There is increasing evidence suggesting that COVID-19 causes both acute and chronic neurological or psychological symptoms. Caregivers of COVID-19 patients also show a higher than average prevalence of mental health concerns. These symptoms result from multiple different factors.
SARS-Coronavirus-2 (SARS-CoV-2) directly infects olfactory neurons (smell) and nerve cells expressing taste receptors. Although these cells communicate directly with the brain, the virus does not exhibit strong infection of other nerve cells in the central nervous system. Many of the neurological sequelae appear to result from damage to the vascular cells of the brain or from damage resulting from hypoxia (i.e., limitations in the oxygen supply for the brain). Chronic effects of COVID-19 can lead to a prolonged inflammatory state, which can increase symptoms resembling an autoimmune disorder. Many patients with COVID-19 experience psychological symptoms that can arise either from the direct actions of the virus, the chronic increase in inflammation or secondary effects, such as post-traumatic stress disorder.
Large community-based testing has also found small but measurable average post-infection cognitive deficits, with larger effects among people who report ongoing symptoms and after more severe or earlier-variant infections.
SARS-CoV-2 can be detected in the brain and cerebrospinal fluid acutely by polymerase chain reaction, and is thought to enter via the olfactory system. Cranial nerves (including the facial nerve and vagus nerve, which mediate taste) provide an additional route of entry. SARS-CoV-2 has been detected in endothelial cells by electron microscopy, although such a method provides evidence that demonstrates the presence of the virus, but does not convey the amount of virus that is present (qualitative rather than quantitative).
Acute neurologic symptoms The fraction of subjects who experience symptoms following an infection with SARS-CoV-2 varies by age. Between 10 and 20% of patients who are infected generally exhibit the clinical syndrome, known as COVID-19. The number of COVID-19 infections are highest in subjects between ages 18–65, while the risk of severe disease or death jumps after age 50 and increases with age. About 35% of patients with symptoms of COVID-19 experience neurological complications. Neurological symptoms are not unique to COVID-19; infection with SARS-CoV-1 and MERS-CoV also give rise to acute and delayed neurological symptoms including peripheral neuropathy, myopathy, Guillain–Barré syndrome and Bickerstaff brainstem encephalitis.
Loss of the sense of taste or smell are among the earliest and most common symptoms of COVID-19. Roughly 81% of patients with clinical COVID-19 experience disorders of smell (46% anosmia, 29% hyposmia, and 6% dysosmia). Disorders of taste occur in 94% of patients (ageusia 45%, hypogeusia 23%, and dysgeusia 26%). Most patients recover their sense of taste or smell within 8 days. Delirium is also a common manifestation of the infection, particularly in the elderly. Recent evidence from a longitudinal study supports an inflammatory basis for delirium. Many patients with COVID-19 also experience more severe neurological symptoms. These symptoms include, headache, nausea, vomiting, impaired consciousness, encephalitis, myalgia and acute cerebrovascular disease including stroke, venous sinus, thrombosis and intracerebral hemorrhage.
Increasing attention has focused on cerebrovascular accidents (e.g., stroke), which are reported in up to 5% of hospitalized patients, and occur in both old and young patients. Guillain–Barré syndrome, acute myelitis and encephalomyelitis have also been reported. Guillain–Barré syndrome arises as an autoimmune disorder, that leads to progressive muscle weakness, difficulty walking and other symptoms reflecting reduced signaling to muscles. The cases of myelitis could arise from direct infection of muscle via local angiotensin-converting enzyme 2, the receptor for SARS CoV-2. COVID-19 can also cause severe disease in children. Some children with COVID-19 who develop Kawasaki disease, which is a multi-system inflammatory syndrome that also cerebrovascular disease and neurologic involvement.
Disorders of smell (olfaction) and taste (gustation)
As mentioned above, many COVID-19 patients suffer from disorders of taste or smell. 41% to 62% of patients (depending on the particular study) have disorders of the sense of smell (olfaction), which can present as anosmia (loss of olfaction), hyposmia (reduced olfaction) or parosmia (distortion of olfaction). However, loss of olfaction is not unique to COVID-19; approximately 13% of patients with influenza also lose olfaction, as do patients with MERS-CoV and Ebola virus. Among the patients with COVID-19, 50% of patients recover olfaction within 14 days, and 89% of patients have complete resolution of their loss of olfaction within 4 weeks. Only 5% of COVID-19 patients experience a loss of olfaction lasting more than 40 days.
The SARS-CoV-2 virus appears to attack the olfactory epithelium (sustentacullar or "support" cells), which are the cells that surround and support olfactory receptor neurons. Little if any virus directly infects these neurons themselves. However, SARS-CoV-2 infection of the sustentacullar cells can lead to desquamation (shedding) of the olfactory epithelium, with collateral loss of olfactory receptor neurons and anosmia. However, the olfactory epithelium is continually regenerated, and neurons that are damaged are typically replaced in about 14 days. The nerve cells controlling taste, termed the gustatory nerve cells, turn over even faster, being renewed in about 10 days.
