Neurological Signs, Symptoms and Diseases following COVID-19

Part II – Cognitive Impairment (Brain Fog)

(See end for a summary of key take-aways)

In my last blog piece, we began an in-depth review of some of the neurological signs, symptoms and diseases that can follow COVID-19. That piece focused on one of the most common symptoms I get asked about – loss of smell (anosmia) or distorted sense of smell (parosmia). In this piece we will review what we know about cognitive impairment following COVID-19, often described by those affected as “brain fog.” As I did in my prior piece, I will review the studies first for the benefit of those who want a deep understanding of the problem, but I will conclude with “Key Take-Aways” for those who just want a summary of the studies in plain English.

It is estimated that 30 percent of persons who develop COVID-19 and require hospitalization will have neurologic symptoms, signs or disease resulting from their infection. However, it is also clear that even those with so-called “mild” COVID-19 can suffer from neurological sequelae following their infection.

Before digging specifically into cognitive impairment, let’s look at what we think we know about the impacts to the brain in general by SARS-CoV-2 infection.

A study published in August of this year[1], examined the molecular, cellular and morphological basis for infection of the brain in patients with COVID-19. This study examined a cohort of 26 individuals who died of COVID-19 in the first 5 months of the pandemic (thus, likely infected with the wild-type or original virus) and underwent autopsy. The investigators examined brain tissue under the microscope and looked for signs of cellular damage.  Among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. On average, SARS-CoV-2 spike protein could be detected in 37% of the brain cells, with about 66% of these cells being astrocytes. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Astrocytes are cells that are important to the support and function of neurons that carry electrical messages up and down the spinal cord and through our brains. Astrocytes are the major source of energy storage for the brain and play a critical role in the repair and regeneration of nerve tissue due to infection and/or inflammation.

SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites that are important to the functioning of neurons, as well as in the production of neurotransmitters. Human astrocyte infection also results in the secretion of substances from the astrocytes that reduce viability of neurons and leads to their death. Thus, this study supports that SARS-CoV-2 can reach the brain in at least some patients with COVID-19, infect astrocytes, and consequently, lead to neuronal death or dysfunction that perhaps explains or at least contributes to the neurological signs, symptoms and diseases that we see in some patients following COVID-19.

The investigators also performed high-resolution, high-magnet strength Magnetic Resonance Imaging (MRI) on 81 subjects diagnosed with mild COVID-19 infection (62 self-reported anosmia or dysgeusia [abnormal taste]) who did not require oxygen support during their infection within weeks to months following a laboratory-confirmed SARS-CoV-2 infection. These subjects were compared to 81 healthy, age- and sex-matched controls. The subjects with “mild” COVID-19 reported higher levels of anxiety and depression symptoms, fatigue, and excessive daytime sleepiness.

Compared to the healthy controls, the group with mild COVID-19 had areas of reduced cortical thickness (the cortex is the outer layer of the brain, the so-called gray matter, which is also the most neuron-rich part of the brain) exclusively in the left hemisphere, including the left gyrus rectus (this is located on the inferior surface of the frontal lobe and thought to be involved in higher cognitive functioning and personality), superior temporal gyrus (a site involved in processing sounds and comprehending language), inferior temporal sulcus (thought to be involved in processing complex visual patterns), and posterior transverse collateral sulcus (thought to be involved in visual processing, especially complex visual patterns).

A subgroup of 61 participants of the COVID-19 group also underwent neuropsychological evaluation, which assessed episodic verbal memory (logical memory subtest, immediate and delayed recall, Wechsler Memory Scale), sustained attention, and alternating attention and cognitive flexibility. The tests were performed a median of 59 days (range between 21 and 120 days) after diagnosis. The investigators observed fatigue in ∼70% of individuals and daytime sleepiness in 36%. Despite the high level of education of the participant subgroup (median of 16 years of education), the comparisons with Brazilian normative data (z scores were adjusted for age, sex, and education) showed that nearly 28% of participants presented impairments in immediate episodic verbal memory (immediate recall, including mild, moderate, and severe impairments), and ∼34 and 56% underperformed on sustained attention and alternating attention and cognitive flexibility, respectively.

The study findings demonstrated that cortical thickness atrophy (thinning) was associated with neuropsychiatric symptoms and cognitive impairment in COVID-19 patients with mild or no respiratory symptoms. Patients with cognitive dysfunction were often noted to have atrophy (shrinkage) in the orbitofrontal cortex (the outer layer of the brain just behind the eyes and over the nasal passages often referred to as prefrontal cortex) and these individuals were far more likely to experience anxiety.

