Sep. 14, 2022
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Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome. The word corona is derived from “crown,” which describes the spike-like proteins on its surface. They are classified as four genera: alpha, beta, gamma, and delta. The alpha, beta, and delta coronaviruses infect mammals, whereas delta and gamma coronaviruses infect avian species. However, the virus has the ability to jump between species, leading to the emergence of Middle East respiratory syndrome (MERS) caused by MERS-CoV, severe acute respiratory syndrome (SARS) caused by SARS-CoV-1, and COVID-19 caused by SARS-CoV-2, with deadly consequences (21). To date, seven human coronaviruses have been identified (Table 1). SARS and SARS-CoV-2 are thought to have originated from bats (06). They use the “spike proteins” to attach to angiotensin-converting enzyme receptor type 2 (ACE2), which is highly expressed in the respiratory tract. ACE2 receptors are also known to be expressed in both neurons and glia in several CNS areas, most notably in the choroid plexus and the thalamus. Several strains of SARS-CoV-2 have been identified. Currently, the most predominant strain is the delta strain. There does not appear to be any major difference in the neurotropism or neurovirulence between the various strains.
ACE=angiotensin converting enzyme; DPP4=Dipeptidyl peptidase 4
The virus has four main structural proteins: Spike (S)-protein is a trimeric protein that mediates attachment to the host receptor and is made of two separate polypeptides called S1 (binding domain) and S2 (stalk). The membrane protein is the most abundant structural protein in the virion. The envelope protein facilitates assembly and release of the virus. The ion channel activity in SARS-CoV envelope protein plays a critical role in pathogenesis. The N-protein constitutes the nucleocapsid that binds the viral RNA. The hemagglutinin-esterase protein is present in a subset of beta-coronaviruses and binds sialic acids on surface glycoproteins and contains acetyl-esterase activity (21). The neuropathogenesis of coronaviruses has been best studied in a mouse model infected with the mouse hepatitis virus.
Coronaviruses are known causes of respiratory, enteric, and systemic infections. Most human coronaviruses cause mild symptoms and resolve. The SARS-CoV-2 virus was first discovered in Wuhan, China, in December 2019, and in just under 2 years, has spread to every country in the world, paralyzed the global economy, devastated health care systems, and sent large populations into isolation.
The clinical syndrome caused by SARS-CoV-2 has been termed “COVID-19.” As of November 7, 2021, more than 250 million persons worldwide had confirmed infections, with more than 5,000,000 deaths (43). The first confirmed case in the United States was reported on January 20, 2020 (14). By October 7, 2020, there were over 47 million cases and more than 700,000 deaths (43).
Symptoms of COVID-19 infection may initially resemble the flu. Fever is present in up to 90% and cough in approximately 70%, with symptoms developing after a median incubation period of 4 days (13). Patients may be infectious during this incubation period. Myalgia and fatigue are seen in about 50% and may persist even after recovery from the other symptoms (25). Headache occurs in 8% (25). Diarrhea occurs in less than 5% and in some patients might be the major symptom (13). Anosmia and ageusia may be heralding manifestations (13). On chest CT scan, more than 50% of patients demonstrate a ground glass opacity. Many patients develop pneumonia. Older patients have more severe disease. In a study from China, mechanical ventilation was required in 6.1% of patients (13), though rates of acute respiratory distress syndrome as high as 29% have been reported. A study of 262 confirmed cases revealed that 17.6% had severe disease, 73.3% were mild, 4.2% were nonpneumonic, and 5.0% were asymptomatic (44); widespread antibody testing when available will likely reveal far higher numbers of asymptomatic or mildly symptomatic persons. Lymphopenia is common (25). Mortality is higher with advanced age and underlying comorbidities, including diabetes, cardiac and respiratory disorders, and immunosuppressed states. Several acute neurologic syndromes have been associated with coronaviruses (Table 2).
Acute disseminated encephalomyelitis
Anosmia. Anosmia and ageusia are commonly reported in 40% to 60% of patients with early infection (20) but can be identified by objective testing in up to 90%. The virus is believed to invade the sustentacular cells in the vicinity of the olfactory nerve endings, which express SARS-CoV-2 receptor ACE2 (03), but no direct infection of the olfactory nerve cells is known. Anorexia and weight loss may result from anosmia. Transient edema of the olfactory nerves and bulb may be seen on MRI. The prognosis for the recovery of olfactory function is favorable and occurs in up to 96.1% by 1 year (38).
