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The “Long Haulers”: Long Lasting Impacts of COVID-19 on Brain Health

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The “Long Haulers”: Long Lasting Impacts of COVID-19 on Brain Health

Vol: | Issue: | Number: | ISSN#: 2563-5972

September 4, 2021 | Article No. 68

The “Long Haulers”: Long Lasting Impacts of COVID-19 on Brain Health

September 4, 2021 | Article No. 99


Ayesha Siddiqua MSc, PhD

Mohit Bhandari MD, PhD


  • A significant portion of individuals infected with SARS-CoV-2 experience post COVID symptoms for four weeks or longer.

  • Neurological complications have been observed in many survivors.

  • Even those who were not admitted to intensive care units for SARS-CoV-2 can experience these complications.

  • Current evidence shows those with pre-existing neurological challenges are at greater risk of experiencing complications.

  • Brain fog has been identified as a prominent long-term consequence of SARS-CoV-2 infection, characterized by poor attention, problem-solving, executive-functioning, and decision-making.

  • The mechanism through which the SARS-CoV-2 virus impacts the brain is still under study, although inflammation and lack of oxygen in the brain have been identified as two leading hypotheses.

  • There are no specific treatments for neurological complications of COVID-19, highlighting the importance of evidence-based preventive strategies to protect the health of individuals and save healthcare resources. 

“Although most people who get a COVID infection recover within a couple weeks, not long after the COVID-19 pandemic began, clinicians started seeing patients who took longer to improve or just didn’t seem to get better at all. These individuals are called “long haulers.”

Dr. Mark Kortepeter,

Professor of Epidemiology at the

University of Nebraska Medical Center (2021) (1)

“New research is now suggesting that there may be long-term neurologic consequences in those who survive COVID infections, including more than seven million Americans and another 27 million people worldwide. Particularly troubling is increasing evidence that there may be mild — but very real — brain damage that occurs in many survivors, causing pervasive yet subtle cognitive, behavioral, and psychological problems.”

Dr. Andrew E. Budson,

Chief of Cognitive & Behavioral Neurology,

Veterans Affairs Boston Healthcare System (2021) (2)

“A large portion of COVID-19 patients—possibly as high as 30 percent, according to an estimate from the National Institutes of Health— suffer some type of neurological or psychiatric symptoms. Even more troubling is that for many of these individuals, these cognitive issues can linger for weeks or months after the initial infection.”


(2021) (3)

Since the beginning of the COVID-19 pandemic, we have witnessed the harrowing realities of the SARS-CoV-2 infection – ranging from mild illness to severe illness that have landed many people in intensive care units and even led to death. Although majority of the infected people do indeed recover from COVID-19, there is emerging evidence about the long-term health consequences of this disease. In our previous OE Insight published in August 2020 (see “Long-Term Health Impact of COVID-19: Emerging Updates” for details), we discussed the evidence available at the time regarding the impact of COVID-19 on the different organ systems, including the neurological, pulmonary, cardiovascular, renal and hepatic systems. A year after our last publication, it is now clear that some people experience a wide range of post-COVID conditions that consist of new, returning, or ongoing health problems that can last for four or more weeks after first being infected with SARS-CoV-2 (4). Notably, people who do not have COVID-19 symptoms in the initial days and weeks after their infection can also have post-COVID conditions (4). These post-COVID conditions have been referred to as long COVID, long-haul COVID, post-acute COVID-19, long-term effects of COVID, or chronic COVID and the medical research community around the world is working hard to understand the reasons and risk factors for these long-term health consequences (4). One of the most troubling observations among people with COVID-19 has been the presence of diverse neurological challenges that often persist after the initial infection with SARS-CoV-2. For example, “brain fog”, which has been defined as poor attention, problem-solving, executive-functioning, and decision-making, has been observed in a significant proportion of people with long COVID (5). Examining the current evidence on the prevalence of these neurological challenges, as well as the demographic and clinical profiles of people who experience them after being infected with SARS-CoV-2 will not only help develop targeted therapeutic strategies, but also highlight the importance of preventing the onset of COVID-19 in the first place to prevent the debilitating long-term sequelae of this disease. 

