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Long Covid and the Brain

A 63-year-old woman comes to the emergency department one evening complaining of crushing chest pain that radiates down her left arm. On physical examination she appears in acute distress and her heart and respiratory rates are elevated. The emergency room physician suspects she is having a heart attack. Her electrocardiogram (EKG) and the results of a blood test called troponin confirm the diagnosis and the woman is moved to the cardiac care unit for further treatment.

Medical diagnoses are based on many factors; in the above scenario, several, including the patient’s report of symptoms, physical examination, and laboratory testing, all come together to confirm a likely diagnosis that leads to the initiation of a treatment plan. In the case of a heart attack, objective biological markers—the EKG and blood test—make the diagnosis initially suspected on the basis of the patient’s subjective report relatively straightforward and reliable. Unfortunately, there are many instances in which making a diagnosis is much more difficult or even impossible because there are no objective markers to confirm a subjective report. This may be the case with the illness now called Long Covid.

Around the world, at the time of this writing, about 1.8 million people have recovered from COVID-19. Studies suggest that at least one in ten of them—and possibly many more—identify having symptoms of fatigue, “brain fog” and other forms of cognitive dysfunction, headaches, muscle aches, chest pain, and breathlessness weeks or months after recovering from the acute bout of infection, even if their original illness was only mild. Although there is no official, consensus agreement on diagnostic criteria yet, if these symptoms linger more than four weeks after recovery from acute COVID-19, the individual is now commonly said to have Long Covid, also known as Post-Acute Sequelae of SARS-CoV-2 infection or PASC. Children and adults both seem susceptible, with middle aged people more likely to be affected than younger or older people and women more likely than men.

The diagnosis of Long COVID, or PASC, is turning out not to be one of those straightforward ones, like the heart attack scenario we described earlier, but difficult because of the lack of objective markers of illness. The symptoms of Long Covid are all non-specific and common to many illnesses—fatigue and “brain fog” are seen in a host of disorders. Millions of people will say they feel as if they have the symptoms of Long Covid, some to the point of experiencing extreme debilitation and inability to function. How to be sure which people indeed have an illness directly related to the COVID-19 virus and which are suffering from a different condition is certain to be challenging.

Another Contested Illness?

The concern with Long Covid is that it will turn into another “contested Illness,” an illness in which there is no clear physiological cause, leading some medical experts to doubt the diagnosis. Examples include chronic Lyme disease, chronic fatigue syndrome, and fibromyalgia. This in turn could lead to various unproven and even dangerous interventions being recommended as treatments for Long Covid. We already see the making of a controversy in a recent article in the journal Science by Long Covid researcher Nisreen A. Alwan. Titled “The road to addressing Long Covid,” the article notes that “Long Covid is likely the first illness in history that has been defined by patients through social media platforms such as Twitter and Facebook.” Alwan writes that “A common theme” about Long Covid is “lack of recognition by the medical profession” and points to “people struggling to make sense of their symptoms and forming their own groups.” All of this sets the stage for an adversarial relationship between people who believe they are suffering from a syndrome caused by the COVID-19 virus and physicians, the kind of relationship that exists for other contested illnesses.

To be sure, Long Covid follows an illness of known physiological cause, COVID-19. Post-viral syndromes are well-described in the medical literature and it is therefore not a surprise that some people will complain of a variety of non-specific symptoms following a recovery from COVID-19, but the cause of these symptoms is not clear. In the case of Long Covid, experts believe it is unlikely that continued viral infection is responsible, because evidence so far suggests that the virus is cleared from the body after a few weeks. Nor does it seem likely that organ damage is the cause of Long Covid symptoms in many cases because there is apparently no relationship between the severity of an individual’s COVID-19 illness and Long Covid symptoms; even people who had only mild COVID-19 seem susceptible to Long Covid.

Is the Brain Involved?

People who suffer from a contested illness understandably balk at the notion that “it is all in your head,” as this implies that what the person is experiencing is somehow not real. We are clear that people with these conditions are experiencing real and very distressing symptoms. At the same time, we do think that when symptoms like fatigue, “brain fog,” memory loss, and poor concentration are at play—as they are prominently in the case of Long Covid— and when rates of depression are elevated after recovery from COVID-19, that it is important to consider whether the central nervous system, composed of the brain and spinal cord, are directly involved.

There is no question that the brain can be involved in acute COVID-19, as conditions like stroke and delirium do sometimes occur. However, it is still unclear how the virus affects the brain during both acute COVID-19 and Long Covid. We consider three possibilities.

The first would be if SARS-CoV-2 directly infected the main cells in the central nervous system, called neurons. Polio virus, rabies virus, and West Nile virus are examples of viruses that can directly infect neurons, but little if any SARS-CoV-2 virus has been detected in postmortem brains of people who succumbed to COVID-19 and it is not thought that it is capable of infecting neurons itself. It may, however, directly infect a second type of brain cell, called the astrocyte, which supports brain function, including the work of neurons. There is early evidence for direct invasion of astrocytes by SARS-CoV-2 and this could be one way that it produces symptoms like fatigue.


Astrocytes are cells in the brain that support a number of functions, including the work of neurons. There is evidence that they may be directly infected by the COVID-19 virus. Here they are shown tethered to small blood vessels (source: Shutterstock).

A second mechanism is immunological. COVID-19 causes significant and sometimes overwhelming activation of the immune system. This includes the release of molecules and cells that cause inflammation. In the brain, immune cells called microglia may be activated during COVID infection. Microglia cells then release these inflammatory molecules and these can have ongoing adverse effects on cognition and mood.

Microglial cells in a brain region called the hippocampus are shown here. They are the brain’s immune cells and when activated release inflammatory molecules that can cause cognitive dysfunction and fatigue (source: Shutterstock).

A third mechanism is vascular. SARS-CoV-2 may cause significant damage to small blood vessels in the brain, leading to reduced blood flow and leakage of blood into surrounding brain tissue. This again could cause neurological and psychiatric symptoms that persist even beyond resolution of the acute infection.

The problem with these three mechanisms is that none of them is detectable in the brains of living human beings. Hence, while astrocyte infection, immunological activation, and vascular damage are all plausible mechanisms for the neurological and psychiatric symptoms of Long Covid, we do not have laboratory tests or imaging to provide objective markers in order to make a diagnosis. That means that the diagnosis of Long Covid will rely mainly on subjective reports, introducing the possibility for controversy about its existence, nature, and treatment.

It is fortunate that the National Institutes of Health have announced there will be substantial research funding available for Long Covid. Hopefully, this will help scientists and clinicians come up with more rigorous diagnostic criteria. Although regarded as a long shot, maybe a biological marker will be discovered to help confirm diagnosis. For now, we can only advocate that both the public and the medical profession keep open minds, recognizing that the diagnosis of Long Covid will be complex and difficult, and trying not to make it the subject of another source of conflict.

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