In the months since the coronavirus disease 2019 (COVID-19) pandemic emerged, the illness has been linked to involvement in multiple organ systems in addition to the lungs. For example, there have been numerous reports of heart failure, renal damage, gastrointestinal symptoms, and liver injury in those with COVID-19.1 Accumulating evidence suggests that the disease can also lead to neurological complications in some cases.2-4

In a review published online in JAMA Neurology, researchers from Yale University School of Medicine in New Haven, Connecticut examined available case reports and clinical studies and found that the most commonly observed neurological effects in COVID-19 to date are headache, anosmia, and ageusia.5 Headache may affect up to one-third of patients, while prevalence rates of olfactory and gustatory dysfunction vary widely across settings. In addition, more severe events including impaired consciousness, seizure, stroke, Guillain-Barré syndrome, and encephalopathy have also been noted in COVID-19 patients. 

As the understanding of neurologic manifestations associated with the virus continues to evolve, the authors recommend close monitoring of patients for early detection of these complications. We spoke with Serena S. Spudich, MD, professor of neurology, division chief of neuroinfectious diseases and global neurology, at Yale University School of Medicine, one of the study authors. Robert D. Stevens, MD, FCCM, director of precision medicine in anesthesiology and critical care medicine, associate director of the Johns Hopkins Neurocritical Care Precision Medicine Center of Excellence, and associate professor of anesthesiology and critical care medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, also provided expert insights.

What are believed to be the mechanisms involved in some of the common neurologic manifestations of COVID-19?   


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Dr Spudich: There are likely different mechanisms underlying the various types of neurological manifestations of COVID-19. For example, sense of smell may be altered by viral invasion into the olfactory nerves and olfactory areas of the brain, or by inflammation of these structures. Headaches and mental status changes including confusion, prolonged coma after withdrawal of pharmacologic sedation, and psychiatric syndromes such as psychosis and catatonia have been described in patients with COVID-19. These may be due in some cases to the effect of inflammatory mediators or immune cells crossing from the blood into the brain, though evidence is scarce.

Strokes that occur in the setting of COVID-19 may relate to hypercoagulability and endothelial activation, which may exacerbate underlying stroke risk factors such as atrial fibrillation, hypertension, and advanced age.

Finally, neuromuscular disorders have been reported, presenting a week or more after onset of COVID-19 symptoms. The spectrum of these nerve and muscle syndromes and their timing suggests an autoimmune post-infectious etiology.

Dr Stevens: There are several postulated mechanisms whereby SARS-CoV-2 might interact with the nervous system. These mechanisms might occur simultaneously:

a. The virus enters the central nervous system and directly infects neurons, glial cells, endothelial or ependymal cells; concurrently, there is an upregulation of local neuroinflammatory/neuroimmunologic signaling. This would be tantamount to encephalitis and has been described with other coronaviruses. The SARS-associated coronavirus, the etiologic agent of the 2003 SARS pandemic, is another example

b. The virus induces a nonspecific systemic inflammatory response (sometimes referred to as a “cytokine storm”) which affects multiple organs, including the brain.

c. The virus induces an adaptive immunologic response mediated by antibody-producing B-lymphocytes and reactive T-lymphocytes directed towards neural antigens (post-viral syndrome).

d. The virus increases the risk of ischemic and/or hemorrhagic strokes due to the induction of a hypercoagulable state.

e. The virus produces metabolic and physiologic derangements – for example, fever, hypoxemia, hypercatabolic state, and acute kidney injury – leading secondarily to brain dysfunction such as delirium and encephalopathy.

What are recommendations for clinicians regarding early detection of these effects in COVID-19 patients?

Dr Spudich: Early detection of neurological effects is crucial to identify patients with COVID-19 in the first place, since some patients – especially the elderly – present primarily with mental status changes or stroke before other classic COVID-19 symptoms appear. 

Dr Stevens: Several principles seem important:

A detailed neurologic history and physical should be conducted whenever possible in all patients with COVID-19.

Patients with an acute onset of a neurological syndrome – encephalopathy, stroke, intracerebral hemorrhage, signs of meningoencephalitis – should be tested for COVID-19.

