrome was heterogeneous. Out of 23 patients, Miller–Fisher syndrome (MFS), a variant of Guillain–Barré syndrome, and postinfectious etiology were considered for six patients. Five patients presented with cerebellar syndrome as a presenting manifestation of COVID-19, while four patients had cytokine release syndrome-associated encephalopathy and two patients had acute ischemic stroke. All six patients with MFS and one patient with cytokine release syndrome-associated encephalopathy received IVIG; the symptoms improved in all patients. Five patients received steroids, while the two patients with ischemic stroke were treated with antiplatelets and statins. Treatment outcomes were available for 20 patients, and all showed good-to-remarkable clinical improvement after the treatment.

Tremor and COVID-19

A total of six patients were reported with de novo isolated COVID-19-associated tremor. All patients except one had action and postural tremor in both hands [Table 2]. One patient had rest tremor of all four extremities.^[55] Two patients had associated orthostatic tremor in the legs.^[8],[54] Brain MRI showed microbleeds in the corpus callosum in two patients, while one patient has normal brain imaging results. Imaging results were not available for two patients. Postinfectious etiology was considered in five patients, while one patient was diagnosed with subacute thyroiditis post-COVID-19 infection^[56] and received oral steroids; clonazepam was given to one patient. Both patients with available treatment outcomes showed remarkable improvement of tremor.

Chorea and COVID-19

To date, there are three reported cases of isolated de novo chorea associated with COVID-19 in the literature. All patients had acute-onset presentation of chorea, out of which two patients had generalized chorea with signs of encephalopathy.^[57],[58] Both patients were considered to have COVID-associated encephalitis with chorea, and they were treated with symptomatic agents (haloperidol and tetrabenazine) and steroids (one patient). One patient from India presented with acute onset of hemichorea-hemiballism, and diabetic ketoacidosis was observed in a previously nondiabetic man in the setting of COVID-19 infection.^[59] Brain MRI of the patient showed left striatal T1 hyperintensity, consistent with diabetic striatopathy. He was treated with supportive and blood sugar control measures. It is debatable whether the chorea was secondary to diabetic striatopathy or related to COVID-19 infection. All patients showed remarkable recovery. Two patients with Sydenham’s chorea presenting with acute chorea in the setting of COVID-19 infection and one patient with multiple substance abuse-related acute chorea (with high urinary levels of cocaine) were excluded.^{[61],[62],[63]}

Dystonia and COVID-19

Two middle-aged women have been described to have acute myoclonus and dystonia involving neck, extremities and torso, 3–4 weeks after COVID-19 lung infection.^[60] This has been termed as COVID-associated Diffuse Myoclonus and Dystonia syndrome. Both patients completely recovered after treatment with immunotherapy (steroids and IVIG) and clonazepam ([Table 2]). This syndrome has been considered to be an immune parainfectious/post infectious condition.

Discussion

Despite COVID-19 primarily being a respiratory disease, an increasing number of neurological manifestations are being recognized as potential complications and rare neurological phenomena (including movement disorders) have been reported.^[64],[65] Notably, myoclonus and ataxia are the most frequently identified movement disorders associated with COVID-19. Majority of the myoclonus cases were either multifocal or generalized, as well as of acute onset. Myoclonus either occurred as an isolated manifestation or along with ataxia/opsoclonus. The severity of myoclonus widely varied from mild, treatable on an outpatient basis to severe, requiring urgent hospitalization. Electrophysiological data physiologically classifying these myoclonic jerks into cortical, cortical–subcortical, subcortical, spinal, or peripheral are scarce. It is important to note that myoclonus associated with COVID-19 is probably multifactorial and associated with hypoxia, metabolic disturbances, and drugs, especially in the setting of the intensive care unit. However, the postinfectious immune-mediated mechanism was considered in majority of the patients. Majority of the patients received symptomatic treatment (antiepileptic medications) with or without immunotherapy. Myoclonus has been previously reported in the setting of other neuroinvasive viruses.^[66] Although the putative pathophysiology involving antigenic crossreactivity with neuronal proteins from the brainstem or cerebellum remains hypothetical, the evidence supporting this finding can be found in a recent case series.^[67] The development of myoclonus can be attributed to hyperexcitability of the brainstem neurons or lack of cerebellar inhibitory output.^[68] Electrophysiological studies such as EEG–electromyography correlate with somatosensory evoked potential and long-loop C-reflex can help in defining the physiology of myoclonus. However, detailed studies describing the electrophysiological findings in patients with COVID-19 are lacking.

