key: cord-0946449-wx23qziw
authors: Shimohata, Takayoshi
title: Neuro‐COVID‐19
date: 2021-09-29
journal: Clin Exp Neuroimmunol
DOI: 10.1111/cen3.12676
sha: dd768b3cd88befb3670e36e833df8b23ce67d7bf
doc_id: 946449
cord_uid: wx23qziw

Neuromuscular manifestations of new coronavirus disease 2019 (COVID‐19) infection are frequent, and include dizziness, headache, myopathy, and olfactory and gustatory disturbances. Patients with acute central nervous system disorders, such as delirium, impaired consciousness, stroke and convulsive seizures, have a high mortality rate. The encephalitis/encephalopathy that causes consciousness disturbance and seizures can be classified into three conditions, including direct infection with the SARS‐CoV‐2 virus, encephalopathy caused by central nervous system damage secondary to systemic hypercytokinemia (cytokine storm) and autoimmune‐mediated encephalitis that occurs after infection. The sequelae, called post‐acute COVID‐19 syndrome or long COVID, include neuromuscular manifestations, such as anxiety, depression, sleep disturbance, muscle weakness, brain fog and cognitive impairment. It is desirable to establish diagnostic criteria and treatment for these symptoms. Vaccine‐induced thrombotic thrombocytopenia, Guillain–Barré syndrome, bilateral facial paralysis, encephalitis and opsoclonus‐myoclonus syndrome have been reported as adverse reactions after the COVID‐19 vaccine, although these are rare.

the onset of COVID-19 cannot be ruled out. A proof of causality is required to confirm the epidemiological increase in the incidence and/or to elucidate the pathogenic mechanism.

In the cerebrovascular diseases associated with COVID-19, cerebral infarct is frequent. 7 In addition, critical-illness microbleeds might occur due to disruption of the blood-brain barrier. 8 In a meta-analysis of hospitalized patients in the USA, Canada and Iran, it was shown that the frequency of cerebrovascular diseases was 1.8% and in-hospital mortality was as high as 34.4%; the risk factors for in-hospital mortality were advanced age, comorbidity and severity of respiratory symptoms. 9 In addition to atherosclerotic factors, such as hypertension, diabetes mellitus, dyslipidemia and obesity, severe COVID-19

has been shown to be a risk factor for developing the cerebrovascular disease. Another meta-analysis showed that the complication rate of cerebrovascular disease increased 4.2-fold in patients with severe COVID-19 compared with those without severe disease. 10

There are at least three types of encephalitis/encephalopathy. 11 The first is considered to be viral encephalitis caused by direct viral infection of the central nervous system (CNS). The second is encephalopathy, in which systemic inflammation (hypercytokinemia/cytokine storm) is followed by the rapid onset of neurological and psychiatric symptoms. The third is autoimmune encephalitis that develops after a certain period of time after COVID-19 infection and meets the diagnostic criteria for "possible autoimmune encephalitis" by Graus et al. 12 Evaluation of cytokines and chemokines might be distinguished by elevation in cerebrospinal fluid in encephalitis and in serum in encephalopathy. 13 As encephalopathy and autoimmune encephalitis can be treated by immunotherapy, an appropriate diagnosis is required.

In addition, a number of encephalitis/encephalopathies with unique clinical and imaging findings have been reported. These include acute hemorrhagic necrotizing encephalitis, 14 acute disseminated encephalomyelitis, 15 mild encephalitis/encephalopathy with a reversible splenial lesion 16 and posterior reversible encephalopathy syndrome. 17

A small number of patients with multiple sclerosis 18 and anti-myelin oligodendrocyte glycoprotein antibody-associated disease 19 have been reported after COVID-19 infection.