“Why are viral infections of the brain so complex to understand? There are a number of underlying reasons. Much of experimental science today is based on testing hypotheses, with the expectation that if the hypothesis is correct, then the outcome is predictable. But even a single type of virus can act in an unpredictable manner in infected individuals, infecting different regions of the brain to evoke different symptoms, or causing CNS disease in only a small minority of infected individuals. Such diversity makes it difficult to provide consistent evidence in favor of viral origin hypotheses.”

Van Den Pol

(2009) (6)

“Encephalitis is inflammation of the active tissues of the brain caused by an infection or an autoimmune response…Infectious encephalitis is typically caused by a viral infection. Vaccines for measles, mumps, rubella and chickenpox have reduced the rate of encephalitis from these diseases, but other viruses can cause encephalitis. The most common causes of viral encephalitis are herpes simplex virus types 1 and 2, varicella zoster virus and enteroviruses, which cause gastrointestinal illness.”


Hopkins Medicine (7)

Viruses and the Brain: What Do We Know So Far?

SARS-CoV-2 is not the first virus that has been associated with neurological challenges. There is considerable evidence of other viruses impacting the brain (Exhibit 1). 

Exhibit 1: Virus impact on brain 

Scroll Horizontally >

Virus Impact
West Nile ~1 in 50 people who are infected develop a severe illness impacting the central nervous system, such as encephalitis (8)
<1 in 100 people who are infected experience serious neurological dysfunction (6)
Zika Infection during pregnancy can lead to microcephaly (where babies have smaller brains that may not have developed properly), along with other severe fetal brain defects (9)
Herpes Simplex Herpes simplex encephalitis is a complication that can emerge from infection (10)
Varicella-Zoster (virus causing chickenpox and shingles) Serious complications include infection or swelling of the brain (encephalitis, cerebellar ataxia) (11) (12)


There is increasing effort to understand the biological mechanisms through which SARS-CoV-2 impacts the brain. In a post-mortem case series of patients who died from COVID-19, an investigation of the brain tissues of these patients showed mild neuropathological changes, where pronounced neuroinflammatory changes in the brainstem was the most common finding (13). In a study investigating 3 different approaches to examine the ability of SARS-CoV-2 to infect the brain (including infection in human brain organoids, mouse models, and patient brain autopsies), there was evidence of the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2 (14). The findings of this study show that SARS-CoV-2 has high replicative potential in the brain and this virus also causes significant neuronal death in human brain organoids (14). However, there are also findings from autopsies of patients with COVID-19 who had neurologic abnormalities where chronic inflammation or marked neural changes typically associated with viral infection were largely absent, and the presence of viral genetic material was also minimal or absent (15). Findings of a recent study published in JAMA Neurology in June 2021 show the presence of megakaryocytes, which are large cells that make platelets and part of the body’s clotting system, in the brain capillaries of 33% of patients who died from COVID-19 (16). These cells are not supposed to be in the brain and have not been observed there before (16). It has been proposed that megakaryocytes can obstruct the flow through individual capillaries and lead to ischemic alternation, which in turn can lead to neurological impairment (16). 

While there is still limited evidence to understand the exact biological mechanisms through which SARS-CoV-2 impacts the brain, two main hypotheses have been proposed. First, it is hypothesized that the infection triggers inflammation in the brain – the pathways for which remain to be confirmed. Some mechanisms that have been proposed to trigger this inflammation include (3): 

  • Immune system becoming hyperactive to fight COVID-19 and producing autoantibodies, which are self-attacking antibodies that can lead to inflammation and blood clots.

  • Microglia, special immune cells in the brain that clear out damaged neurons, attacking healthy neurons. These immune cells get activated by signaling molecules called inflammatory cytokines found in patients with severe COVID-19. Inflammatory cytokines help regular the immune system, but too many of these molecules can be released in response to a viral infection. 

The second hypothesis for cognitive challenges is that COVID-19 can restrict blood flow to the brain and deprive it of oxygen, which is crucial for the brain to carry out all its functions (3). 