Myalgia. Myalgia may occur at any point during the acute illness and may be associated with myositis. However, up to 50% may experience worsening symptoms after recovering from the acute infection (10). Patients with persistent myalgia also tend to report three or more concurrent post-COVID symptoms. Paraspinal muscle involvement may manifest as back or chest pain and prolong hospitalization (29). Rarely, rhabdomyolysis with increased risk of renal toxicity may result, which requires careful monitoring and hydration. MRI in such patients may show myonecrosis with inflammatory infiltrates on histology.
Meningoencephalitis. Although headache is a common symptom, direct viral invasion causing meningoencephalitis is rare with SARS-CoV-2, unlike the previously reported cases of SARS, MERS-CoV, and HCoV-OV43. An index case of SARS-CoV-2 meningoencephalitis was identified from Japan (30). The patient had generalized seizures, and imaging showed lesions in the temporal lobe, adjoining ventriculitis, and pansinusitis. Other reports have been rare. In a postmortem analysis of 43 cases, SARS-CoV-2 RNA was identified in 53%, but with low copy numbers and a rare presence of infected cells (27). However, the presence of the virus showed no association with other neuropathological changes, such as astrogliosis or ischemic or inflammatory lesions. Most other reported autopsy series have been unable to identify the virus in the brain.
Stroke. Both arterial and venous strokes may be encountered in patients with SARS-CoV-2 infection (Table 1). Some patients may develop microhemorrhages and have other signs of microvascular injury (05). Spinal cord infarcts may also occur.
Altered coagulation pathways are often present in acute SARS-CoV-2, as suggested by elevated D-dimer levels, deranged prothrombin and activated partial thromboplastin times, and disseminated intravascular coagulation. However, in addition to altered coagulation, endothelial cell injury (as the ACE2 receptor is expressed on endothelial cells) and immobility (Virchow triad) are also probably contributory. Myocarditis may also be conducive to increased stroke risk. Concordantly, strokes have also been reported in patients with no other risk factors.
Early single-center case series reported a prevalence of ischemic stroke in up to 4.6% and intracerebral hemorrhage in 0.5% (23). However, large studies have shown that acute ischemic stroke is not common in COVID-19 (1.3% in 8163 patients with SARS-CoV-2 infection versus 1.0% of 19,513 noninfected patients) (35). SARS-CoV-2 stroke patients are likely to have other comorbid risk factors as well. They are also more likely to have outcomes other than death or discharge, possibly indicating prolonged disability.
Cerebral venous thrombosis
Metabolic encephalopathy. Patients who develop acute respiratory distress syndrome, often have alteration in mentation and level of consciousness. This is attributed to hypoxia and multiorgan involvement. Most patients who recover from the infection seem to also regain their cognitive status, although long-term effects are unknown.
Acute disseminated encephalomyelitis. This is a postviral syndrome that can be triggered by a variety of different viral infections, including coronaviruses. In fact, the pneumonia associated with SARS-CoV-2 usually occurs after a week or more of systemic or milder respiratory symptoms and is characterized by massive inflammation in the lungs causing an acute respiratory distress syndrome that is fatal in many. Similarly, extensive inflammation involving the brain, cerebellum, and spinal cord has been described in several patients with HCoV-OC43 a week or two after the infection suggestive of an acute disseminated encephalomyelitis (47). A similar syndrome may occur with SARS-CoV-2 in patients who survive the acute phase or may have minimal systemic symptoms during the acute phase (24; 34). In one MRI study of hospitalized patients with neurologic symptoms, 17% had leptomeningeal enhancement and 13% had encephalitis (19). Neuropathological studies show presence of perivascular macrophages and cytotoxic lymphocytes. These lesions were predominantly present in the brainstem and cerebellum as well as the meninges (37).
Acute necrotizing hemorrhagic encephalopathy. This is a feared complication of several viruses, most notably influenza. It is thought to result from cytokine release syndrome rather than direct viral invasion of brain parenchyma, which is especially salient given the propensity of SARS-CoV-2 for causing similar cytokine storms in the lungs. Cases have included bilateral lesions, including those of the thalami, cerebral hemispheres, and the cerebellum, in patients who presented with several days of more typical COVID-19 symptoms (34; 31).
