While the most widely known and acutely threatening element of COVID-19 is its respiratory effects, mounting evidence is revealing that COVID-19 may pose both short and long-term health risk to the brain and central nervous system. Research has revealed that many infections and the resulting immune system activity anywhere in the body may have lasting impacts on brain health. Increasingly, it is becoming apparent that there are less prevalent but distinctly neurological symptoms of the disease.
Because of the interaction among the virus, microbiome, immune system, and central nervous system, research is underway to determine the risks COVID-19 poses to neurological health.
First Signs
The first signs of COVID-19 affecting the Central Nervous System (CNS) occurred in late February in Wuhan, China. Health records there from 214 coronavirus-positive patients indicated that 36.4 percent showed signs of nervous-system related symptoms. The most common symptoms observed among these patients were ones which are typical of a viral infection, particularly in elderly populations: muscle pain, headaches, dizziness, or confusion. But other patients experienced more uncommon neurological syndromes including stroke, prolonged seizure, and loss of the sense of smell. In some of these cases, particularly those in which headaches were present, the neurological symptoms began days before a cough and fever set in (Molteni, 2020).
Other reports include symptoms of slow cognitive processing and Guillain-Barré syndrome (an affliction that can lead to temporary paralysis), plus instances of confusion and severe agitation. All of which point to disruptions in the nervous system (Nania, 2020).
More recent reports reveal another life-threatening neurological complication of the disease, Acute Necrotizing Hemorrhagic Encephalopathy is known to occasionally accompany influenza and other viral infections (Molteni, 2020). Current data suggests that neurological symptoms appear more frequently in severe cases as a patient’s condition declines. “New confusion or an inability to rouse” has been added by the US Centers for Disease Control (CDC) as a warning sign for which any ill person should seek immediate medical care (Mundell, 2020).
The source of these neurological symptoms is the current subject for many disease researchers, as this could have major effects on the course of treatment of those who exhibit these symptoms.
Inflammation
The body’s natural response to a health threat of any kind is inflammation. Get sick, your body induces a fever, injure yourself and your body swells with blood containing fresh immune cells. However, excessive inflammation which becomes chronic or prolonged is increasingly linked to disease. Basically the immune system begins to malfunction as a result of being overworked by stress and threats to health.
Some believe that similar to cases of the flu, brain damage which accompanies some COVID cases, may be caused by “cytokine storms”. Cytokines are inflammation-inducing molecules which when produced in excess, by a malfunctioning immune system, flood the brain causing a frenzy of friendly fire. This often leads to neuronal death and loss of function whether temporary (like in the case of a loss of smell) or permanent (like cases of stroke).
Scientists are working to determine whether this immune-overload is responsible for neurological issues observed in some cases of COVID-19, or if the coronavirus itself is invading the CNS directly. The answer will have vital implications for how doctors diagnose and treat COVID-19 patients (Molteni, 2020).
Neurodegenerative Disease
Some researchers suspect an infectious disease may play a role in the onset and progression of neurodegenerative diseases such as Parkinson’s. It is suspected that this relationship between infectious and degenerative brain disease may be mediated by the immune response. It will be hard to determine whether COVID-19 may be a cause or risk factor for neurodegenerative disease, but studying its effects on other CNS cells may help to reveal some clues.
The question is whether anosmia, the loss of smell which is sometimes a symptom of COVID-19, could be caused by the immune response. Neurons in the brain show receptors for immune cells called cytokines, and one theory suggests that cytokine interaction with olfactory (smell) cells may affect neural development and activity. In this case, disrupting the sense of smell. Research is being conducted to determine whether such an impact is occuring in response to COVID-19 and whether it may apply to neuron’s that perform other functions such as memory, learning, emotion, etc.
Research with Alzheimer’s patients investigating the Blood-Brain Barrier (BBB) could be revealing on how coronavirus affects the brain. One study is currently examining whether BBB permeability varies from person to person. For instance, there may be genetic differences which increase susceptibility of the BBB to viral entry. This is similar to the BBB model for Alzheimer’s disease which suggests greater susceptibility to plaque buildup in the brain due to carrying the ApoE gene. Uncovering this will help to determine potential risk factors. Another study seeks to determine whether an overactive cytokine storm immune response may increase permeability of the BBB and increased susceptibility of the central nervous system (CNS; MIT, 2020)
The Blood-Brain Barrier
A second theory for the neurological effects of COVID-19 suggests that the virus itself may be a brain invader. Typically the BBB protects the brain from infection and harm by selective release and intake of chemical components between the brain and bloodstream. This ensures that harmful infections don’t gain access to the brain and do major central-nervous system damage. Research is underway to investigate whether coronavirus may be able to evade or bypass that safeguard. Evidence for this possibility comes from documented case:
One young adult male in central Japan who initially tested negative for SARS-CoV-2 was rushed to the hospital in fits of seizures. The CT scans that followed showed inflammation in the brain. When subsequently tested for SARS-CoV-2 via spinal fluid, the test came back positive, demonstrating SARS-CoV-2 can invade the central nervous system.