As the body of evidence on the impact of SARS-CoV-2 on brain health continues to grow, it has been noted that the study of neurological disease in patients with COVID-19 is challenging for several reasons, including: 1) a small subset of patients exhibiting neuroinvasion, 2) lack of technology to sample central nervous system tissues directly, and 3) distinguishing between direct neuroinvasion versus systemic viremia (a medical condition where viruses enter the bloodstream) in the brain (14). Furthermore, it has been noted that the sample size of post-mortem studies is small, thus the generalizability of their findings is still largely limited. These post-mortem studies only illustrate the final picture of the disease and show what happens in the sickest patients (17). For example, since most virus in the lung is already cleared by the time a patient dies, it has been hypothesized that the same may be true for the brain as well (17). 

“The expectation was that all these people in the ICU were going to have really long protracted recovery periods…The big surprise was the people who never required hospitalization that are having persistent trouble.”

Dr. Walter Koroshetz,

Director of the National Institute of

Neurological Disorders and Stroke,

National Institutes of Health (3)

“People who had been hospitalised showed substantial scaled global performance deficits (for cognition) dependent on whether they were (−0.47 standard deviations (SDs) N = 44) vs. were not (−0.26 SDs N = 148) put onto a ventilator. Those who remained at home (i.e., without inpatient support) showed small statistically significant global performance deficits (assisted at home for respiratory difficulty −0.13 SD N = 173; no medical assistance but respiratory difficulty −0.07 SDs N = 3,386; ill without respiratory difficulty −0.04 SDs N = 8,938).”

“On the worst extreme of the spectrum, people who had gone to hospital (for COVID-19) and been put onto a ventilator showed the largest underperformance cognitively speaking. These individuals had more trouble with reasoning, problem solving, and spatial planning on the test compared to people of their same age group and educational backgrounds who hadn’t been hospitalized with COVID-19. The difference was similar to the average cognitive decline seen over 10 years of aging.”

Findings from

“Cognitive deficits in people who have recovered from COVID-19”,

published in the Lancet on July 22, 2021 (18)

“It’s fairly common for patients admitted to the ICU to suffer lasting cognitive issues… about a third of ICU patients who have acute respiratory failure have symptoms that are similar to those of traumatic brain injury…One reason is because patients are often sedated in the ICU to reduce anxiety and discomfort, such as that caused by mechanical ventilators. Sedatives slow down brain activity and in doing so can cause delirium, a sudden change in mental status that leads to confusion and disorientation. Patients have trouble focusing or they may not know where they are; it’s a condition that can last hours, days, or even weeks”.


(2021) (3)

Evidence So Far: COVID-19 Does Matter for Brain Health

Although our current understanding of how SARS-CoV-2 infection manifests to influence the brain is limited, the evidence so far suggests neurological impact associated with COVID-19 is undeniable. Hampshire et al. (2021) found that people who recovered from COVID-19, including those who no longer reported any symptoms, demonstrated significant cognitive deficits compared to controls after controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety (18). In fact, these deficits were of substantial effect size for those who were hospitalized as well as those who were not hospitalized but had confirmation of SARS-CoV-2 infection – with increasing degrees of cognitive underperfomance observed as the level of medical assistance received for COVID-19 respiratory symptoms increased – where patients hospitalized and put on a ventilator showed the greatest deficit (-0.47 SD). Importantly, analysis of markers of premorbid intelligence did not support the presence of the observed differences prior to infection. 

Findings of a survey of people with suspected and confirmed COVID-19, with illness lasting over 28 days, showed that cognitive dysfunction was among one of the most frequent symptoms after 6 months (5). Specifically, 85.1% of the participants (n=3203) reported experiencing brain fog and cognitive dysfunction, which included poor attention, executive functioning, problem solving, and decision making. Among 31.2% of the participants, the onset of brain fog/cognitive dysfunction was observed in the first week of symptoms. Moreover, the prevalence of cognitive dysfunction increased over the first three months, with 66.7% at the peaking point, then declined slightly in the following months. Overall, more than half of the participants (55.5%) experienced cognitive dysfunction during the seventh month post-infection. The probability of memory loss also increased in the first few months and half of the participants exhibited memory symptoms in the seventh month. Additionally, 88% of participants experienced cognitive dysfunction, memory loss, or both at similar rates across all age groups. Other neuropsychiatric symptoms reported in this survey included sensorimotor symptoms (91.4%), speech and language issues (48.6%), headaches (77.0%), emotion and mood (88.3%), taste and smell (57.6%), hallucinations (23.2%), and difficulty with sleep (78.6%). 

