Clinical manifestations

Systemic symptoms. Coronaviruses are known causes of respiratory, enteric, and systemic infections. Most human coronaviruses cause mild symptoms and resolve.

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 (07). 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 (23). Headache occurs in 8% (23). Diarrhea occurs in less than 5% and in some patients might be the major symptom (07). On chest CT scan, more than 50% of patients demonstrate a ground glass opacity. Many patients develop pneumonia. Older patients have more severe disease. 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 (45). Lymphopenia is common (23). Mortality is higher with advanced age and underlying comorbidities, including diabetes, obesity, cardiac and respiratory disorders, and immunosuppressed states.

Neurologic complications. Although COVID-19 is largely a respiratory disorder, neurologic complications are frequently encountered throughout the course of the illness. Several acute neurologic syndromes have been associated with coronaviruses (Table 2). In some patients, neurologic manifestations may precede respiratory symptoms or be the sole manifestation of COVID-19. There are multiple proposed mechanisms by which SARS-CoV-2 is theorized to cause neurologic effects, including direct viral infection, immune-mediated injury, blood-brain barrier dysfunction, cytokine toxicity, and indirect sequalae of critical illness (48). Given the heterogeneity of neurologic manifestations, the pathophysiology of disease is likely multifactorial and involves multiple mechanisms. However, most evidence supports a systemic inflammatory response with CNS involvement rather than direct viral invasion of the CNS.

Table 2. Neurologic Complications of SARS-CoV-2 Infection

Acute neurologic complications

Anosmia and ageusia. Anosmia and ageusia are commonly reported in over 80% of patients with early infection, even in the absence of other nasal symptoms (17). The virus is believed to invade the sustentacular cells in the vicinity of the olfactory nerve endings, which express SARS-CoV-2 receptor ACE2 (04). Ageusia results from anosmia. Anosmia and ageusia may, in turn, cause anorexia and weight loss. Transient edema of the olfactory nerves and bulb may be seen on MRI (44). The prognosis for the recovery of olfactory function is favorable and occurs in up to 96.1% by 1 year (35).

Encephalopathy. Encephalopathy is common in patients with COVID-19 and is likely multifactorial in etiology. Encephalopathy is particularly common in critically ill patients with significant pulmonary involvement. Hypoxia and multiorgan involvement are thought to play a significant role in the pathogenesis of encephalopathy in patients with COVID-19. Rarely, encephalopathy may be the sole presenting sign of COVID-19, particularly in individuals older than 65 years of age (11). Neuroimaging and CSF examination are usually normal unless there are other coexisting neurologic complications of COVID-19. It is important to note that COVID-19-associated encephalopathy is associated with longer length of hospital stay and increased 30-day mortality (20).

Cerebrovascular disease. As with other viruses and severe infections, arterial and venous strokes may be encountered in patients with SARS-CoV-2 infection (Table 3). Interestingly, some studies have suggested a higher risk of stroke in patients with COVID-19 compared to influenza and bacterial pneumonia (51).

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% (19). 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) (33). SARS-CoV-2 stroke patients are likely to have other comorbid risk factors as well. The management of stroke in the setting of COVID-19 should be approached similarly to stroke patients without COVID-19.

Table 3. Vascular Complications of SARS-CoV-2 Infection

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 (27), and several additional cases have also been reported. In a systematic review and meta-analysis of COVID-19-associated encephalitis, the incidence of encephalitis as a complication of COVID-19 infection was estimated to be approximately 0.215% (42). 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 (25). 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.

For this reason, it has been postulated that the pathophysiology of encephalitis seen in COVID-19 may be mediated by a cytokine-release syndrome rather than direct viral invasion (32).

Seizures. Rarely, patients with COVID-19 infection may develop seizures. The reported incidence of seizures as a complication of COVID-19 is estimated to be less than 1% and is mostly seen in patients who are critically ill or have other neurologic complications of COVID-19, such as meningoencephalitis (16). The pathogenesis is likely multifactorial and often related to underlying toxic-metabolic disturbances and critical illness.