Patients with known COVID-19 who develop acute neurological symptoms such as focal neurological signs, seizures, delirium, and loss of consciousness should be evaluated urgently with neuroimaging, and EEG, as well as lumbar puncture when deemed safe.

What are recommendations for long-term monitoring and potential treatment of these neurological effects?

Dr Spudich: Since the pathogenesis of many of the neurologic syndromes associated with COVID-19 is still unknown, interventions for the associated symptoms are still unproven. However, standard treatments for conditions such as stroke and Guillain-Barre syndrome are indicated, and supportive care should be instituted promptly in patients with these conditions to prevent further associated complications.

The duration of neurologic effects likely differs between the disparate neurologic syndromes. There are some reports that sense of smell and taste usually recovers after 6-8 weeks, though this can vary widely. Patients with strokes should receive rehabilitation and are expected to have recovery of some of the lost functions, similar to what we see in stroke in non-COVID-19 patients.

We don’t yet know whether the mental status changes seen in hospitalized patients leaves any lasting effects, though we have definitely seen patients with prolonged coma regain consciousness and some patients who presented with acute confusion have shown significant functional recovery. Overall, patients with neurologic conditions in the setting of acute COVID-19 should be followed for cognitive, mood, motor, and sensory function some months after recovery to ensure that they do not have lingering or worsening symptoms.

Dr Stevens: Since COVID-19 is a new disease, virtually nothing is known about the longer-term outcomes, let alone recommendations for monitoring or treatment in the long term. Several longitudinal cohort studies are underway, and others are planned to start soon, so we should know much more about this in the next 6-12 months.

What are the most pressing research needs in this area?

Dr Spudich: Though we have seen the rapid dissemination of numerous case reports on neurologic manifestations of COVID-19, we need systematic epidemiologic and clinical studies to determine the frequency and risk factors for these different syndromes. Additionally, we need translational research studies that obtain biological and clinical data from individuals with COVID-19, including detailed neuroimaging studies, cerebrospinal fluid, and neuropsychological and psychiatric assessments. 

Such research will help us understand how much of the conditions relate to direct viral neuroinvasion vs inflammatory or autoimmune effects, or downstream effects of severe systemic illness such as hypoxia, acute renal injury, or systemic cytokine storm. We will learn a great deal from pathological examination of the brain in unfortunate cases where individuals with COVID-19 pass away.

Finally, studies that comprehensively assess the nervous system in patients 6 months, and then even later after recovery from acute disease, will be crucial to determine whether there are long-term consequences of COVID-19. Historically, some pandemic respiratory illnesses have been associated with post-encephalitic catatonia or Parkinsonism. There is currently no evidence that this will be true of COVID-19, but we need long-term studies to confirm that we don’t see these conditions or persistent cognitive or mood disorders in survivors of this pandemic.

Dr Stevens: Observations made over the past 6 months indicate that COVID-19 is a complex disease with extreme heterogeneity in susceptibility, clinical presentation, natural history, response to treatment and outcome. The most pressing needs are to develop effective antiviral and/or immune-modulating therapies to reduce the severity and mortality of the disease, and to create and test effective vaccines against SARS-CoV-2.

Additional research is needed to identify and characterize the biological mechanisms of COVID-19, particularly the genetic and molecular determinants of disease susceptibility, severity, and host response. We need to gain knowledge on the different immunologic signaling pathways that are likely to play a critical role in disease expression in multiple organ systems including the brain.

References

1. Zaim S, Chong JH, Sankaranarayanan V, Harky A. COVID-19 and multiorgan response. Curr Probl Cardiol. 2020;45(8):100618.

2. Yashavantha Rao HC, Jayabaskaran C. The emergence of a novel coronavirus (SARS-CoV-2) disease and their neuroinvasive propensity may affect in COVID-19 patients. J Med Virol. 2020;92(7):786-790.

3. Román GC, Spencer PS, Reis J, et al. The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries. J Neurol Sci. 2020;414:116884.

4. Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg. 2020;194:105921.

5. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. [published online May 29, 2020.]. JAMA Neurol. doi:10.1001/jamaneurol.2020.2065