Three Stages to COVID-19 Brain Damage, New Review Suggests

Batya Swift Yasgur MA, LSW

June 29, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

A new review outlines a three-stage classification of the impact of COVID-19 on the central nervous system and recommends hospitalized patients with the virus all undergo MRI to flag potential neurologic damage and inform postdischarge monitoring.

In stage 1, viral damage is limited to epithelial cells of the nose and mouth, and in stage 2 blood clots that form in the lungs may travel to the brain, leading to stroke. In stage 3, the virus crosses the blood–brain barrier and invades the brain.

"Our major take-home points are that patients with COVID-19 symptoms, such as shortness of breath, headache, or dizziness, may have neurological symptoms that, at the time of hospitalization, might not be noticed or prioritized, or whose neurological symptoms may become apparent only after they leave the hospital," lead author Majid Fotuhi, MD, PhD, medical director of NeuroGrow Brain Fitness Center, McLean, Virginia, told Medscape Medical News.

"Hospitalized patients with COVID-19 should have a neurological evaluation and ideally a brain MRI before leaving the hospital; and, if there are abnormalities, they should follow up with a neurologist in 3 to 4 months," said Fotuhi, who is also affiliate staff at Johns Hopkins Medicine in Baltimore, Maryland. 

The review was published online June 8 in the Journal of Alzheimer's Disease.

Wreaks CNS Havoc

It has become "increasingly evident" that SARS-CoV-2 can cause neurologic manifestations, including anosmia, seizures, stroke, confusion, encephalopathy, and total paralysis, the authors write.

The authors note that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) that facilitates the conversion of angiotensin II to angiotensin. After ACE2 has bound to respiratory epithelial cells, and then to epithelial cells in blood vessels, SARS-CoV-2 triggers the formation of a "cytokine storm."

These cytokines, in turn, increase vascular permeability, edema, and widespread inflammation, as well as triggering "hypercoagulation cascades," which cause small and large blood clots that affect multiple organs.

If SARS-CoV-2 crosses the blood–brain barrier, directly entering the brain, it can contribute to demyelination or neurodegeneration.

"We very thoroughly reviewed the literature published between January 1 and May 1, 2020 about neurological issues [in COVID-19] and what I found interesting is that so many neurological things can happen due to a virus which is so small," said Fotuhi.

"This virus' DNA has such limited information, and yet it can wreak havoc on our nervous system because it kicks off such a potent defense system in our body that damages our nervous system," he said.



Three-Stage Classification

Stage 1

The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining "low and controlled." During this stage, patients may experience smell or taste impairments, but often recover without any interventions.

Stage 2

A "robust immune response" is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes.

Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, double vision, tetraplegia, aphasia, or ataxia.

Stage 3

The cytokine storm in the blood vessels is so severe that it causes an "explosive inflammatory response" and penetrates the blood–brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis.

This stage can be characterized by seizures, confusion, delirium, coma, loss of consciousness, or death.

"Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years," said Fotuhi.

"Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson's disease even decades later," he added.

"Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don't look for them, you won't see them," Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, "it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment," said Fotuhi.

"The good news is that neurological manifestations of COVID-19 are treatable," and "can improve with intensive training," including lifestyle changes—such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation," Fotuhi added.

Routine MRI Not Necessary

Kenneth Tyler, MD, chair of the Department of Neurology at the University of Colorado School of Medicine, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

"Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients," he told Medscape Medical News.

Instead, "the indication is in patients who develop unexplained neurological manifestations — altered mental status or focal seizures, for example —because in those cases, you do need to understand whether there are underlying structural abnormalities," said Tyler, who was not involved in the review.

Also commenting on the review for Medscape Medical News, Vanja Douglas, MD, associate professor of clinical neurology, University of California San Francisco, described the review as "thorough" and suggested it may "help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection."

Douglas, who was not involved in the review, added that it is "helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic."

The study had no specific funding. Fotuhi has disclosed no relevant financial relationships. Coauthor Cyrus Raji reports consulting fees as a member of the scientific advisory board for Brainreader ApS and reports royalties for expert witness consultation in conjunction with Neurevolution LLC. Tyler and Douglas have disclosed no relevant financial relationships.

J Alzheimers Dis. Published online June 10, 2020. Full text

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