Myositis and other neuromuscular complications. Similar to other viral illnesses, myalgias are a commonly reported symptom in COVID-19 infection. However, myositis temporally associated with COVID-19 infection has also been reported, both as a complication associated with acute infection, with proximal weakness and highly elevated creatine kinase levels (24), as well as a later complication with subacute or chronic features consistent with an immune-mediated postinfectious process. Other neuromuscular complications can include polyneuropathy, facial nerve palsy, cranial neuropathy, and inflammatory plexopathies. Critically ill patients may also develop critical illness neuropathy and myopathy as a result of prolonged and severe illness.

Parainfectious and post-infectious complications

Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis (ADEM) is a post-viral 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 ADEM (50). 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 (21; 31). In one MRI study of hospitalized patients with neurologic symptoms, 17% had leptomeningeal enhancement and 13% had encephalitis (15). 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 (34).

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 (31; 28).

Myelitis. Cases of acute transverse myelitis associated with SARS-CoV-2 have been reported. 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) (37). 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. Additionally, myelitis may be a presenting feature of another post-infectious immune-mediated process, such as neuromyelitis optica spectrum disorder (NMOSD) or myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (06).

Autoimmune encephalitis. Although rare, there are numerous reports of autoimmune encephalitis developing after COVID-19 infection. A systematic review on autoimmune encephalitis associated with COVID-19 identified 23 definite and 48 possible cases of autoimmune encephalitis associated with COVID-19 infection or vaccination (39). Anti-NMDAR encephalitis was the most common type of definite autoimmune encephalitis reported in this meta-analysis (12 cases total). Molecular mimicry has been proposed as a possible pathophysiological mechanism.

Another study, emphasizing the rarity of encountering post-COVID autoimmune encephalitis cases, demonstrated that 0.05% of patients with COVID-19-related diagnoses in 2020 included post-COVID autoimmune encephalitis (47). This study examined residual sera from 556 consecutive Mayo Clinic Rochester patients who underwent autoimmune encephalopathy neural antibody evaluations and were tested for total antibodies against SARS-CoV-2, and medical records were reviewed. From the laboratory SARS-CoV-2 antibody cohort, diagnoses included post sequelae of SARS-CoV-2 infection (PASC), toxic-metabolic encephalopathy during COVID-19 pneumonia, diverse non-COVID-19 relatable neurologic diagnosis, and autoimmune encephalitis.

Guillain Barré syndrome. A postinfectious brainstem encephalitis and Guillain-Barré syndrome has also been described with MERS (12). 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 (46). A later, more comprehensive review of 73 patients showed that more than three quarters had predominantly demyelinating features (02). 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. Miller-Fisher syndrome with ophthalmoparesis has also been reported (08).

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 (24), as well as a later complication with subacute or chronic features consistent with an immune-mediated postinfectious process (03).

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 (36). 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 as treatment options, but neither has proved to have a greater comparative advantage (26).

Post-acute sequalae of COVID-19 (PASC)

Many patients who recover from COVID-19 continue to experience symptoms months to years after recovery from the acute infection. Several terms have emerged to describe this phenomenon, including post-acute sequalae of COVID-19 (PASC), long haul COVID, and post-COVID-19 syndrome. Frequently reported symptoms include fatigue, cognitive dysfunction, dyspnea, headache, and dizziness. A meta-analysis found that nearly 50% of patients with COVID-19 infection reported at least one post-COVID symptom, and nearly 20% of patients reported at least one neurologic symptom (52). The pathophysiologic mechanism underlying PASC remains unclear, and it is likely that multiple mechanisms may contribute. When evaluating patients with PASC, it is important to ensure that an alternate diagnosis would not better explain the patient’s symptoms.

Headache. Approximately 10% of patients report persisting headaches after COVID-19 infection (52). This can be either new-onset headaches or exacerbation of a previous headache disorder. There is no unique headache phenotype related to COVID-19 infection, though migraine and tension-type headaches are the most commonly reported. The management of headaches in this setting is similar to the management in patients without COVID-19.