In a prospective study of patients hospitalized for COVID-19, abnormalities in functional outcomes, activities of daily living, anxiety, depression, and sleep were observed in more than 90% of patients six months after hospitalization (19). Importantly, patients who had a history of neurological complications were at a higher risk of developing new ones while they were hospitalized for COVID-19. 

Currently in the U.S. alone, millions of individuals have developed lasting neurological challenges long after their initial SARS-CoV-2 infection, with growing concerns regarding long-term implications – including their ability to work at their pre-infection level which can eventually have a tremendous impact on the economy (3). Current evidence does support these concerns – findings of the abovementioned survey showed that cognitive dysfunction/memory loss left 86.2% of the participants feeling mildly to severely unable to work (5). As we have mentioned earlier, long COVID is defined as the condition characterized by symptoms that last for four or more weeks after the initial SARS-CoV-2 infection, and to our knowledge, there is a paucity of large-scale population-based research examining patients for long periods of time (e.g., more than a year) to examine the long-term sequelae. As we proceed through the pandemic and more evidence becomes available, we will be better positioned to appreciate the true impact of COVID-19 on brain health in the long-term. 

“The best way to prevent post-COVID conditions is by getting vaccinated against COVID-19 as soon as you can. COVID-19 vaccination is recommended for all people ages 12 years and older, including if you had COVID-19 or a post-COVID condition.”

Centers for

Disease Control and Prevention (4)

“For those (with long COVID) who returned to their job, respondents reported experiencing relapses triggered by the mental exertion and stress of work, often needing to go back on leave. This emphasizes the importance of all patients having adequate time off to recover, being able to qualify for disability benefits if long-term assistance is needed, and receiving accommodations at work including telecommuting, flexible hours, and phased returns.”

Davis et al

(2021) (5)

Treating Neurological Symptoms of COVID-19: Trying What Works

Thus far, there is not one specific approach for treating the neurological symptoms of COVID-19. Instead, clinicians are turning to a wide range of therapeutic options to support patients with their recovery, including (3): 

  • Cognitive therapy

  • Occupational therapy

  • Speech-language therapy 

The lack of definitive therapeutics can be attributed to the lack of knowledge about the exact biological mechanisms through which SARS-CoV-2 infection effects the brain. While many are relying on anecdotal data to figure out what helps patients and what does not, the journey to determine concrete treatments for neurological complications from COVID-19 is still a long one. 

“Hannah Davis contracted COVID-19 in March 2020, the early days of the pandemic. At the time, the New Yorker was a healthy, 32-year-old freelance data scientist and artist. But unlike many people who come down with the disease, Davis’s first sign of infection wasn’t a dry cough or fever. Her first symptom was that she couldn’t read a text message from a friend…More neurological issues followed. She developed sudden and severe headaches. Her attention span suffered…She had trouble concentrating on everyday tasks like cooking...She failed to look both ways while crossing the street, narrowly missing traffic. She’d never had any of these issues before COVID-19.”

“In one post-COVID-19 clinic at Northwestern Memorial Hospital in Chicago, researchers found that many individuals with long COVID were never hospitalized yet had neurologic symptoms lasting longer than six weeks. Out of 100 patients, the most common neurologic manifestations were brain fog, and numbness and tingling, which affected 81 percent and 60 percent of patients respectively, according to a study published in March. These individuals also performed worse in attention and working-memory cognitive tasks compared to people their age who hadn’t gotten sick with COVID-19.”


(2021) (3)

Compromising Brain Health with COVID-19: Is It Worth the Risk?

