Neurological complications of coronavirus infections: knowns, unknowns, and who knows

Avindra Nath MD (Dr. Nath is Clinical Director and Senior Investigator of the Section of Infections of the Nervous System at the National Institutes of Neurological Disorders and Stroke, National Institutes of Health in Bethesda, Maryland.)
Bryan Smith MD (Dr. Smith is Staff Clinician and Unit Head of the Neuro HIV Unit, Division Of Neuroimmunology and Neurovirology at the National Institutes of Neurological Disorders and Stroke, National Institutes of Health in Bethesda, Maryland.)
Originally released April 10, 2020; Expires April 10, 2023

For inquiries and comments: medlinkcorp54@gmail.com

Coronaviruses

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 4 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 (Li 2016). To date, 8 human coronaviruses have been identified (Table 1). SARS and SARS-CoV-2 are thought to have originated from bats (Chan et al 2020). They use the “spike proteins” to attach to angiotensin-converting enzyme receptor type 2 (ACE-2), which is highly expressed in the respiratory tract (Lu et al 2020).

Table 1. Types of Human Coronaviruses And Their Receptors

Alpha

Receptor

 

HCoV-NL63

ACE2

 

HCoV229E

 

Beta

 

 

SARS-CoV1

ACE2

 

SARS-CoV-2

ACE2

 

MERS

DPP4

 

HCoV-OC43

 

 

HCoV-HKU1

 

ACE=angiotensin converting enzyme; DPP4=Dipeptidyl peptidase 4

The virus has 4 main structural proteins: Spike (S)-protein is a trimeric protein that mediates attachment to the host receptor and is made of 2 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 (Li 2016). The neuropathogenesis of coronaviruses has been best studied in a mouse model infected with the mouse hepatitis virus.

Clinical manifestations

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 a few months, has spread to nearly 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 April 7, 2020, nearly 1.5 million persons worldwide have confirmed infections with almost 80,000 deaths (Schiffmann 2020). In the United States, the rate of infection has rapidly increased as documented through availability of testing. The first confirmed case in the United States was reported on January 20, 2020 (Holshue et al 2020); as of April 7, 2020, there were over 400,000 cases and nearly 13,000 deaths (Schiffman 2020).

Symptoms of COVID-19 infection are clinically indistinguishable from those of 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 (Guan et al 2020). 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 (Lu et al 2020). Headache occurs in 8% (Lu et al 2020). Diarrhea occurs in less than 5% and in some patients might be the major symptom (Guan et al 2020). Anosmia and ageusia may be heralding manifestations (Guan et al 2020). On chest CT scan, more than 50% of patients demonstrate a ground glass opacity. Most patients develop pneumonia. Older patients have more severe disease. In a study from China, mechanical ventilation was required in 6.1% of patients (Guan et al 2020), 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 (Tian et al 2020); widespread antibody testing when available will likely reveal far higher numbers of asymptomatic or mildly symptomatic persons. Lymphopenia is common (Lu et al 2020). 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).

Table 2. Acute Neurologic Complications Of Coronavirus Infections

Para-infectious syndromes

 

Encephalopathy
Central hypoventilation
Viral meningitis
Anosmia and ageusia
Encephalitis
Stroke
Acute necrotizing hemorrhagic encephalopathy
Myositis

Postinfectious syndromes

 

Acute disseminated encephalomyelitis
Brainstem encephalitis
Transverse myelitis
Guillain Barré syndrome
Sensory neuropathy

Parainfectious complications

Anosmia. Loss of smell seems common and, in many cases, transient. In few patients it may be permanent. It is frequently accompanied by ageusia or loss of taste (Guan et al 2020; Zhou et al 2020). It is thought that anosmia is due to direct invasion of the olfactory pathways. This may be concerning because in mice the coronavirus can enter the brain via the olfactory pathways and cause encephalitis (Dube et al 2018). It would be important to monitor patients with anosmia for extended periods of time to make sure that other neuroinflammatory or neurodegenerative diseases are not emerging as a consequence of this phenomenon.

Myalgia. This can occur at any time during the course of the illness and can persist after recovery of the other symptoms. Occasionally, rhabdomyolysis may occur, and there may be risk for renal toxicity (Jin and Tong 2020). Hence, these patients need to be carefully monitored and treated with hydration accordingly.

