Potential long-term implications of COVID-19 infection in the brain


As COVID-19 spreads throughout the country, much attention has been paid to the devastating effects of the virus on the lungs. But doctors are learning how the virus may affect other organs, including the brain.

Some patients with COVID-19 have had neurological symptoms, which may include an increased risk of stroke. Other symptoms may include headache, loss of the senses of smell and taste, hallucinations, vivid dreams, meningitis and seizures.

Neurologists Elyse Singer, MD and David Liebeskind, MD, explain what is known — and not yet known — about the neurologic complications of COVID-19.

Dr. Singer is the director of the Neuro-Infectious Diseases Program at UCLA, as well as the founder of the National Neurological AIDS Bank. Dr. Liebeskind is director of the UCLA Stroke Center.

Is there evidence that this virus can infect the brain and nervous system?

Dr. Singer: Yes. Reports are beginning to trickle in of patients who have had strokes, brain swelling, seizures and other neurological problems, but it is not certain that this is a direct effect of the virus. We know that this type of coronavirus can invade the brain and cause disease. For many respiratory coronaviruses, that’s uncommon. However, this particular virus is closely related to the SARS virus, which has been found in the nervous system.

Dr. Liebeskind: In terms of direct neurological involvement, the best way to think about this is in terms of what path the virus can take to get into the nervous system. The lack of smell and taste that occurs early on has been linked to invasion of the olfactory bulb, the part of the brain that processes smell, and that may be a way the virus can directly penetrate and get into the nervous system.

If a person experiences loss of smell or taste, does that mean the virus has infected their nerve cells?

Dr. Singer: Loss of smell and loss of taste is turning out to be a very common early symptom of COVID-19. Experience with previous coronaviruses indicates they can easily infect the nasal epithelium, the lining of the nose and mouth. These tissues are very rich with something called the ACE2 receptor, which is what the virus binds to in order to infect the cell.

In studies of animals with this virus, and in humans with other coronaviruses, researchers have been able to demonstrate that the virus can infect the olfactory nerve, which goes from the nose into the brain. That might be one way that it gets into the brain. It doesn’t necessarily mean you’ll get a horrible brain infection, because you have an immune system in your brain.

I’ve actually talked to physicians who have had COVID-19, and they weren’t that sick, but their first symptom was loss of taste and smell, and it preceded the other symptoms by a number of days.

Could people who have mild cases of COVID-19 and recover go on to develop neurological complications later?

Dr. Liebeskind: That is a scenario that does exist with some viral disorders, and we don’t know yet how this coronavirus is likely to behave. One thing I predict we’ll hear more about in the next two or three weeks, there are some reports that have come out in the last several days of significant effects on the central nervous system, in terms of hallucinations, or wild dreams, or other alterations in mental status.

Such symptoms don’t evolve from nothing, but the question is, does that represent infection of the CNS, or secondary involvement somehow?

The initial focus was on breathing and respiratory complications, and it’s taken a couple months, but people are starting to delve into secondary impacts, either neurological complications or how it affects patients with neurologic disorders.

Dr. Singer: I think it’s too early to say, and I certainly hope it’s not the case. There is another issue, which is the extreme stress that COVID-19 places on the person’s psychological behavior.

Many people who have COVID-19 become extremely anxious, and if they have to be hospitalized and put on a respirator, this is an incredibly stressful and frightening experience. There is likely going to be some element of PTSD in COVID-19 survivors after going through the ventilator experience.

What role does inflammation play in how COVID-19 affects the brain?

Dr. Singer: In almost every neurodegenerative disease, there is a role for inflammation in the brain and in general, inflammation makes things worse. In COVID-19, people get something called a cytokine storm, where their body pours out inflammatory chemicals in an attempt to rid itself of the virus.

However, these chemicals can have long-term effects on the body, and probably on the brain as well. Because of the intense systemic inflammation, which can cause many organs to fail, there’s also the possibility that some of the neurological problems are due to other occurrences in the body, such as a drop in blood pressure, sepsis, fever and abnormal coagulation of the blood, which could lead to stroke.

Are there other ways that COVID-19 can cause neurological damage?