The main message that is clear from the available evidence is that the neurological complications from COVID-19 are not to be taken lightly given their ability to significantly compromise the well-being and quality of life of those infected. Given the absence of any widely agreed upon interventions to treat these neurological complications, the importance of preventive measures is emphasized. Taking a proactive and evidence-based approach to prevent SARS-CoV-2 will not only protect the health of individuals, but also reduce the burden on healthcare systems that are already struggling to keep up with the pandemic. 


Ayesha Siddiqua MSc, PhD

Ayesha Siddiqua is a Senior Epidemiologist working for the Public Health Agency of Canada. She is also an Assistant Professor (Part-Time) in the Department of Health Research Methods, Evidence, and Impact in the Faculty of Health Sciences at McMaster University.

Mohit Bhandari MD, PhD

Dr. Mohit Bhandari is a Professor of Surgery and University Scholar at McMaster University, Canada. He holds a Canada Research Chair in Evidence-Based Orthopaedic Surgery and serves as the Editor-in-Chief of OrthoEvidence.


1.    Kortepeter M. Could You Have Long Covid? Here Are The Common Signs And Symptoms [Internet]. 2021 [cited 2021 Sep 2]. Available from:
2.    Budson A. The hidden long-term cognitive effects of COVID-19 [Internet]. Harvard Health. 2021 [cited 2021 Sep 2]. Available from:
3.    Mullin E. How does COVID-19 affect the brain? A troubling picture emerges. [Internet]. Science. 2021 [cited 2021 Sep 2]. Available from:
4.    CDC. COVID-19 and Your Health [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2021 Sep 2]. Available from:
5.    Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine [Internet]. 2021 Aug 1 [cited 2021 Sep 2];38. Available from:
6.    van den Pol AN. Viral infection leading to brain dysfunction: more prevalent than appreciated? Neuron. 2009 Oct 15;64(1):17–20.
7.    Johns Hopkins Medicine. Encephalitis [Internet]. [cited 2021 Sep 2]. Available from:
8.    CDC. Symptoms, Diagnosis, & Treatment | West Nile Virus | CDC [Internet]. 2021 [cited 2021 Sep 2]. Available from:
9.    CDC. Health Effects & Risks of Zika Infection [Internet]. CDC. 2014 [cited 2021 Sep 2]. Available from:
10.    National Organization for Rare Diseases. Encephalitis, Herpes Simplex [Internet]. NORD (National Organization for Rare Disorders). [cited 2021 Sep 2]. Available from:
11.    CDC. Chickenpox complications [Internet]. Centers for Disease Control and Prevention. 2021 [cited 2021 Sep 2]. Available from:
12.    Mayo Clinic. Shingles - Symptoms and causes [Internet]. Mayo Clinic. [cited 2021 Sep 2]. Available from:
13.    Matschke J, Lütgehetmann M, Hagel C, Sperhake J, Schröder A, Edler C. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series - The Lancet Neurology [Internet]. 2020 [cited 2021 Sep 2]. Available from:
14.    Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brainNeuroinvasion of SARS-CoV-2 in humans and mice. Journal of Experimental Medicine [Internet]. 2021 Jan 12 [cited 2021 Sep 2];218(3). Available from:
15.    Mukerji SS, Solomon IH. What can we learn from brain autopsies in COVID-19? Neurosci Lett. 2021 Jan 18;742:135528.
16.    Nauen DW, Hooper JE, Stewart CM, Solomon IH. Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol. 2021 Jun 1;78(6):760–2.
17.    Zimmer K. COVID-19’s Effects on the Brain [Internet]. The Scientist Magazine®. [cited 2021 Sep 2]. Available from:
18.    Hampshire A, Trender W, Chamberlain SR, Jolly AE, Grant JE, Patrick F, et al. Cognitive deficits in people who have recovered from COVID-19. EClinicalMedicine [Internet]. 2021 Jul 22 [cited 2021 Sep 2];0(0). Available from:
19.    Frontera JA, Yang D, Lewis A, Patel P, Medicherla C, Arena V, et al. A prospective study of long-term outcomes among hospitalized COVID-19 patients with and without neurological complications. Journal of the Neurological Sciences [Internet]. 2021 Jul 15 [cited 2021 Sep 2];426. Available from:

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