Meningitis. Headache is a common complaint. However, it is not certain how many patients with SARS-CoV-2 have the virus in the CSF of if they have other signs of aseptic or viral meningitis. Virus has been detected in the CSF of a SARS-CoV-2 infected patient (Michael 2020). SARS-CoV-1 has been detected in the CSF of a patient with encephalitis and acute respiratory distress syndrome (Hung et al 2003).

Encephalitis. Terminally, patients go into coma, which is thought to be due to hypoxia or multiorgan failure. However, the possibility exists that direct invasion of the CNS may occur in SARS-CoV-2-infected individuals. A case of SARS-CoV-2 meningoencephalitis has been reported from Japan where the patient presented with generalized seizures with paranasal sinusitis and lesions on the temporal lobe with adjoining ventriculitis and lesions in the paranasal sinuses. The virus could be detected in the CSF but not in the nasal swabs. There was a mild pleocytosis with 12 cells/µL in the CSF (Moriguchi et al 2020).

Another case of encephalitis was reported from China where the patient developed coma with generalized seizures. This patient also had acute respiratory distress syndrome, and the virus was isolated and sequenced from the CSF. The genome was registered in GISAID database and named ICDC-DT005 (personal communication). This is in keeping with the SARS-CoV-1 epidemic, where SARS genome sequences were detected in the brain of all (n=8) SARS autopsies with immunohistochemistry, electron microscopy, and with real-time RT-PCR. The signals were confined to the cytoplasm of numerous neurons in the hypothalamus and cortex.

Edema and scattered degenerating neurons were present in the brains of 6 of the 8 confirmed cases of SARS (Gu et al 2005). MERS-CoV can cause a severe acute disseminated encephalomyelitis and a vasculopathy (Arabi et al 2015). A fatal encephalitis can occur in immunocompromised patients with HCoV-OV43. In these patients, infection of neurons has been demonstrated at autopsy (Morfopoulou et al 2016).

Stroke. Patients with SARS-CoV-2 and SARS-CoV-1 infection develop a hypercoagulable syndrome causing both arterial and venous occlusions in the brain vasculature. Elevated D-dimer levels and increased PT and aPTT and well as DIC has been observed. Elderly patients who may have underlying cardiovascular risk factors are prone to developing vascular occlusive syndromes, including stroke and deep vein thrombosis (Tsai et al 2005). Some patients have been reported to develop myocarditis, which may be another risk factor for stroke. However, strokes are being reported in individuals who have no other risk factor other than COVID-19. This may be supported by the observation that the viral receptor ACE2 is present in endothelial cells, including the cerebral vasculature.

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.

Postinfectious complications

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 (Yea et al 2004). 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.

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. A case described bilateral lesions of the thalami and temporal lobes in a patient who presented with several days of altered mental status in addition to more typical COVID-19 symptoms (Poyiadji et al 2020).

Transverse myelitis. Reports of transverse myelitis with SARS-CoV-2 are also beginning to emerge. In a case report from Wuhan, China, a 66-year-old man presented with typical COVID-19 symptoms and then later developed acute flaccid paralysis with upper extremity 3/5 paresis, lower extremity plegia and hyporeflexia, a spinal sensory level, and bowel and bladder incontinence. Notably, an MRI and LP were not performed to further differentiate Guillain- Barré syndrome from flaccid myelitis. He was treated with ganciclovir, lopinavir/ritonavir, moxifloxacin, meropenem, glutathione, dexamethasone (10 mg daily for 10 days), immunoglobulin (15 g daily for 7 days), and vitamin B12. His strength minimally improved at the time of discharge (Zhao et al 2020a).

Guillain Barré syndrome. A postinfectious brainstem encephalitis and Guillain-Barré syndrome has also been described with MERS (Kim et al 2017). A case of Guillain-Barré syndrome has been described by authors in China in a woman who had recently visited Wuhan. Although she did not have COVID-19 symptoms prior to the Guillain-Barré syndrome onset, she developed dry cough and fever several days after onset; however, she had a negative oropharyngeal swab for COVID-19. The authors postulate that she may have been infected at some point and that she may have acquired it from her close relatives who did have positive tests, though it is likely that the Guillain-Barré syndrome was unrelated to COVID-19 (Zhao et al 2020b).