Evidence points toward this possibility. While only a few dozen autopsies were ever performed during the 2003 SARS epidemic that killed 774 people, at least eight of them, showed evidence of the virus and its genome in the lungs, kidneys, digestive tract, spleen, and brain. Research suggests that the virus’ entry point into these diverse tissues may be a receptor called ACE2, which SARS-CoV uses to enter human cells.
Animal tests show that SARS-CoV spread to the brain via these receptors by way of the nasal cavity and olfactory neurons. (This is interesting given the symptom of anosia, loss of smell.) The virus spreads rapidly and eventually leads to death. This work was later replicated with the coronavirus that causes MERS. In both cases, the virus showed a preference for neurons in certain areas, including the brainstem which is involved in regulating involuntary respiration.
More recent research demonstrates that, similar to its genetic cousin, SARS-CoV-2 also uses ACE2 as a molecular doorway into human cells.
Interestingly, the human olfactory neurons do not express ACE2. Amnesia is typically one of the first symptoms to appear and occurs in 30-50 percent of those affected by COVID-19. However, it is not often accompanied by some of the more severe neurological symptoms and is typically a marker of a mild case. This suggests SARS-CoV-2 may be attempting to make its entrance into the brain via the olfactory CNS cells. If that were the case we would expect to see more serious symptoms in addition to anosia. The answer to this counterintuitive phenomenon could be highly revealing in terms of diagnostics and treatment of the disease (Molteni, 2020).
Stroke
Stroke is a major complication in some COVID-19 cases. Research is currently being conducted as to whether the root cause of these neural events lies in stress on the vascular system or the brain itself. One theory is that some strokes are triggered by COVID’19’s effects on blood clotting, causing thickening and coagulation which can lead to clots. Yet another theory suggests that the immune response to severe illnesses predisposes those affected to stroke events. This is the case of other viral infections like influenza. In these cases, oversaturation of tissues with cytokines causes small hemorrhages in many organs, including the brain, leading to a bleed (Mundell, 2020).
The exact cause of stroke activity in patients with severe cases of COVID-19 is another important area of current research into the effects of the disease on the brain.
Prenatal Exposure
Evidence suggests that the longer-term effects of the pandemic may be felt in future generations. Researchers have traced a pathway by which infection of a pregnant mother and fetal exposure can result in autism like symptoms in her offspring. Research in this vein is being conducted for COVID-19. Mouse models have revealed that immune cells in pregnant mice expressed elevated levels of the immune molecule cytokine IL-17a. Exposure to IL-17a directly influenced fetal brain development, causing neural circuits governing autism-like behavioral symptoms to develop improperly. It is suspected coronavirus may operate similarly.
One factor research shows may moderate infectious diseases’ effect on fetal development is maternal gut microbiome. The gut microbiome, a population of bacteria which guards and protects the health of the body, is a crucial part of the body’s immune system. Recent research continues to reveal how gut and brain health are linked via the immune system. This would apply to the COVID-19 pandemic as well. If the composition of the microbiome turns out to be a protective factor, then perhaps diet or probiotics could improve health outcomes, particularly the brain health of those infected with COVID-19. Perhaps pregnant mothers can boost their gut health as a protective factor for their fetus’ mental health. Research documenting gut microbiome composition and COVID-19 outcomes will help to answer these conjectures (MIT, 2020).
Conclusion
While published data on how frequently COVID-19 expresses neurological symptoms is still sparse, experts expect they occur in a minority of the 2 million infections worldwide. Answers to these issues are crucial for determining an appropriate line of treatment, which in some cases will be designed for the brain rather than the body.
Most pharmaceutical treatments do not pass through the BBB. If coronavirus is breaching that protective mechanism, effective treatments will need to do the same. Answers to these issues are important to the diagnostic process — altered brain function may increasingly need to be considered as a cause for testing in order to avoid misdiagnosis or false negatives. An inability by the medical community to recognize and identify these symptoms could result in patients being discharged and unknowingly exposing others to the virus and increasing risk for contamination.
Research highlights the vital need for preventative measures above and beyond social distancing.
It emphasizes the necessity for measures to increase and boost immunity on all levels. By maintaining a strong immune defence, one protects oneself not only from infection, but from falling ill to more severe symptomatology such as neurological impacts.
References:
MIT. (2020). How could Covid-19 and the body’s immune response affect the brain? Neuroscience News. https://neurosciencenews.com/coronavirus-immune-system-brain-16274/?fbclid=IwAR1wyE2FFF7tmM09wpZyfFcbVdhafy_fmKT_MEXHnSLqtzDjVSwD79sc9Oc
Nania, R. (2020). Effects of COVID-19 on the Brain. AARP.
https://www.aarp.org/health/conditions-treatments/info-2020/covid-19-brain-symptoms.html
Mundell, E.J.(2020). In Some Cases, COVID-19 May Harm the Brain. WebMD.
https://www.webmd.com/lung/news/20200402/in-some-cases-covid-19-may-harm-the-brain#1
Molteni, M. (2020). What Does Covid-19 Do to Your Brain? WIRED.
https://www.wired.com/story/what-does-covid-19-do-to-your-brain/
