A new research review has analyzed six potential causes for one of the most common yet elusive long Covid symptoms. Brain fog is an often debilitating condition affecting executive function, the set of mental abilities that includes focusing attention, holding information in the mind, and blocking out distractions.
Despite affecting many with certain chronic illnesses and post-viral syndrome for years, the condition has been poorly understood from a neurobiological and neuropsychological perspective with few tools for diagnosis or treatment. Doctors often diagnose it using the Montreal Cognitive Assessment, which was originally designed to assess elderly dementia patients. Patients are also assessed against the average population, not against their previous baselines. Neither are effective diagnostic tools for the diverse population affected.
However, brain fog is receiving renewed attention and research focus because of its prominence in long Covid patients, bringing hope for better diagnostic tools and treatment. Researchers at Yale and Stanford University reviewed the literature relevant to cognitive dysfunction after Covid-19 infection and analyzed six potential causes for covid-related cognitive dysfunction.
1. Respiratory inflammation causing neuroinflammation and neural dysregulation
The first potential cause identified is that the immune response by the respiratory system to SARS-CoV-2 may cause neuroinflammation, thereby increasing cytokines, chemokines, and immune cell trafficking in the brain and inducing reactive states of resident microglia and other immune cells in the brain and brain borders. The white-matter-selective microglial reactivity which appears after SARS-CoV-2 infection is also observed in other diseases such as cancer-related cognitive impairment.
Deciphering the precise mechanisms by which respiratory inflammation triggers each aspect of neuroinflammation will be critical for developing therapeutic interventions to mitigate the effects of Covid-19 and other respiratory infections on the brain.
2. Direct infection of the brain
Direct infection of the central nervous system by SARS-CoV-2 is possible, neuroinvasive infection can contribute to acute and chronic brain pathology through neuroinflammatory and cytotoxic mechanisms. Cases of SARS-CoV-2 neuroinvasion have been reported, with SARS-CoV-2 detected in brains, but durable infection was found to be uncommon amongst the research reviewed. This suggests that direct central nervous system infection is rare and does not account for the majority of neurological symptoms associated with Covid-19.
3. Autoimmune response
Another possibility is that SARS-CoV-2 may evoke an autoimmune response against the nervous system. A review of the research points out that while autoimmune encephalitis can and does occur, it remains to be determined whether anti-neural antibodies occur commonly in mild to moderate Covid-19 and whether subclinical autoimmunity contributes to chronic neuroinflammation and lasting cognitive impairment.
4. Reactivation of latent herpesviruses
The reactivation of latent herpesviruses, like the Epstein-Barr virus, may also trigger neuropathology. There are many viruses that remain latent in the brain. Epstein-Barr virus is a highly prevalent γ-herpes virus that persistently infects over 90% of the human population. Epstein-Barr virus may contribute to neuroinflammation in long COVID patients due to viral pathogenesis (viral proteins and viral transcription factors) and/or host immune response to EBV infection (cytokines, Th2 responses, and autoantibody production). A study that followed 309 Covid-19 patients found that Epstein-Barr virus at the time of Covid-19 diagnosis was one of the four predictive factors for long Covid development.
The herpes simplex virus type 1 and 2 can also result in herpes encephalitis, a life-threatening brain infection producing behavioral changes, seizures, and altered levels of consciousness. There are rare cases of herpes encephalitis occurring within the weeks following Covid-19 diagnosis. These studies suggest that certain herpesvirus reactivation is somehow more frequent in those who develop long Covid and could provide clues for investigation.
5. Cerebrovascular and thrombotic disease
Another theory explored by Iwasaki and Monje is that cerebrovascular and thrombotic disease may disrupt blood flow, disrupt blood-brain-barrier function, and contribute to further neuroinflammation and ischemia of neural cells. Covid-19 increases the risk of ischemic stroke and other thrombotic complications, highlighting the potential thrombotic and vascular effects of Covid-19 on the brain.
Finally, pulmonary and multi-organ dysfunction occurring in severe Covid-19 can cause hypoxemia, hypotension, and metabolic disturbances that can negatively affect neural cells causing cognitive impairment. Critical illness in general is associated with a high rate of persistent cognitive impairment. This hypothesis requires further testing but it explains the increased rate and severity of chronic neurological complications in people who survived more severe acute disease.
All of these possible causes of brain fog and other neurological symptoms related to Covid-19 are not mutually exclusive, and many long Covid patients may be experiencing a combination, with varying frequency and timing. Based on the literature review, brain inflammation triggered by the immune response to the respiratory system infection and consequent dysregulation of neural homeostasis and plasticity is most likely a common cause in those who have experienced mild disease.
Brain fog and other neurological symptoms associated with Covid-19 have a profound effect on patients’ lives, often preventing them from working, pursuing passions or caregiving. Therapies that are effective in the treatment of cancer-therapy-related cognitive impairment and strategies to reset microglia to homeostatic, non-reactive states are avenues that should be explored for treatment.