• 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. 

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. 

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). 

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). 

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. 

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. 

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.