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
An olfactory receptor neuron (ORN), also called an olfactory sensory neuron (OSN), is a sensory neuron within the olfactory system.
Structure
Humans have between 10 and 20 million olfactory receptor neurons (ORNs). In vertebrates, ORNs are b ...
(smell) and nerve cells expressing
taste receptor
A taste receptor or tastant is a type of cellular receptor which facilitates the sensation of taste. When food or other substances enter the mouth, molecules interact with saliva and are bound to taste receptors in the oral cavity and other locat ...
s. 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
Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on ...
.
SARS-CoV-2 can be detected in the brain and
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) acutely by
PCR, and is thought to enter via the olfactory system.
Cranial nerve (including facial nerve and vagus nerve, which mediate taste) provides 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 COVID-19 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 with SARS-CoV-2 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
Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; or Severe acute respiratory syndrome coronavirus, SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for ...
and
MERS-CoV
''Middle East respiratory syndrome–related coronavirus'' (''MERS-CoV''), or EMC/2012 ( HCoV-EMC/2012), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, bats, and camels. Th ...
also give rise to acute and delayed neurological symptoms including
peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
,
myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...
,
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often ...
and
Bickerstaff brainstem encephalitis
Bickerstaff brainstem encephalitis is a rare inflammatory disorder of the central nervous system, first described by Edwin Bickerstaff in 1951. It may also affect the peripheral nervous system, and has features in common with both Miller Fish ...
. The
influenza pandemic of 1918
The 1918–1920 influenza pandemic, commonly known by the misnomer Spanish flu or as the Great Influenza epidemic, was an exceptionally deadly global influenza pandemic caused by the H1N1 influenza A virus. The earliest documented case was ...
was well known for producing post-viral Parkinsonism, which was memorialized in the writings of
Oliver Sacks
Oliver Wolf Sacks, (9 July 1933 – 30 August 2015) was a British neurologist, naturalist, historian of science, and writer. Born in Britain, Sacks received his medical degree in 1958 from The Queen's College, Oxford, before moving to the Uni ...
and the movie ''
Awakenings
''Awakenings'' is a 1990 American drama film directed by Penny Marshall. It is written by Steven Zaillian, who based his screenplay on Oliver Sacks's 1973 memoir ''Awakenings''. It tells the story of neurologist Dr. Malcolm Sayer (Robin Williams ...
''.
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
Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells.
Anosmia can be due to a num ...
, 29%
hyposmia
Hyposmia, or microsmia, is a reduced ability to smell and to detect odors. A related condition is anosmia, in which no odors can be detected. Some of the causes of olfaction problems are allergies, nasal polyps, viral infections and head trauma. ...
, and 6%
dysosmia
Dysosmia is a disorder described as any qualitative alteration or distortion of the perception of smell. Qualitative alterations differ from quantitative alterations, which include anosmia and hyposmia. Dysosmia can be classified as either paros ...
).
Disorders of taste occur in 94% of patients (
ageusia
Ageusia (from negative prefix ''a-'' and Ancient Greek ''γεῦσις'' geûsis 'taste') is the loss of taste functions of the tongue, particularly the inability to detect sweetness, sourness, bitterness, saltiness, and umami (meaning 'pleasant ...
45%,
hypogeusia
Hypogeusia is a reduced ability to taste things (to taste sweet, sour, bitter, or salty substances). The complete lack of taste is referred to as ageusia.
Causes of hypogeusia include the chemotherapy drug bleomycin, an antineoplastic, antitumor ...
23%, and
dysgeusia
Dysgeusia, also known as parageusia, is a distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is a decrease in taste sensitivity. An alteration in taste or ...
26%). Most patients recover their sense of taste or smell within 8 days.
Delirium is also a common manifestation of COVID-19 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
Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into Intraparenchymal hemorrhage, the tissues of the brain, into its Intraventricular hemor ...
.
Increasing attention has focused on
cerebrovascular accidents
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
(e.g., stroke), which are reported in up to 5% of hospitalized patients, and occur in both old and young patients.
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often ...
, acute
myelitis
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged re ...
and
encephalomyelitis
Encephalomyelitis is inflammation of the brain and spinal cord. Various types of encephalomyelitis include:
* ''Acute disseminated encephalomyelitis'' or ''postinfectious encephalomyelitis'', a demyelinating disease of the brain and spinal cord, p ...
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
Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 a ...
, the receptor for SARS CoV-2.
COVID-19 can also cause severe disease in children. Some children with COVID-19 who develop
Kawasaki disease
Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more tha ...
, 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
The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste.
In humans, it ...
), which can present as
anosmia
Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells.
Anosmia can be due to a num ...
(loss of olfaction),
hyposmia
Hyposmia, or microsmia, is a reduced ability to smell and to detect odors. A related condition is anosmia, in which no odors can be detected. Some of the causes of olfaction problems are allergies, nasal polyps, viral infections and head trauma. ...
(reduced olfaction) or
parosmia
Parosmia (from the Greek παρά ''pará'' and ὀσμή ''osmḗ'' "smell") is a dysfunctional smell detection characterized by the inability of the brain to correctly identify an odor's "natural" smell. Instead, the natural odor is usually tr ...
(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
''Middle East respiratory syndrome–related coronavirus'' (''MERS-CoV''), or EMC/2012 ( HCoV-EMC/2012), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, bats, and camels. Th ...
and
Ebola virus
''Zaire ebolavirus'', more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and ot ...
.
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
sustentacullar cells (also referred to as "support cells"), which are the cells that surround and support
olfactory receptor neuron
An olfactory receptor neuron (ORN), also called an olfactory sensory neuron (OSN), is a sensory neuron within the olfactory system.
Structure
Humans have between 10 and 20 million olfactory receptor neurons (ORNs). In vertebrates, ORNs are b ...
s.
Little if any virus directly infects the olfactory receptor neurons themselves.
However, SARS-CoV-2 infection of the sustentacullar cells can lead to desquamation (shedding) of the
olfactory epithelium
The olfactory epithelium is a specialized epithelial tissue inside the nasal cavity that is involved in smell. In humans, it measures
9 cm2 and lies on the roof of the nasal cavity about 7 cm above and behind the nostrils. The olfactory ...
, 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
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
therapy can help, but is optional.
alpha-lipoic acid
Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA is made in animals normally, and is essential for aerobic metabolism. It is ...
is another remedy that has been proposed, but the accumulated literature on this suggests that it does not improve symptoms or recovery.
Chronic COVID-19 neurologic symptoms
![Impact of COVID-19 on neurological and psychiatric outcomes in the subsequent 6 months compared with other respiratory tract infections](https://upload.wikimedia.org/wikipedia/commons/1/1a/Impact_of_COVID-19_on_neurological_and_psychiatric_outcomes_in_the_subsequent_6_months_compared_with_other_respiratory_tract_infections.jpg)
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.
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_
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.
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_Magnetic_resonance_imaging">MRI_
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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.
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).