There are many reports of patients with myoclonus 20 and opsoclonus-myoclonus syndrome 21 symptoms. In addition, acute onset of parkinsonism after infection 22 and anti-amphiphysin antibody-positive cerebellar ataxia 23 have been reported. As there have been reports of an increase in functional movement disorders in both adults and children after the pandemic, an appropriate diagnosis is necessary. 24 

In a systematic review of 18 cases of Guillain-Barré syndrome (GBS), the median time from COVID-19 onset to GBS onset was 10 days, and most patients presented with demyelinating GBS, with a prognosis of eight (44%) on artificial ventilators and two (11%) deaths. 25 In a study in northern Italy, the incidence of GBS in March and April 2020 was reported to have increased 2.6-fold compared with the same period a year earlier. 26 Miller Fisher syndrome, 27 isolated peripheral facial paralysis 28 and sudden sensorineural hearing loss 29 have also been reported.

Furthermore, compression neuropathy caused by supine posture management, which is recommended for respiratory failure associated with acute respiratory distress syndrome, has also been reported. 30 The most commonly injured nerves are the ulnar, radial, sciatic, brachial plexus and median nerves, in that order. It is necessary to avoid prolonged compression and extension of the elbow, upper arm, and shoulder. 

Patients with COVID-19 might present with myalgia and flaccid tetraplegia, hyperCKemia and abnormal muscle magnetic resonance imaging signals. A patient with a positive anti-small ubiquitin-like modifier 1 activation enzyme antibody specific for dermatomyositis and myopathological findings consistent with dermatomyositis has been reported, 33 and the possibility that COVID-19-related myositis is dermatomyositis has been discussed. 33, 34 Although dermatomyositis is a type I interferonopathy in which type I interferon is involved in the pathogenesis, type I interferon, an antiviral cytokine induced by a viral infection, might cause dermatomyositis-like myositis. In severe cases, critical illness myopathy might be considered as a differential diagnosis.

For remdesivir (Veklury), the adverse effects of headache, seizures, myoclonus, delirium and encephalopathy should be noted. For favipiravir (Avigan), the adverse effects of abnormal behavior, delirium, hallucinations, delusions, seizures and consciousness disturbance should be noted.

The 36 It has also been speculated that the SARS-CoV-2 virus spreads from the lungs and lower respiratory tract to the medulla oblongata through mechanoreceptors and chemoreceptors in a trans-synaptic manner. 37 In fact, in human autopsy findings, viral proteins were found in the brainstem and lower cranial nerves, indicating that the virus can reach the brain. 38 The ability of the SARS-CoV-2 virus to infect the brain (neurotropism) has been confirmed by several methods, including infection experiments using transgenic mice expressing the human angiotensin-converting enzyme 2 receptor. 39 However, there are some criticisms of the hypothesis that direct infection of the CNS is the primary pathogenesis, based on the fact that animal models are artificial and overexpress the human angiotensin-converting enzyme 2 receptor, and that viral RNA levels in the brains of most human patients are much lower than those in the nasal cavity. 40 With regard to direct infection of cerebral blood vessels, it has been reported that the SARS-CoV-2 virus is replicated in pericytes and can infect astrocytes. 41 The disruption of the blood-brain barrier has been confirmed by analysis of cerebrospinal fluid findings in patients with encephalopathy, 42 and by experiments using infected animals in which viral proteins were transferred to the brain. 43 Regarding thrombus formation, it has been considered that coagulopathy in COVID-19 is similar to, but not identical to, sepsisinduced coagulopathy and disseminated intravascular coagulation syndrome, and that some features overlap with antiphospholipid antibody syndrome, hemophagocytic syndrome and thrombotic microangiopathy. 44 The release of neutrophil extracellular traps, which is a known mechanism of intravascular thrombus formation in the antiphospholipid antibody syndrome, has also been confirmed, suggesting its involvement in the pathogenesis of the disease. 45 Finally, indirect neurological damage might be associated with systemic conditions, such as hypoxia, multiple organ failure, sepsis and shock. In addition, systemic hypercytokinemia (cytokine storm) might cause secondary neuroinflammation by disruption of the blood-brain barrier. 46 It has also been shown that various autoantibodies, including an anti-hypocretin receptor antibody produced after infection may cause CNS disorders. 47 Brain fog is a type of cognitive impairment that presents as a "foggy brain state", and includes a lack of intellectual clarity, poor concentration, mental fatigue and anxiety. Several studies on cognitive impairment have been carried out. First, it was reported that cognitive impairment with frontal and parietal lobe dysfunction, and frontal and parietal hypometabolism on fluorodeoxyglucose positron emission tomography occurred in the subacute phase of patients hospitalized with COVID-19. 51 In a study of hospitalized patients, the frequency of cognitive impairment 4 months after onset was reported to be 61 out of 159 (38%). 52 In addition, the frequency of cognitive impairment was 18% in all age groups and 11% in the 16-30 age group, suggesting that cognitive impairment as a sequela is an important problem, even in the younger generation. 53 The following hypotheses have been proposed for the mechanism of brain fog and cognitive impairment. First, although the SARS-CoV-2 virus does not directly infect the CNS, microglial activation and abnormal mitochondrial function occur. 54 Second, systemic inflammation crosses the blood-brain barrier and causes inflammation in the CNS, resulting in brain cell changes similar to those seen in neurodegenerative diseases, such as Alzheimer's disease. Third, neuroinflammation after viral infection leads to aggregation of tau protein, resulting in neurodegeneration. 55 A recent review proposed that chronic neurological sequelae can be classified into four categories, including: (i) cognitive, mood and sleep disorders; (ii) dysautonomia; (iii) diverse pain syndrome; as well as (iv) marked exercise intolerance and fatigue, although more longterm follow-up studies are required. 56 In any case, it is necessary to recognize that neuromuscular complications can occur even in mild cases and young people undergoing home treatment, and infection should be avoided as much as possible.

