As positive cases of coronavirus infectious disease (COVID-19) continue to increase in the United States, clinicians have identified atypical symptoms that may be present in a small proportion of individuals with the disease. The hallmark symptoms of COVID-19 are fever, cough, and shortness of breath, but some patients also have experienced neurological symptoms, such as headaches, confusion, seizures,1 loss of smell, stroke, brain damage, or total paralysis.2 Although these neurological symptoms at first were thought to be relatively rare, researchers now estimate that up to 20% of COVID-19 patients who were admitted to an intensive care unit were admitted because of neurological problems. These patients were also more likely to die as a result of COVID-19,2 indicating an urgent need to understand the mechanisms underlying neurological symptoms of this illness.
New research on this emerging issue suggests that there is a correlation between the severity of COVID-19 illness and subsequent brain injury, even if patients do not show neurological symptoms before or during the course of the virus. Specifically, researchers believe that the body’s natural immune response to SARS-CoV-2 (the virus that causes COVID-19) can damage certain brain cells, resulting in injury to the central nervous system (CNS), which consists of the brain and the spinal cord. One research team studied the relationship between COVID-19 and CNS cells called neurons (cells that transmit nerve signals) and astrocytes (cells that support and protect neurons), two cell types that are critically important for addressing CNS damage. When the CNS detects an injury or infection, astrocytes are activated to protect neurons from further injury. Astrocytes that have been injured or have already died cannot adequately protect neurons, leading to irreversible neuron death and subsequent neurological symptoms. When COVID-19 infects CNS cells, researchers suspect that the body’s immune response causes rapid, uncontrolled activation and inflammation of astrocytes, rendering them unable to protect neurons from further injury.1
Researchers know that these cellular processes exist, but they often struggle to observe them in real time because they occur rapidly on a microscopic levels. As a result, researchers have developed proxy measures that can indicate the presence of a cellular process without requiring direct observation of the process while it occurs. These proxy measures are called biomarkers, or specific molecules or compounds in the body that act as indicators for a physiological process that is otherwise difficult to observe.
To study the relationship between COVID-19 and astrocytic damage, researchers used blood samples from COVID-19 patients to measure levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp), biomarkers that are known to indicate neuronal injury and astrocytic activation/injury, respectively.3,4 When elevated levels of these biomarkers are present in the blood, researchers know that a patient is experiencing CNS injury. After the researchers analyzed COVID-19 patients’ blood samples, they determined that patients with severe illness had higher plasma concentrations of both biomarkers, while moderate patients displayed higher levels of GFAp only. Comparing the blood samples taken during the initial and follow-up stages of the study, concentrations of GFAp and NfL did not substantially change in the mild and moderate patients. However, the severe patients showed decreases in GFAp levels but increased NfL levels over time, suggesting an early astrocyte activation response to the COVID-19 illness, followed by delayed neuron injury. The researchers also found that high NfL concentration was associated with decreased white blood cell count, indicating that high levels of neuronal injury are related to lower immune function. Ultimately, the study concluded that injury to neurons and astrocytes were most severe among patients diagnosed with moderate to severe COVID-19.1
Another review article noted a potential theory for how the virus initially gains access to the brain to destroy astrocytes and neurons. When the body becomes a host for a virus such as SARS-CoV-2, the virus can trigger what is called a cytokine storm. During the immune response process, the body releases cytokines (proteins produced by the immune system) to respond to an infection. Sometimes, however, the immune system releases a catastrophic number of cytokines, which may begin to attack the body’s own tissues and cells rather than specifically targeting the bacteria or virus responsible for the infection. The ensuing cytokine storm often causes inflammation, fluid retention and swelling, blood clots, and vascular injury. In severe cases, it a cytokine storm can destroy the blood brain barrier, the brain’s protective barrier that prohibits unwanted substances in the bloodstream from entering and interfering with the brain. Scientists theorize that the SARS-CoV-2 virus may be able to enter the CNS after a cytokine storm response to the initial infection has deteriorated the blood brain barrier, leaving the brain and spinal cord vulnerable to attack.5
The article recommended using a method called “NeuroCOVID staging” to classify three different stages of COVID-19 interference with the CNS. In the first stage, the virus is confined to outer surface cells that line the mouth and nasal cavity, causing loss of taste and smell. The immune system is still functional and cytokine levels remain controlled. By the second stage, the immune system begins to hyperactivate. Cytokine levels rapidly increase, potentially leading to blood clots, strokes, blood vessel inflammation, and nerve damage. In the third stage, the immune response escalates to a full cytokine storm and begins to damage the blood brain barrier, allowing the virus to infiltrate the CNS, where it begins to destroy astrocytes and neurons. Patients whose disease progresses to the third stage usually experience brain injury, explaining the unusual neurological and psychiatric symptoms sometimes associated with COVID-19.2
Scientists warn that the COVID-19 pandemic likely will cause a massive surge in cases of depression, anxiety, cognitive impairment, insomnia, PTSD, and other conditions in the months and years to come. Many physicians and scientists now recommend that all patients admitted to the hospital with COVID-19 (especially those with severe illness) should receive brain imaging scans to gain a baseline record of their neurological health, followed by six to eight months of follow-up monitoring after recovery. Close attention to blood test results, specifically cytokine levels and CNS biomarkers, may be key for protecting long-term neurological and psychiatric health among patients infected with COVID-19.2