Dr. Liebeskind: The other very unusual impact of COVID-19 is the nature of the stroke cases that we’re seeing. There appears to be a clear link with a clotting disorder that will increase the tendency to have blood clots form in the larger vessels, and cause stroke in relatively younger patients than we would normally expect. This has been suggested from cases in Italy, New York, and other locations. In some severe cases you see clotting in the blood vessels of the heart and lungs, and they’ve tried treating that with blood thinners. Experience has been limited, because their attempted use has been in the most severe cases, who have a high mortality rate, so it’s hard to determine whether these medications are working or not.

Are patients with existing neurological disorders at increased risk of complications from COVID-19?

Dr. Singer: We don’t know, but I would be very concerned about that. Obviously, people with severe cardiovascular or cerebrovascular disease would be at higher risk of stroke than other patients. Many people with neurologic diseases, such as multiple sclerosis, are on treatment that suppresses the immune system, and we don’t know how that is going to interact with a COVID-19 infection. If you go to a neurology clinic right now, something like 10-20% of our patients are immunosuppressed, because they have an inflammatory disease. We give them a medicine to get rid of their inflammation, but that also gets rid of their natural protective mechanisms against viruses and bacteria.

Dr. Liebeskind: It’s quite complex, because a lot of neurological disorders may limit one’s ability to either communicate or to walk or to function normally. That may predispose those individuals to infection. That is a great concern. In general, individuals with neurologic disorders often are seen to be more severely affected, and therefore the benefit of interventions may not be that great. That’s a bias we have to avoid as much as possible.

What kind of research is going on now on this problem?

Dr. Singer: Obviously, this is a very interesting area, and I think that it’s getting a lot of people in neurology engaged. Unlike other health problems, it’s affecting everybody. There are people in our department doing niche research, and basic science research, who are rather removed from taking care of sick humans in a clinic, that are jumping into this because it’s affecting their lives. I see a tremendous amount of motivation for people to get engaged with trying to solve this problem.

Dr. Liebeskind: Every single center is looking at their data on strokes during this period as it relates to a similar period from a year ago, to see how it’s impacting not just the volume of stroke patients they see but also the nature of the stroke patients and the care they’ve been given. In the coming weeks and months, there’s going to be a lot of data reported on that.

I think that some of the most strategic research is going to revolve indirectly around the pandemic, and that’s going to be around the use of telemedicine. Is it simply easier and more effective, and more appreciated by patients, to be seen in telemedicine?

I think the answer will be yes, but proving it will be a big battle. The question will arise, do we return to the way we used to do things, or do we stay with the new normal?

Those are societal questions that relate to public health and health care delivery on a larger scale. There are positive and creative and productive side effects of this pandemic, and I would say that the maturation and graduation of telemedicine during this period, I applaud, and I would recognize as a significant achievement and a productive step forward.

Since 11 March 2020, The World Health Organization has characterized coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (1) as a pandemic. The outbreak started in the city of Wuhan in China and quickly spread worldwide. Coronaviruses have previously caused two large-scale pandemics in the past two decades, SARS (2) and Middle East respiratory syndrome (MERS) (3).

SARS-CoV-2 is closely related to other CoV found in zoonotic reservoirs, such as bats, camels, and pangolins (4). Since SARS-CoV-2 is considerably more infectious than both SARS-CoV and MERS-CoV, many countries have determined a strict policy of “shelter-in-place” to contain the virus spread through social contagion.

However, many questions remain regarding the clinical outcomes of human infection by SARS-CoV-2, including the possibility of the development of neurological disorders (5).

Some viruses possess a tropism for neural tissue and are thus classified as neurotropic (e.g., herpes simplex virus type 1, rabies virus). Those viruses enter the brain through various routes, including retrograde axonal transport along axons, hematogenous spread via the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier, meningeal-cerebrospinal fluid barrier, via direct infection of endothelial cells or through spreading of infected leukocytes to the brain across the BBB (6).

Once in the brain, these viruses disrupt the complex organization of neural circuits either directly by neuronal damage or indirectly through host immune response pathways, causing immediate, or delayed neuropathology and neurological manifestations (6) (see below).