Another study published in September of this year[2], examined the outcomes of those with COVID-19 who survived the at least a month from the date of their infection. The investigators reviewed the medical records of 154,068 patients with SARS-CoV-2 infection, including those with “mild” COVID-19, and 5,638,795 uninfected contemporary controls that were in the Veteran’s Administration medical record system. To further validate the estimates, the investigators built a pre-pandemic, historical control cohort of 5,859,621 patients. Those persons with COVID-19 had an increased risk of a wide range of post-acute neurological disorders after 1 year compared with an uninfected control population, including cerebrovascular disorders, cognition and memory disorders (memory problems and Alzheimer’s disease), peripheral nervous system disorders, extrapyramidal and movement disorders, musculoskeletal disorders, and sensory disorders. Overall, the investigators determined that patients with COVID-19 had a 42% increased risk of developing a neurological sequela in the year after infection, translating to 7% of infected people. Some of the neurological sequelae are chronic conditions that will require lifelong care and might impact patients’ lives and livelihood. The risks were higher in those who required hospitalization for their COVID-19, and even higher in those who required intensive care during their hospitalization.

Specific neurological sequelae included:

1.41 – 1.61 times increased risk of ischemic stroke resulting in 2.75 – 4.09 ischemic strokes per 1,000 persons infected at 12 months.

1.63 – 2.95 times increased risk of hemorrhagic stroke resulting in burden 0.11 – 0.35 brain bleeds per 1,000 infected persons at 12 months.

1.5 – 1.75 times increased risk for transient ischemic attacks (TIAs) resulting in 1.64 – 2.46 such events per 1,000 infected persons at 12 months.

1.29 – 5.62 times increased risk for cerebral venous thrombosis resulting in 0.01 – 0.14 cases per 1,000 infected persons at 12 months.

1.28 – 1.40 times increased risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations sometimes accompanied by weakness in the extremities) resulting in 4.67 – 6.65 cases per 1,000 infected persons at 12 months.

1.25 – 1.39 increased risk of experiencing paresthesia (abnormal sensations usually in the arms and legs such as tingling or burning) resulting in 2.27 – 3.55 cases per 1,000 infected persons at 12 months.

1.21 – 1.40 increased risk of developing dysautonomia (a disorder of the autonomic nervous system which can result in a myriad of distressing symptoms including faintness or dizziness with changes in posture, rapid heart rate and palpitations, and frequent urination) resulting in 1.12 – 2.12 55 cases per 1,000 infected persons at 12 months.

1.24 – 1.77 times increased risk for developing Bell’s palsy (a partial paralysis of one side of the face) resulting in 0.16 – 0.51 cases per 1,000 infected persons at 12 months.

1.14 – 1.28 times increased risk for experiencing migraine headache disorder resulting in 1.36 – 2.76 new cases per 1,000 infected persons at 12 months.

1.25 – 1.45 times increased risk for developing non-migraine headache disorders resulting in 1.06 – 1.89 cases per 1,000 infected persons at 12 months.

1.61 – 2.01 increased risk for developing epilepsy and seizures resulting in 1.47 – 2.63 cases per 1,000 infected persons at 12 months.

1.32 – 1.50 times increased risk of experiencing abnormal involuntary movements resulting in 2.24 – 3.49 cases per 1,000 infected persons at 12 months.

1.25 – 1.51 times increased risk for developing a tremor resulting in 0.73 – 1.51 cases per 1,000 infected persons at 12 months.

1.28 – 1.75 times increased risk of developing Parkinson-like disease resulting in 0.50 – 1.34 cases per 1,000 infected persons at 12 months.

1.29 – 1.9 times increased risk of developing dystonia (abnormal and often repetitive movements) resulting in 0.21 – 0.63 cases per 1,000 infected persons at 12 months.

 1.13 – 1.79 tines increased risk for myoclonus (sudden, brief involuntary twitching or jerking movements) resulting in 0.04 – 0.26 cases per 1,000 infected persons at 12 months.

1.39 – 1.48 times increase in major depressive disorders resulting in 15.43 – 19.18 cases per 1,000 infected persons at 12 months.

1.34 – 1.44 times increase in stress and adjustment disorders resulting in 12.66 – 16.07 cases per 1,000 infected persons at 12 months.

1.33 – 1.42 times increase in anxiety disorders resulting in 10.93 – 13.99 cases per 1,000 infected persons at 12 months.

 1.33 – 1.71 times increase in psychotic disorders resulting in 0.66 – 1.43 cases per 1,000 infected persons at 12 months.