Transverse myelitis. Cases of acute transverse myelitis associated with SARS-CoV-2 are also beginning to emerge. In a case series of 43 patients, the latency period from the onset of COVID-19 symptoms to the onset of transverse myelitis symptoms was bimodal, with one group presenting concurrently (15 hours to 5 days in 11 of 34 patients) and a separate group presenting as a more postinfectious phenomenon (10 days to 6 weeks in 23 of 34 patients) (41). The majority of cases were longitudinally extensive, with three or more vertebral segments involved. Lesions had extended into the brainstem in some patients, whereas others had lesions that extended caudally into the conus medullaris.
Guillain Barré syndrome. A postinfectious brainstem encephalitis and Guillain-Barré syndrome has also been described with MERS (15). In the SARS-CoV-2 epidemic, Guillain Barré syndrome has been seen not uncommonly. In a case series from Italy, five patients developed symptoms of Guillain Barré syndrome 5 to 10 days after first developing COVID-19 symptoms, with both axonal and demyelinating features (45). A later, more comprehensive review of 73 patients showed that more than three quarters had predominantly demyelinating features (01). In that large series, the time to neurologic nadir was a median of 4 days. Prognosis for a worse outcome was associated with the severity of COVID-associated pneumonia. Other involvement has included Miller-Fisher syndrome with ophthalmoparesis.
Myositis. Myositis temporally associated with COVID-19 infection has been reported, both as a complication associated with acute infection, with proximal weakness and highly elevated creatine kinase levels (26), as well as a later complication with subacute or chronic features consistent with an immune-mediated postinfectious process (02).
Sensory neuropathy. The association of peripheral sensory neuropathy with COVID-19 infection is less clear, with few detailed reports in the literature other than those associated with critical illness. Not much has been written about sensory neuropathy and COVID-19 yet except for some mention of “neuralgia.”
For example, in a large series of all neurologic complications of COVID-19, less than 3% of cases had sensory abnormalities (07). Neuropathy has been a common symptom reported by patients, although electrophysiologic confirmation of new distal, sensory polyneuropathies have been so far limited.
Multisystem inflammatory syndrome. This is a rare but severe syndrome in patients infected with SARS-CoV-2. It is more well-defined in children and adolescents (MIS-C) as a hyperinflammatory syndrome resembling Kawasaki disease and is characterized by fever, marked elevation of inflammatory biomarkers (CRP, D-dimer, and ferritin), and multiple organ system involvement (40). Gastrointestinal complaints are frequently reported, and myocardial injury with left ventricular dysfunction and shock requiring inotropic support may occur. A similar syndrome may also occur in adults (MIS-A), with greater complexity. It usually follows within days to 2 to 3 weeks after the acute infection. Neurologic manifestations typically include encephalopathy and generalized weakness, dysarthria, and dysphagia. MRI may reveal abnormal signals in the splenium of the corpus callosum on diffusion-weighted imaging. Cerebrospinal fluid analysis is usually normal. The pathophysiology of this syndrome is incompletely understood. Intravenous human immunoglobulin and corticosteroids are often used, but neither has proved to have a greater comparative advantage (28).
Myasthenia gravis. The onset of SARS-CoV-2 pneumonia in a patient with pre-existing myasthenia gravis is of major concern. In addition, a small number of cases have been reported in which there was apparently a new onset of ocular or systemic myasthenia in association with COVID-19 infection (39; 36). It is not known whether these cases represented truly new onset of myasthenia or unmasking of subclinical disease.
Risk factors for neurologic complications. Advanced age, cardiac and respiratory disorders, hypertension, and diabetes are the most common comorbidities present in patients with more severe manifestations of the infection. An interesting hypothesis has emerged around the use of ACE inhibitors to treat hypertension and diabetes to explain this phenomenon. ACE2 is the receptor for SARS-CoV-2 (46). The use of ACE inhibitors leads to increased expression of ACE2, making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. ACE2 can also be found on endothelial cells in the brain and can be induced in neurons, raising the possibility that strokes associated with SARS-CoV-2 might be directly related to the infection.
Risks of COVID-19 for patients with neurologic diseases. Patients with neurologic diseases tend to be older than those without, so risks associated with COVID-19 are of particular concern for neurologists who care for these patients. Additionally, inflammatory-mediated neurologic diseases necessitate immunosuppressive medications. In myasthenia gravis, for example, a registry study of 91 patients reported that 22 (24%) died from COVID-19 (32). Also, because patients with neurologic disability often require physical assistance and care from loved ones or from specialized facilities, there are additional risks of infection from this loss of independence.
