What’s happening in the brain with COVID-19?

Posted by Emily Baltz on July 30, 2020 in Neurological Disorders, News | 3 Comments

[En español]

What are the neurological symptoms of COVID-19? 

At this point, most of us are familiar with the common symptoms of COVID-19: fever, cough, sore throat, muscle ache, diarrhea, and fatigue. We also know that the worst complications can be pneumonia and acute respiratory distress syndrome.  Acute respiratory distress syndrome can lead to hypoxia (not getting enough oxygen to the tissues like the brain), and ischemia (inadequate blood supply to the organs like the brain).  

However, on top of the respiratory symptoms, there are a number of less-reported neurological symptoms [1]. Two of the most common are headache and dizziness. Some people also experience declining ability to reason and concentrate, problems with memory, personality changes, and seizures. This group of symptoms is called encephalopathy. Impaired consciousness is also possible. In addition to effects on the brain, there are effects on some nerves responsible for sending signals from the body to the brain, which accounts for the loss of smell and taste experienced by some patients [2,3] 

How are these neurological effects arising? One possibility is that the virus that causes COVID-19, SARS-CoV-2, is directly infecting brain cells (see this article for more information on how SARS-CoV-2 is getting into cells [4]). The other possibility is that the neurological symptoms we see are due to secondary causes, like lack of oxygen or blood supply to the brain. While we might assume that these neurological effects are because of the virus infecting the brain, only recently have studies tested this hypothesis. 

Is SARS-CoV-2 getting into the brain? 

In order to figure out if SARS-CoV-2 is getting into the brain, one study examined brain tissue from 18 patients who died within 32 days of the onset of COVID-19 symptoms. The brains of patients showed hypoxic changes [5]. The presence of hypoxic changes in brain cells could be due to a direct effect of SARS-CoV-2 on the brain, could result from secondary effects of virus elsewhere in the body, or could be related to some of the other diseases that these patients already had. In this study, the scientists also used a technique to look for presence of the virus in brain tissue samples. They found minimal amounts of virus in 5 patients, and the amounts of virus didn’t relate to how quickly the patient died. The positive amounts of virus detected could have been from viral RNA from blood, or from the whole virus. These results call into question the hypothesis that SARS-CoV-2 is making it into the brain through the blood-brain-barrier. 

However, another study provided some evidence for SARS-CoV-2 getting into the cerebrospinal fluid. One individual with COVID-19 experienced decreased consciousness. There were no abnormal structural changes to the brain when they did a CT scan on the patient. To better understand what was going on, they sequenced samples of cerebrospinal fluid, which is the protective fluid that cushions the brain and spinal cord, and found evidence of RNA of SARS-CoV-2. SARS-CoV-2 could be found in the brain, and potentially caused encephalitis in this individual [6]. However, two other studies found that in patients with similar symptoms, there was no evidence of SARS-CoV-2 in the cerebrospinal fluid [7,8]. Lack of detection could just mean there is a very low amount of virus in the cerebrospinal fluid of those patients, or it could mean that the patient with SARS-CoV-2 RNA in his cerebrospinal fluid was unusual.

It’s unclear if SARS-CoV-2 is acting directly on the brain, but we can still investigate if the brain is being damaged when people are sick with COVID-19. 

Does COVID-19 change the structure of the brain? 

One study sought to understand the gross effects of COVID-19 on brain structure [9]. They used magnetic resonance imaging (MRI) of the brain in 19 patients within 24 hours of death in order to look at changes in size and structure of individual brain parts. In 4 patients, they found changes to the brain tissue, including changes to the parts of brain cells that conduct information (white matter) and evidence of bleeding, which could have been from blood-brain barrier breakdown. They also found asymmetrical olfactory bulbs, which are needed for the sense of smell, in 4 patients. It appears that sometimes, some structural changes occur in patients with COVID-19, but with these small sample sizes and patients having more than one disease, it’s hard to know if COVID-19 is causing these structural changes. Another way to look at damage to the brain is through biomarkers in live patients. 

What biomarkers of neural changes exist in COVID-19 patients?

Biomarkers are measurable substances that can indicate a disease, infection, or environmental exposure. There are biomarkers for central nervous system injury that scientists can measure in blood plasma. One study looked for biomarkers of central nervous system injury in the plasma of 47 patients [10].  They looked for a marker of neuron injury (NfL), which would indicate that neurons’ ability to send information was damaged. They also looked at a marker of glial cell activation and injury, (GFAp). In patients with severe COVID-19, they saw an increase in both NfL and GFAp. GFAp was also increased in patients with moderate COVID-19. In a follow up plasma test, GFAp concentrations decreased, but NfL increased. These data provide evidence for neuronal injury and glial activation in patients with severe and moderate COVID-19. This data tells us there is neurological injury happening from COVID-19, but it’s still unclear as to what the root cause of the injury is (viral infection or secondary effects). Knowing that NfL is elevated may allow clinicians to identify the severity of the neurological damage, and potentially may serve as a target for drug development to prevent further neural injury. 

Conclusion

Overall, it’s still unclear whether SARS-CoV-2 directly acts on the brain, or if the injury seen is primarily from hypoxia and ischemic events. More work needs to be done to find evidence to suggest that SARS-CoV-2 is infecting the central nervous system. Regardless, we definitely see structural and biological indicators of damage to the central nervous system as a result of COVID-19. More research to better parse out the mechanism of how COVID-19 is causing brain damage is needed. 

For further in depth review of the current data, see reviews by Wood and Fotuhi [11,12]. To learn more about the neurological effects of other human coronaviruses like SARS-CoV-1 that have been more extensively studied, see the review by De Felice [13]. 

References: 

1. Helms, J. et al. Neurologic Features in Severe SARS-CoV-2 Infection. N. Engl. J. Med. 382, 2268–2270 (2020).
2. CDC. Coronavirus Disease 2019 (COVID-19) – Symptoms. Centers for Disease Control and Prevention https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html (2020).
3. COVID-19 basics – Harvard Health. https://www.health.harvard.edu/diseases-and-conditions/covid-19-basics.
4. Meet ACE2, the Enzyme at the Center of the Covid-19 Mystery. Wired.
5. Solomon, I. H. et al. Neuropathological Features of Covid-19. N. Engl. J. Med. (2020) doi:10.1056/NEJMc2019373.
6. Wang, H.-Y. et al. Potential neurological symptoms of COVID-19. Ther. Adv. Neurol. Disord. 13, 1756286420917830 (2020).
7. Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019 – Yin – – Journal of Medical Virology – Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25888.
8. Duong, L., Xu, P. & Liu, A. Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020. Brain. Behav. Immun. 87, 33 (2020).
9. Coolen, T. et al. Early postmortem brain MRI findings in COVID-19 non-survivors. Neurology (2020) doi:10.1212/WNL.0000000000010116.
10. Kanberg, N. et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology (2020) doi:10.1212/WNL.0000000000010111.
11. Wood, H. New insights into the neurological effects of COVID-19. Nat. Rev. Neurol. 1 (2020) doi:10.1038/s41582-020-0386-7.
12. Fotuhi, M., Mian, A., Meysami, S. & Raji, C. A. Neurobiology of COVID-19. J. Alzheimers Dis. 76, 3–19 (2020).
13. De Felice, F. G., Tovar-Moll, F., Moll, J., Munoz, D. P. & Ferreira, S. T. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System. Trends Neurosci. 43, 355–357 (2020).

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