1.31 – 1.38 times increase in arthralgias (joint pain) resulting in 25.01 – 30.35 cases per 1,000 infected persons at 12 months.

1.77 – 1.9 times increase in myalgia (muscle pains) resulting in 14.75 – 17.23 cases per 1,000 infected persons at 12 months.

2.3 – 3.32 times increase in myopathy (muscle disease, weakness) resulting in 0.52 – 0.93 cases per 1,000 infected persons at 12 months.

1.18 – 1.25 times increase in hearing abnormalities or tinnitus (ringing in the ears) resulting in 10.05 – 13.75 cases per 1,000 infected persons at 12 months.

1.24 – 1.36 times increase in vision abnormalities resulting in 4.55 – 6.68 cases per 1,000 infected persons at 12 months.

3.45 – 4.75 times increase in anosmia (loss of smell) resulting in 0.86 – 1.32 cases per 1,000 infected persons at 12 months.

1.54 – 3.32 times increase in loss of taste resulting in 0.05 – 0.21 cases per 1,000 infected persons at 12 months.

1.38 – 1.5 times increase in dizziness resulting in 5.72 – 7.61 cases per 1,000 infected persons at 12 months.

1.31 – 2.12 times increase in somnolence resulting in 0.26 – 0.94 cases per 1,000 infected persons at 12 months.

1.40 – 3.35 times increase in Guillain–Barré syndrome resulting in 0.04 – 0.22 cases per 1,000 infected persons at 12 months.

1.16 – 2.84 times increase in encephalitis or encephalopathy resulting in 0.01 – 0.16 cases per 1,000 infected persons at 12 months.

1.11 – 2 times increase in transverse myelitis resulting in 0.00 – 0.11 cases per 1,000 infected persons at 12 months.

Focusing now on the subject of this blog piece – cognitive impairment following COVID-19, this study showed:

1.68 – 1.85 times increase in memory problems resulting in 9 – 11.2 cases per 1,000 infected persons at 12 months.

1.79 – 2.31 times increase in Alzheimer’s disease resulting in 1.27 – 2.10 cases per 1,000 infected persons at 12 months.

Another study published in October of this year[3] describes the neurobiology of the neurological sequelae of Long COVID.

Prominent among the lasting neurological sequelae following COVID-19 is a syndrome of persistent cognitive impairment known as “brain fog,” characterized by impaired attention, concentration, memory, speed of information processing, and executive function. Neuroinflammation alone can cause dysregulation of glial and neuronal cells and, ultimately, neural circuit dysfunction that negatively impacts cognitive and neuropsychiatric functions.

Infection due to SARS-CoV-2 may affect the central nervous system in (at least) six main ways:

  1. The immune response to SARS-CoV-2 in the respiratory system may cause neuroinflammation—increasing cytokines, chemokines, and immune cell trafficking in the brain, inducing reactive states of resident microglia and other immune cells in the brain and brain borders.
  2. SARS-CoV-2 rarely may directly infect the nervous system.
  3. SARS-CoV-2 may evoke an autoimmune response against the nervous system.
  4. Reactivation of latent herpesviruses, like the Epstein-Barr virus, may trigger neuropathology.
  5. Cerebrovascular and thrombotic disease may disrupt blood flow, disrupt the blood-brain-barrier function, and contribute to further neuroinflammation and/or ischemia of neural cells.
  6. Pulmonary and multi-organ dysfunction occurring in severe COVID-19 can cause hypoxemia (low oxygen levels in the blood), hypotension (low blood pressure), and metabolic disturbances that can negatively affect neural cells. 

Again, it is important to keep in mind that multiple mechanisms may be at play in the same patient and that different mechanisms may be triggered in different people. For example, neuroinflammation triggered by the immune response to the respiratory system infection and consequent dysregulation of neural homeostasis and plasticity is likely a more common mechanistic principle that occurs even after mild disease in the acute phase, while direct brain infection is likely an uncommon mechanism associated with severe COVID-19.

Cognitive function depends upon precision of activity in neural circuits, which in turn depends upon finely regulated interactions of neurons with glial cells, most notably astrocytes. In healthy, stable states of health, astrocytes control the formation and function of synapses (connections between neurons in these neural circuits). Another type of glial cell, oligodendrocytes, are important to fine tune these neural circuits by modulating the speed and amplitude of the electrical transmissions within and between axons (the portion of the neuron that transmits the electrical impulses (signals). Oligodendrocytes also provide important metabolic support to the axons to keep them healthy and high performing.