Sensory neuropathy. Not much has been written about sensory neuropathy and COVID-19 yet except for some mention of “neuralgia.” However, a postinfectious sensory neuropathy that manifests as paresthesias or pain and progresses in an ascending manner may occur and could be considered a variant of Guillain-Barré syndrome (personal communication).

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 (Yan et al 2020). 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, and for the large number of patients on these therapies, it is yet unknown how much of an additional risk there is both for infection and for developing a more severe disease course. 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.

Unknowns and challenges

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.

Pathology. Autopsy findings have not yet been reported, in part because the hardest hit places do not have the personal protection equipment to conduct the autopsies.

Long-term consequences remain unknown. Many unanswered questions remain. It is interesting that children infected with the virus develop only very mild symptoms. Could a component of the respiratory failure for some patients be due to brainstem involvement? What might be the effect on patients with other underlying neurologic illnesses who develop pulmonary complications? Is there permanent lung injury; if so, can that effect overall neurologic health?

Coronaviruses in chronic neurologic disease

Seropositivity for coronaviruses has been reported in a variety of neurologic disorders, including encephalitis (Li et al 2016), optic neuritis (Dessau et al 1999), multiple sclerosis (Salmi et al 1982), and Parkinson disease (Fazzini et al 1992). Virus has also been isolated from CSF and brain of patients with multiple sclerosis (Burks et al 1980). 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.

Management

Antiviral. Currently, there is no proven antiviral therapy for the human coronaviruses, and the main treatment is supportive and symptomatic. However, several drugs are being considered for clinical trials and empirical treatment of patients (Table 3).

Table 3. Antiviral Agents Being Considered Against SARS-CoV-2

Favipiravir (T-705)

Selective and potent inhibitor of the RNA-dependent RNA polymerase of RNA viruses

Remdesivir (GS-5734)

A nucleotide analog inhibitor of RdRp. Against SARS-CoV, MERS-CoV and Ebola virus. Inhibits SARS-CoV-2 in vitro.

Chloroquine phosphate

An antimalarial agent. Inhibits autophagy and toll-like receptors (TLRs). Inhibits SARS-CoV-2 in vitro.

Hydroxychloroquine sulfate

An antimalarial and anti-inflammatory agent. Inhibits TLR7/9 signaling. Inhibits SARS-CoV-2 infection in vitro.

Saquinavir

An HIV protease inhibitor

Carfilzomib

An irreversible proteasome inhibitor

Nelfinavir

An orally bioavailable HIV-1 protease inhibitor (Ki=2 nM) and antiviral agent

Bimosiamose

A nonoligosaccharide pan-selectin inhibitor with anti-inflammatory effects

Zanamivir

An influenza viral neuraminidase inhibitor

Ribavirin

An antiviral agent against a broad spectrum of viruses including hepatitis C, HIV, and respiratory syncytial virus

Ivermectin

A parasitic agent with broad antiviral effects of unknown mechanism

Antisense oligonucleotides

Specifically target the virus and degrades the viral RNA

In vitro studies have shown some efficacy with chloroquine and hydroxychloroquine. These drugs cause acidification of the endosome-lysosomes and prevent viral replication. They have an anti-inflammatory effect. However, drug pretreatment of cells prior to infection has only a minimal effect post-infection. Several HIV protease inhibitors have been shown to bind to the SARS-CoV-2 protease, but clinical experience in small numbers of humans infected with the virus has failed to show clinical efficacy with lopinavir/ritonavir combination. Many clinical trials are currently underway that include nucleoside analogs, such as remdesivir, anti-inflammatory agents, including IL-6 receptor inhibitors, and convalescent serum or intravenous immunoglobulin. The ability of any of these agents to enter the CNS is unknown.

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.

Teleneurology

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 have 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 (Klein and Busis 2020; Waldman et al 2020).

Ethical dilemma

The COVID-19 pandemic has 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 (Kim and Grady 2020). 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.

Acknowledgement

Funding for this article was supported by intramural funding from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

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