Clinical help exists for patients experiencing disorders of olfaction. Patients who experience of loss of smell for longer than two weeks are recommended to obtain olfactory training. Olfactory training helps to "teach" the new olfactory neurons how to link with the brain so that odors can be noticed and then recognized. Personal accounts of the process of olfactory training post COVID-19 infection have been covered in media outlets such as the New York Times. Patients experiencing loss of smell for more than 2 weeks are also recommended to obtain a referral to an ear nose and throat (ENT) physician. Oral corticosteroid therapy can help, but is optional. alpha-lipoic acid is another remedy that has been proposed, but the accumulated literature on this suggests that it does not improve symptoms or recovery.
Chronic neurologic symptoms
A study of 236,379 COVID-19 survivors showed that the "estimated incidence of a neurological or psychiatric diagnosis in the following 6 months" after diagnosed infection was 33.62% with 12.84% "receiving their first such diagnosis" and higher risks being associated with COVID-19 severity.
Neuroinflammation as a result of viral infection (e.g., influenza, herpes simplex, and hepatitis C) has been linked to the onset of psychiatric illness across numerous publications. Coronavirus infections are defined as neurotropic viral infections (i.e., they tend to target the nervous system) which increases the risk of neuroinflammation and the induction of immune system dysfunction. Psychotic disorders are characterized by neuroinflammation, more specifically maternal inflammation, and abnormally high mesolimbic dopamine (DA) signaling. Excess inflammation following a COVID-19 infection can alter neurotransmitter signaling which contributes to development of psychotic and mood related disorders.
A large study showed that post COVID-19, people had increased risk of several neurologic sequelae including headache, memory problems, smell problems and stroke; the risk was evident even among people whose acute disease was not severe enough to necessitate hospitalization; the risk was higher among hospitalized, and highest among those who needed ICU care during the acute phase of the infection. About 20% of COVID-19 cases that pass through the intensive care unit (ICU) have chronic neurologic symptoms (beyond loss of smell and taste). Of the patients that had an MRI, 44% had findings upon MRI, such as a FLAIR signal (fluid-attenuated inversion recovery signal), leptomeningeal spaces and stroke. Neuropathological studies of COVID-19 victims show microthrombi and cerebral infarctions. The most common observations are hypoxic damage, which is attributable to use of ventilators. However, many patients who died exhibited perivascular T cells (55%) and microglial cell activation (50%). Guillain–Barre Syndrome occurs in COVID-19 survivors at a rate of 5 per 1000 cases, which is about 500 times the normal incidence of 1 per 100,000 cases. A related type of autoimmune syndrome, termed Miller-Fisher Syndrome, also occurs.
COVID-19 patients who were hospitalized may also experience seizures. One paper suggests that seizures tend to occur in COVID-19 patients with a prior history of seizure disorder or cerebrovascular infarcts, however no reviews are yet available to provide data on the incidence relative to the general population. Acute epileptic seizures and status epilepticus tend to be the seizures reported. 57% of the cases occur among patients who had experienced respiratory or gastrointestinal symptoms. Although treatment with benzodiazepines would seem to be contraindicated because of the risk of respiratory depression, COVID-19 patients with acute epileptic seizures who are treated have a 96% favorable outcome, while patients with acute epileptic seizures who are not treated appear to have higher rates of mortality (5-39%).
A large scale study of 6,245,282 patients have revealed an increased risk of Alzheimer's disease diagnosis following COVID-19 infection. Many pathways involved in Alzheimer's disease progression are also implicated in the antiviral response to COVID-19, including the NLRP3 inflammasome, interleukin-6, and ACE-2.
Acute psychiatric symptoms Reported prevalence of mental health disorders vary depending on the study. In one review, 35% of patients had mild forms of anxiety, insomnia, and depression and 13% of patients had moderate to severe forms. Another review reports frequencies of depression and anxiety of 47% and 37%. According to a large meta-analysis, depression occurs in 23.0% (16.1 to 26.1) and anxiety in 15.9% (5.6 to 37.7). These psychological symptoms correlate with blood based biomarkers, such as C-reactive protein, which is an inflammatory protein. Psychiatric symptoms were also associated with severity of COVID-19 infection with those bedridden for an extended period of time having a higher prevalence of depressive and anxiety symptoms.
A case report of acute psychiatric disturbance noted an attempted suicide by a patient who had no prior noted psychiatric problems.
Chronic psychiatric symptoms A 2021 article published in Nature reports increased risk of depression, anxiety, sleep problems, and substance use disorders among post-acute COVID-19 patients. In 2020, a Lancet Psychiatry review reported occurrence of the following post-COVID-19 psychiatric symptoms: traumatic memories (30%), decreased memory (19%), fatigue (19%), irritability (13%), insomnia (12%) and depressed mood (11%). Other symptoms are also prevalent, but are reported in fewer articles; these symptoms include sleep disorder (100% of patients) and disorder of attention and concentration (20%). These accumulated problems lead to a general (and quantified) reduction in the quality of life and social functioning (measured with the SF-36 scale). Studies have found evidence of cultural differences in mental health outcomes during the pandemic, such as higher rates of anxiety in southern China than northern China. There is also increasing evidence to suggest that ongoing psychiatric symptoms, including post-traumatic stress and depression, may contribute to fatigue in post-COVID syndrome.
Pediatric symptoms