Microglia (including both astrocytes and oligodendrocytes) act as the main immune defense in the central nervous system. Similar to roles played by macrophages outside of the brain, these cells scavenge for the development of plaques, infectious agents and damaged neurons and synapses. They are exquisitely responsive to immunological signals and rapidly assume reactive phenotypes. However, in the reactive form, they do not retain the functions and ability to preserve the stable environment and plasticity of neurons. Microglial reactivity leads to secretion of cytokines and enhanced phagocytosis (ingestion of cells – in this case infected and damaged cells) that is intended to limit the spread of pathogens. When not properly regulated, these reactive microglia can profoundly disrupt neural circuit regulation, function, and plasticity in ways that can contribute to cognitive impairment and neuropsychiatric diseases.

Reactive astrocytes can further contribute to pathology, with certain states of reactive astrocytes inducing cell death of oligodendrocytes and of susceptible neurons. The neurotoxic sub-state of reactive astrocytes does not adequately support synaptic connections, which can further add to circuit dysfunction. This complex cellular dysregulation is thought to contribute significantly to cognitive impairment.

Alarmingly, a neuro-psychometric study examining patients with mild, moderate, or severe COVID-19 in a New York City hospital system followed from spring of 2020 through spring of 2021, found impairment in attention (10%), processing speed (18%), memory encoding (24%), and executive function (16%) evident at 7 months after infection.

A 2-year retrospective cohort study following 1,487,712 individuals with COVID-19 and a similar number of matched controls with a different respiratory infection found continued risk of cognitive impairment at 2 years from diagnosis.[4] 

The UK Biobank study compared magnetic resonance imaging (MRI) data before and after SARS-CoV-2 infection in 401 individuals and 385 matched controls. MRI data obtained an average of 141 days following COVID-19 diagnosis revealed widespread structural abnormalities, including a small but significant global decrease in brain volume, changes throughout the olfactory system, and structural abnormalities in the limbic system, cerebellum, and major white matter tracts (fimbria and superior fronto-occipital fasciculus).[5]

Another mechanism by which COVID-19 may injure the nervous system is through the production of autoantibodies and autoimmunity. In a study of six individuals hospitalized for COVID-19 with acute neurological symptoms, including encephalopathy, headache, and seizures, analyses of immune cells in blood and cerebral spinal fluid (CSF) revealed activated T cells and clonal expansion of unique T cell clones in the CSF not found in blood, suggesting a compartmentalized T cell response to an antigen in the central nervous system.[6] This is not a complete surprise as we have known for more than a year that hospitalized patients with moderate and severe COVID-19 produce a diverse set of serum autoantibodies against vascular cells, coagulation factors and platelets, connective tissue, extracellular matrix components and various organ systems, including the central nervous system.[7] In fact, cases of autoimmune encephalitis have been reported in patients with severe COVID-19 with the identification of anti-neuronal autoantibodies in patient CSF and sera in individuals with prominent neurological symptoms.

Another potential contributor to the pathophysiology of Long COVID and its neurological sequelae is reactivation of latent viruses. There are a number of viruses that humans are commonly exposed to that cause infection during which time the viruses are contained, but not eliminated (e.g., herpes viruses, Epstein-Barr Virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), and human papilloma virus (HPV)). These latent viruses do not cause any direct clinical disease in their latent state, but they may contribute to the development of other diseases indirectly, for example cancers from EBV and HPV and multiple sclerosis from EBV. However, states of immune compromise or other acute viral infections can trigger the reactivation of these latent viruses, resulting in the production of infectious viral particles that can cause significant inflammation and symptoms, e.g., reactivation of varicella-zoster infection can result in painful shingles.

A study that followed 309 COVID-19 patients from the initial diagnosis to convalescence (2–3 months later) found that EBV viremia (Epstein Barr Virus in the blood) at the time of COVID-19 diagnosis was one of the four predictive factors for long COVID development.[8] Based on prior studies contributing to our understanding of EBV, this 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 (including the production of cytokines and autoantibodies).

Another latent virus that has been reported to be reactivated in some persons with COVID-19 is a collection of viruses known as herpes viruses, specifically herpes simplex viruses 1 and 2. Even before COVID-19, we would see cases of herpes simplex reactivation that results in herpes encephalitis, a life-threatening infection of the brain. Herpes virus reactivation could be a result of the steroids that we use to treat COVID-19 patients with severe disease, or it could be due to the immunopathology that can result from SARS-CoV-2 infection relating to T-cells (more on that in a later blog post). In this case, we have reports of herpes encephalitis occurring within several weeks of COVID-19 diagnosis suggesting that the steroids may be the most likely cause.