Cognitive dysfunction. Many patients with COVID-19 will report symptoms of brain fog after infection, similar to recovery from other viral infections. The pathophysiology is not well understood but is suspected to be multifactorial. Neuropsychological testing may help quantify the degree of cognitive dysfunction, if present. Comorbid psychiatric conditions, such as depression, anxiety, or posttraumatic stress disorder (PTSD), may further contribute to cognitive symptoms. For patients with objective cognitive dysfunction or significant disability, it is important to evaluate for other underlying causes of cognitive decline that may have been exacerbated with COVID-19 infection.

Dysautonomia. Symptoms related to autonomic dysfunction are not infrequently reported after COVID-19 infection. These symptoms include lightheadedness, dizziness, small fiber neuropathy, exercise intolerance, and fatigue, among others. As many of these symptoms overlap with symptoms seen in postural orthostatic tachycardia syndrome (POTS), the diagnosis of POTS had been increasingly made in this patient population (30). The management of POTS is similar in patients with or without preceding COVID-19 infection.

Dizziness. Dizziness is frequently reported both during and after COVID-19 infection. The description of the dizziness is often variable and nonspecific. Vestibular rehabilitation may be helpful in management and aiding recovery (40).

Neuropathy and pain. Patients who recover from COVID-19 often report the development of neuropathic symptoms. The distribution of neuropathy can be variable in patients and may include length-dependent, focal, or patchy distribution. It has been proposed that small fiber neuropathy may be the underlying etiology of neuropathy in a proportion of these patients (01). Management is largely symptomatic, and there is currently no specific treatment for COVID-19-related neuropathy and pain.

Sleep disturbance. Some patients report significant sleep disturbances after COVID-19 infection, particularly insomnia. This may further exacerbate other symptoms, such as fatigue. Management is similar to that for patients without COVID-19 infection.

Vaccine-associated adverse neurologic events

Remarkably, severe COVID-19 has become a largely preventable disease since the introduction and widespread availability of several different vaccines against the SARS-CoV-2 virus. At the time of this writing, there are currently three vaccines authorized for use in the United States. Of these, two are mRNA-based vaccines and one is recombinant spike protein subunit. As with other vaccines, there have been rare reports of neurologic complications. Neurologic adverse events are estimated to occur in 0.03% of all doses administered based on information available via the Vaccine Adverse Event Reporting System (VAERS). The vast majority of adverse events are transient and include headache, myalgia, fatigue, and syncope. However, there are also rare reports of immune-mediated and cerebrovascular events, which are briefly outlined below. Despite this, it is important for patients to know that neurologic complications following COVID-19 infection are estimated to be 617-fold higher than neurologic complications following COVID-19 vaccination (05).

Immune-mediated events. Similar to other vaccines, several immune-mediated events have been reported in association with COVID-19 vaccines. These syndromes typically present several days to weeks after vaccination and include Guillain-Barré syndrome, Bell palsy, and a wide variety of demyelinating events (multiple sclerosis, NMOSD, MOGAD, ADEM, transverse myelitis, optic neuritis) (05). These complications are quite rare and, importantly, were most frequently encountered with the adenoviral vector–based vaccine, which is no longer approved for use in the United States.

Cerebrovascular events. There have been rare reports of ischemic stroke, hemorrhagic stroke, and cerebral venous sinus thrombosis following COVID-19 vaccination, though the causal relationship is unclear. A systematic review concluded that the proportion of acute ischemic stroke following COVID-19 vaccination is similar to the general population and significantly less than risk associated with COVID-19 infection (43). It is important to note that the vast majority of reported cases describing venous sinus thrombosis following COVID-19 vaccination were associated with the adenoviral vector–based vaccine, which is no longer available in the United States.

Other complications

Risk factors for neurologic complications. Advanced age, obesity, 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 (49). The use of ACE inhibitors may lead to increased expression of ACE2, theoretically making the cells more vulnerable to infection with the virus. However, there is currently no evidence that stopping ACE inhibitors or angiotensin receptor blockers (ARBs) improves outcome in COVID-19 infection, and it may potentially worsen outcomes (22). Therefore, patients receiving treatment with these agents should continue unless there is another strong indication to discontinue.

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 (29). 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.

Important lessons from the COVID-19 pandemic

Teleneurology. The barriers to physical contact necessitated by the pandemic have 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 (14).

Ethical dilemma. 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 (13). 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.