Following are the unknowns and challenges in studying the neurologic complications of SARS-CoV-2:
Brain imaging. It has been challenging to perform MRI scans on patients with acute respiratory distress syndrome who develop encephalopathy due to the infectious nature of the illness. CT is more widely available because CT of the chest provides diagnostic and management utility for these patients. However, this is often limited to ruling out a structural neurologic cause of encephalopathy, so the importance of a complete patient history and physical examination for the treating neurologist in these cases can provide invaluable diagnostic utility.
Long COVID. Perhaps most concerning of long-term consequences is the idea of “long-haul COVID” (33). The number of patients affected with COVID-19 who later report ongoing, often disabling neurologic symptoms is staggering. Many patients complain of persistent symptoms, such as exercise intolerance, dysautonomia/postural orthostatic tachycardia syndrome, sleep disturbances, loss of appetite, or pain syndromes. Focused care clinics have expanded to provide centers of expertise for affected patients. However, dedicated clinical research reports have, so far, been limited to cohort data that describe difficulty concentrating (23.8%) and memory deficits (18.6%) as the most commonly reported neurologic symptoms in patients who have recovered from COVID-19 (12). The etiology of these persistent symptoms remains elusive. It is possible that multiple etiologies may contribute to different phenotypes of this phenomenon. Clinical trials to address different management strategies are currently underway.
Seropositivity for coronaviruses has been reported in a variety of neurologic disorders, including encephalitis (21), optic neuritis (08), multiple sclerosis (42), and Parkinson disease (09). Virus has also been isolated from CSF and brain of patients with multiple sclerosis (04). Viruses implicated include HCoV-229E, HCoV-293, and HCoV-OC43. But the significance of these findings is not clear because these viruses are prevalent and their causative role in these diseases has not been established.
Remarkably, COVID-19 has become a largely preventable disease since the introduction and widespread availability of several different vaccines against the SARS-CoV-2 virus. As with other vaccines, there have been reports of neurologic complications, including cranial nerve palsies and Guillain Barre syndrome temporally associated with COVID-19 vaccines (11). One vaccine study was temporarily halted because of associated transverse myelitis (18).
Antiviral. In October 2020, the FDA approved remdesivir for certain patients with COVID-19. In November 2021, both baricitinib and a combination of monoclonal antibodies (casirivimab and imdevimab) received emergency use authorizations for use in COVID-19. There are additional antiviral agents that have shown promise in clinical trials.
Supportive therapy. Supportive therapy should include prevention of deep vein thrombosis because patients are hypercoagulable and may have endothelial cell damage. Due to lung involvement, patients are hypoxic for prolonged periods of time and may lose their chemoreceptor-driven central respiratory drive, making it more critical to intubate sooner and possibly requiring prolonged intubation. Some patients who recover from the infection may develop pulmonary fibrosis and require long-term oxygen therapy.
The barriers to physical contact necessitated by the pandemic have quickly altered the landscape for providing neurologic care. In order to continue providing both inpatient and outpatient services, neurologists at many centers quickly adopted teleneurology protocols that were previously limited to telestroke or for geographically isolated settings. Teleneurology has to date included emergency department consults done remotely from other areas of the hospital, policy restrictions being relaxed at both a hospital level and a government level, and some states allowing remote practice of medicine across state lines. These changes were adapted quickly, using in many cases the existing infrastructure, and could potentially alter the care and practice of neurology if many of the changes persist beyond the current pandemic (17).
The COVID-19 pandemic brought to light numerous ethical issues involving neurologists and their patients, notably that many of our patients are unable to advocate for themselves because of neurologic disease or that because of neurologic disease, their lives are considered less valuable. In times when medications and life-saving devices may be limited, patients with neurologic diseases have often been at the forefront of scenarios, eg, the idea that patients with COVID-19 and comorbid dementia may be removed from a ventilator because of resource scarcity (16). These scenarios are difficult to imagine, but as neurologists, our role is certainly to continue to be an advocate for our patients, especially when they are at their most vulnerable.
Funding for this article was supported by intramural funding from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
Avindra Nath MD
Dr. Nath of the National Institutes of Neurological Disorders and Stroke, National Institutes of Health has no relevant financial relationships to disclose.See Profile
Bryan Smith MD
Dr. Smith of the National Institutes of Neurological Disorders and Stroke, National Institutes of Health has no relevant financial relationships to disclose.See Profile
Rohit Benjamin MD
Dr. Rohit of Christian Medical College Vellore has no relevant financial relationships to disclose.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine received a records review fee from Sommers Schwartz as an expert witness.See Profile
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