Among cases presenting with ataxia, majority were acute in onset and often presented as a manifestation of COVID-19. Compared to cases with myoclonus, the disease course of patients with isolated cerebellar ataxia was milder and less frequently required intensive care management. Ataxia was frequently associated with other neurological symptoms such as myoclonus, opsoclonus or other oculomotor abnormalities, mental confusion/altered sensorium, and cognitive/psychiatric changes. Although the etiology of patients with ataxia was heterogeneous, the most common postinfectious etiology was MFS. The frequent occurrence of MFS and Guillain–Barré syndrome with COVID-19 suggests a possible role of molecular mimicry between SARS-CoV-2 and the central nervous system. In addition, a parainfectious inflammatory mechanism involving the brainstem, cerebellum, and striatum may be contributory to cases of myoclonus and ataxia associated with COVID-19. This finding is supported by increased proinflammatory cytokine interleukin-6 in the serum/cerebrospinal fluid in many of these cases. Considering this proposed para/postinfectious mechanism, both myoclonus and ataxia may be self-limiting, particularly with the resolution of systemic inflammation.

Cases of COVID-19-associated OMAS are being increasingly identified. For a diagnosis of OMAS, at least three out of the following four criteria need to be fulfilled: (1) opsoclonus, (2) myoclonus or ataxia, (3) behavioral changes or sleep disturbances, and (4) the presence of underlying malignancy or antineuronal antibodies.^[69] Although only one case met the above criteria with ataxia, behavioral changes, and opsoclonus,^[35] most cases often had two of the four features, which were a combination of either opsoclonus–myoclonus or opsoclonus–ataxia. OMAS has been associated with various viral and bacterial infections such as Epstein–Barr virus,^[70] cytomegalovirus,^[71] enterovirus-71,^[72] hepatitis viruses, human immunodeficiency virus,^[73] West Nile virus,^[74] dengue,^[75] mycoplasma pneumonia,^[76] streptococcus,^[77] and Lyme disease.^[78] The exact pathophysiology of OMAS is unclear, but it is thought to be immune-mediated inflammation, proposedly involving antibodies against Purkinje cells in the cerebellum^[79]; this finding is supported by a favorable response to immunotherapies, such as steroids and IVIG. The dysfunction of Purkinje cells probably leads to disinhibition of other deep cerebellar nuclei and subsequent hyperexcitability of the cortical motor areas.^[69]

The medical literature on COVID-19-associated other hyperkinetic movement disorders such as tremor, chorea, dystonia, and tics is scarce and is limited to isolated case reports. Additional studies are needed to conclude the influence of COVID-19 on the occurrence of these de novo abnormal movements. Furthermore, studies on the long-term prognosis of these de novo movement disorders, the duration of treatments required, and the outcomes are needed in future.

The number of published reports of COVID-19-associated movement disorders from India is limited^{[26],[27],[29],[44],[59]}; however, their prevalence may actually be high. The possible reasons for the underreporting of such cases may be the high number of COVID-19 cases; busy outpatient clinics; lack of neurology consultation in remote areas; limitation of thorough patient assessment with masks, gowns, etc.; differences in healthcare systems compared to the first-world countries, non-reporting of cases with a mild disease course (those being treated at home); and lack of uniform data registry and publications. The Movement Disorders Society of India can help by forming a case repository or data registry to prospectively collect the data and maintain long-term follow-up of such patients to know the natural course of such disorders.

Despite our promising findings, our review has some limitations, such as heterogeneity of samples (with majority of the published reports being case reports/series); heterogeneity of available clinical information (in view of lack of thorough examination due to the current pandemic situation) and laboratory, imaging, and electrophysiological data; and ascertainment bias of reporting only hospitalized patients with moderate-to-severe COVID-19 infection while overlooking patients with milder infections. In addition, we have not included non-English articles. Despite these shortcomings, we hope that our review will act as a preliminary guide for clinicians when treating hyperkinetic movement disorders in the setting of COVID-19.

Conclusion

With the ongoing COVID-19 pandemic, an increasing number of cases with various hyperkinetic movement disorders are being reported. Although the cases summarized in our review may be an underestimate of the total number of actual cases, myoclonus and ataxia deserve a special mention in future studies. However, the direct link between COVID-19 and movement disorders is yet to be established. As more cases of COVID-19-associated movement disorders are identified, future investigations will be required to provide more insight into the relationship between these movement disorders and SARS-CoV-2.

Acknowledgement

None.

Author contribution

Research project: A. Conception, B. Organization, C. Execution

Statistical analysis: A. Design, B. Execution,

Manuscript preparation: A. Writing of the first draft, B. Review and Critique

MC: 1A, 1B, 1C,2A, 2 B, 3A;

HS: 1B, 1C, 2 A, 2B, 3B;

SD: 1A, 1B, 1C, 2A, 3B

Ethical compliance statement

The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. 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. Dr Soaham Desai would act as the guarantor and corresponding author of this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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