In the short-term, neurotropic viral infections can cause inflammation of the brain parenchyma and lead to encephalitis or brain-targeted auto-immune responses in susceptible individuals (7).

Possible long-term effects on hosts can include alterations on emotional and cognitive behavior, as shown in experimental animals through persistent alterations in the expression of genes involved in the regulation of synaptic activities in key brain areas (8).

The axonal transport of neurotropic viruses can also turn intrinsically disordered proteins, such as α-synuclein (α-syn), into promiscuous binders that can form toxic aggregates and travel along neuronal pathways and cause cell death in areas of the brain (9).

While the most common symptoms of COVID-19 at the onset of illness include fever, fatigue, dry cough, myalgia, and dyspnea, other less common symptoms are headache, abdominal pain, diarrhea, nausea, and vomiting (10).

Furthermore, it’s been recently reported that most patients also complain of impairment of both olfactory and gustatory perception (11) and those are being considered early markers of COVID-19 infection.

Though there is longstanding evidence that human coronaviruses, such as SARS-CoV-2, can spread to the brain from the respiratory tract (5, 12, 13), the occurrence of gastrointestinal symptoms (14) suggests that the gastrointestinal system is a possible route of invasion and transmission to the enteric nervous system (ENS) (see Figure 1).

While the effects of COVID-2019 on olfactory and gustatory perception may be transient, the possibility that viruses and other contaminant agents can be the initiating etiology of neurodegenerative diseases such as Parkinson’s disease (PD) has been raised before (16).

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Figure 1
SARS-CoV-2 invades the body through the nasal and oral cavities and may be transmitted to the brain via the olfactory bulb and the enteric nervous system (ENS). In the brain, the virus can cause neuroinflammation by microglial activation and also synucleinopathy that can be transmitted prion-like to other brain regions via the vagus nerve [adapted from Fonseca et al. (15)], from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License (https://www.smart.servier.com/), and Patrick J. Lynch, licensed under a Creative Common Attribution 2.5 License (https://commons.wikimedia.org/wiki/File:Head_olfactory_nerve_-_olfactory_bulb_en.png).

Parkinson’s disease (PD) is a common neurodegenerative disorder associated with the progressive loss of dopaminergic neurons located in the midbrain nucleus substantia nigra pars compacta (SNpc) due to the accumulation of α-synuclein (α-syn) aggregates.

The Braak hypothesis (9) for the etiology of sporadic Parkinson’s disease (PD) proposes that a neurotropic virus invading neural tissue through the nasal cavity and the gastrointestinal tract causes α-syn to turn into a promiscuous binder and be transmitted, prion-like, to key areas such as the SNpc (15). Interestingly, the prodromal or preclinical phase of PD is also characterized by olfactory and gastrointestinal symptoms (17).

The cellular receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), which has a role in the metabolism of angiotensin peptides involved in the control of vasoconstriction and blood pressure (18). ACE2 is found in several tissues associated with cardiovascular function, but also in the brain, including brainstem nuclei involved with cardio-respiratory regulation (19, 20).

Thus, respiratory problems in COVID-19 patients could also derive from the direct action of SARS-CoV-2 in respiratory control nuclei in the Brain (21). Through its binding to ACE2 receptors, SARS-CoV-2 may spread transneuronally to distant brain targets, similar to other neurotropic viruses (22), as predicted by the Braak hypothesis.

Thus, recovery may be an ambiguous term regarding COVID-19. Though recovery from the acute phase of the infections is certainly a relief in public health terms, helping to stop the spreading of the infection, one must consider the long-term neurological effects of the disease.

This discussion has been conspicuously lacking in pertinent forums and needs to be adequately addressed as an important concern by public health officials. Many authorities are focusing only on the risks posed to the elderly and immunocompromised subjects, downplaying the threats to younger populations.

Though the neurological risks described in the present work are particularly important to the elderly, due to age-related degenerative processes in the immunologic system and the brain, the population needs to be alerted to the chronic neurological risks during the pandemic and maintain social distancing for as long as it is necessary.


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