Several mRNA vaccines and viral vector vaccines have been developed, and have shown remarkable efficacy in preventing infection and severe disease. However, adverse reactions after vaccines have been reported (Table 3) . Specifically, vaccine-induced immune thrombocytopenia (VITT; AstraZeneca), 57 GBS and its subtype (Johnson & Johnson) , 58 bilateral facial paralysis (AstraZeneca), 59 encephalitis, and opsoclonus-myoclonus syndrome (AstraZeneca) 60 have been reported. VITT is particularly important, because it is associated with cerebral venous thrombosis and cerebral hemorrhage, is difficult to treat, and has a severe outcome. The prognosis of VITT is worse than that of usual cerebral venous thrombosis, and the mortality rate is reported to be as high as 73% when the platelet count is <30 000 and intracranial hemorrhage is present. 61 In addition, it has been shown that the causative VITT antibody has been shown to bind to the same platelet factor 4 region as heparin. 62 Although all of these adverse reactions are extremely rare, neurologists should be aware of the high incidence of adverse neurological reactions. However, the preventive effect of vaccines and their ability to reduce the severity of COVID-19 greatly outweigh the risk of adverse reactions, and it is important to inform the public that vaccination is recommended.

Importantly, as a very large number of people are vaccinated, it is natural that some people will develop neurological diseases after vaccination. If this is mistakenly diagnosed as an adverse reaction to the vaccine, and the information spreads through SNS and so on, it might lead to a decrease in the vaccination rate and, as a result, unnecessary infections and deaths. 63 Therefore, to determine causality, an epidemiological increase in incidence and clarification of pathological mechanisms are required.

In addition, functional movement disorders after vaccines have also become a problem, as detailed on SNS. For example, "rapidonset tic-like behavior" in young girls has been reported. 64 It is characterized by predominance in young, severity and inducibility by unusual stimuli, as well as its spread through SNS. As these functional movement disorders also increase vaccine anxiety, it is necessary for healthcare providers to communicate appropriately with the general public to prevent a decline in vaccination rates and unnecessary expansion of the pandemic. 65 

In this article, I have detailed that COVID-19 can cause neuromuscular manifestations during the course of the disease and that the disease can start with neuromuscular manifestations. I have also detailed that COVID-19 can cause brain fog and cognitive impairment in patients of all ages, showing that the disease should be avoided, even by young people. I hope that the COVID-19 pandemic resolves, and the knowledge described here will no longer be necessary.

The author declares no conflict of interest. 

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How to cite this article: Shimohata T. Neuro-COVID-19