Another potential pathophysiological basis for long-term cognitive dysfunction following COVID-19 is ischemic stroke. Compared to other respiratory viruses, ischemic stroke is a greater risk from infection with SARS-CoV-2 than those other viruses. Ischemic strokes can confer lasting neurological sequelae and impair cognitive functions in a vascular-territory-dependent manner. Short of an ischemic stroke, small vessel thromboses and vascular dysfunction, including blood-brain-barrier disruption, can also influence neurological function in subtle but debilitating ways. This increased risk of thrombosis has been shown in studies demonstrating fibrin micro-clots and activated platelets in the blood of patients with long COVID.[9] Ischemic strokes and brain hemorrhages have been seen on autopsy of patients who died with severe COVID-19. However, other vascular injuries to the brain have been seen on autopsies of those who died with COVID-19, including microvascular (small blood vessels) injury and endothelial cell (the cells that line the blood vessels) activation with perivascular leakage (leakage surrounding the blood vessel) of the large plasma protein fibrinogen, indicative of blood-brain-barrier dysfunction, found throughout the brain and most prominent in the hindbrain (cerebellum [critical to functions such as balance and arm, leg and eye movements] and brainstem [critical to breathing, many of the cranial nerves and the transmission of signals from the brain to the body and vice versa]).

Key Take-aways

  1. Neurological sequelae are not uncommon following COVID-19 with estimates of impacting ~ 30% of those hospitalized with COVID-19 and perhaps ~ 7% of those with “mild” COVID-19.
  2. COVID-19 is able to cause damage to the brain in a number of different ways. As we discussed in the prior blog piece relating to anosmia, it appears that direct viral invasion of nerve cells is possible, but not the dominant mode of damaging the brain.
  3. SARS-CoV-2 can directly infect certain cells that are important to healthy, properly functioning nerve cells, namely astrocytes and oligodendrocytes. When these supporting cells are infected, they in turn both directly and indirectly can harm neurons.
  4. Various mechanisms may be involved in damaging the brain besides direct viral invasion, including the immune reaction to SARS-CoV-2 infection, reactivation of latent viruses, the formation of autoantibodies and damage to blood vessels large (ischemic stroke) and small (microvascular injury and endotheliitis).
  5. The changes caused by any of these pathophysiologic mechanisms, by themselves or in combination, may be sufficiently severe to cause neurocognitive and neuropsychiatric disorders. In fact, imaging studies have shown striking reductions in brain volumes following SARS-CoV-2 infection, with further studies showing that the loss of brain matter may disproportionately affect the cerebral cortex, the part of the brain that is most rich in number of neurons.
  6. There are many unanswered questions. While it appears that some people with cognitive impairments will improve with time, it is unknown whether these impairments can be permanent, and if so, what proportion of patients this may affect. Concerning for the possibility of life-long impairment in at least some people is the increased risk for development of Alzheimer’s dementia following COVID-19.
  7. It also is not clear whether all variants of SARS-CoV-2 have equal neuropathologic potential, or whether they may vary in their proclivity to cause neurological damage or the severity of that injury.
  8. It appears that the risk for neurological sequelae following COVID-19 increases with reinfections, and there is emerging data that indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals, although this decrease appears to be relatively small (somewhere around a 15% risk reduction). 
  9. My greatest concern is for the neurological harm that may be suffered by children, especially with repeated infections. There is simply little data to draw conclusions from, though there is reason for concern given that we know children can develop Long COVID. Further, the brains of children and young adults up to age 25 is still developing and presumably more vulnerable than older adults. While stress, anxiety, depression and educational loss has been ascribed to remote learning, little consideration has been given to the potential that COVID-19 may itself be responsible or contributing to these problems.

[1] Morphological, cellular, and molecular basis of brain infection in COVID-19 patients | PNAS.

[2] Long-term neurologic outcomes of COVID-19 | Nature Medicine.

[3] The neurobiology of long COVID: Neuron (cell.com).

[4] Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients – The Lancet Psychiatry.

[5] SARS-CoV-2 is associated with changes in brain structure in UK Biobank | Nature.

[6] Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms: Cell Reports Medicine.

[7] Diverse functional autoantibodies in patients with COVID-19 | Nature.

[8] Multiple early factors anticipate post-acute COVID-19 sequelae: Cell.

[9] Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) | Cardiovascular Diabetology | Full Text (biomedcentral.com).

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