Neurological and psychiatric complications of severe SARS infections: review and meta-analysis

EM of sars-cov-2 budding from apoptotic (dying) cells–NIAID

A review of psychiatric and neurological complications from SARS and MERS compared with COVID-19, published in Lancet Psychiatry May 18 (full text)  assessed common symptoms associated with acute illness and after recovery by meta-analysis of multiple articles (65 articles and seven pre-prints were selected for quality and comprehensiveness) :

Neuropsychiatric symptoms associated with COVID-19

Acute neuropsychiatric symptoms of SARS and MERS (both diseases with much higher mortality rates but caused by closely related coronaviruses): confusion, impaired memory, insomnia, anxiety, and depressed mood.  Post-illness (assuming the patient recovered from the acute illness): insomnia, anxiety, irritability, memory impairment, fatigue, depressed mood, and “traumatic memories” (similar to post-traumatic stress disorder.)  Three-quarters of recovered patients had returned to work after three years of followup.

Neuropsychiatric symptoms associated with  COVID-19: delirium (and confusion with agitation) occurred in two-thirds of patients admitted to intensive care.  Altered consciousness on admission was seen in about 20% of patients who subsequently died.  At discharge, a third of patients assessed had “dysexecutive syndrome” (difficulty in making decisions, apparently.)

Exact figures from the text:

Acute illness; “common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5–36·0] of 129 patients), depressed mood (42 [32·6%; 24·7–40·9] of 129), anxiety (46 [35·7%; 27·6–44·2] of 129), impaired memory (44 [34·1%; 26·2–42·5] of 129), and insomnia (54 [41·9%; 22·5–50·5] of 129). ”

Post-illness: “depressed mood (35 [10·5%; 95% CI 7·5–14·1] of 332 patients), insomnia (34 [12·1%; 8·6–16·3] of 280), anxiety (21 [12·3%; 7·7–17·7] of 171), irritability (28 [12·8%; 8·7–17·6] of 218), memory impairment (44 [18·9%; 14·1–24·2] of 233), fatigue (61 [19·3%; 15·1–23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9–37·3] of 181) and sleep disorder (14 [100·0%; 88·0–100·0] of 14)”

Meta-analysis: “point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7–42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1–18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1–19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1–84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1)”

COVID-19: ” delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis.”

So these diseases shared similar mental symptoms during the acute illness and we would expect chronic symptoms after recovery to be similar as well.  This is important, because about a third of patients demonstrated post-traumatic stress disorder after discharge.  About 15% of these patients had anxiety or depression as well.  Three quarters of them returned to work, but the study followed them for three years after discharge, so we would expect prolonged disability with COVID-19 as well.

Underlying Neurobiological Pathology in COVID-19

Another study published June 30 in the  Journal of Alzheimer’s Disease described itself as reviewing the neurobiology of COVID-19 and postulated three distinct phases of infection. The article summarizes a number of published reports relating to neurological symptoms in acute infection.   It says that there are a number of common symptoms that could represent direct invasion of nerve cells or a sign of the body’s reaction to the virus: “Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19” but it is not obvious what is the underlying cause (or causes) of these symptoms.

The three phases of infection hypothesized in the article are: first, direct invasion of cells lining the upper respiratory tract which express ACE-2 on their surfaces (ACE-2 is the protein to which the virus binds before it enters the cell.)  Anosmia (loss of smell sensation) and dysgeusia or ageusia (perversion or loss of taste sensation) are, the article says, separate symptoms– and dysgeusia is actually more common than anosmia.  Both symptoms, it says, are caused by direct virus invasion and damage to the epithelial cells of the nose, mouth, and throat.

By the same token, airway epithelial cells of the trachea and lungs are hosts to direct viral invasion and result in cough, dyspnea, and chest pain.

It is not known whether the virus can directly invade the brain through the cranial nerves and infect central structures responsible for processing of smell and taste signals, but it is presently considered unlikely.

The second source of neuropsychiatric symptoms is through blot clots in the arteries leading to the brain and in the veins draining blood therefrom.  This is due to a hypercoagulable state (excessive blood clotting) which is brought on by pathologies associated with higher mortality: obesity, high blood pressure, and diabetes.  In these conditions, levels of inflammation-related blood proteins like interleukins are already higher than normal and rapidly become even more elevated.  These mechanisms are responsible for strokes, known as cerebrovascular accidents (CVAs.)

Some patients experience cerebral hemorrhages, which seems counterintuitive but appears to be related to vasoconstriction (closing of blood vessels by contraction of their intrinsic muscles.)

The third stage of brain injury in COVID-19 is also caused by excessive inflammation.  In more severe cases, there is a “cytokine storm”, which involves the small blood vessels in the brain and results in leakage of blood proteins into the brain matter.  Normally, the brain is protected by a membrane called the blood-brain barrier (BBB) which prevents all but a select few blood components from entering the brain.  This barrier is tight enough to prevent many drugs that normally diffuse into tissues elsewhere in the body from entering brain tissue.  When the endothelium (cells lining blood vessels) becomes inflamed, the BBB is breached and inflammatory molecules enter, damaging brain tissue.

The BBB breach causes symptoms of confusion, delirium, reduced level of consciousness (encephalopathy), seizures, coma, and death in extremis (at the end.)  If a patient recovers from a partial BBB breach, he or she may be permanently disabled by memory loss and poor “executive function” (decision-making ability.)  Depression, anxiety, and agitation are particularly common after recovery in these cases.

Some evidence suggests that SARS-COV-2 viral particles may, in some cases, directly enter the brain and infect neurons (some do have ACE-2 on their surfaces.)  This may cause symptoms of meningitis and encephalitis: stiff neck, headache, and seizures.  However, the virus has not been detected in cerebrovascular fluid as would be expected if there were direct viral invasion.

Cranial and peripheral nerves may be involved in COVID-19, similar to what was seen in SARS and MERS.  There have been reported cases of Guillain-Barre syndrome (GBS) (flaccid paralysis with loss of reflexes and sensory loss or cranial neuropathy), caused by immune cross-reaction between nerves and the virus.  These cases have responded to intravenous administration of immune globulin, typical of GBS.  Therefore, these cases are not thought to be due to virus invasion of nerves but to immune reactions.

Heart and Skeletal Muscle Involvement in COVID-19

There is some evidence that invasion of cells with the virus leads to downregulation of ACE2 expression in the affected cells.  This could lead to systemic effects of local invasion, by reducing the  ACE-2 function, leading to hypertension, inflammation, and prothrombosis (increased blood clotting.)

Myocardial infarction in COVID-19 is thought to be due to the hypercoagulable state induced by severe inflammation.  In addition, there is a suggestion that the nerves responsible for controlling the heart’s intrinsic rhythm may be involved by direct viral invasion.  Early reports from Wuhan, China (also here) found frequent instances of arrhythmia and heart muscle weakness even in patients without myocardial infarction.

Viral invasion of heart cells would be described as myocarditis (heart muscle inflammation) as opposed to cardiomyopathy (weakness of the heart muscle caused by ischemia or other pathologies.)  ACE-2 is expressed on the cell surface of many heart cells at high levels, including the heart’s smooth muscle (heart muscle, like other unconsciously controlled muscles, is smooth but skeletal muscle is striated.)

Skeletal muscles often show signs of involvement in COVID-19: the enzyme responsible for much of muscle’s activity, creatine phosphokinase (CPK), leaks out of damaged muscle cells and is found in elevated levels in the blood.  However, direct injury of striated (skeletal) muscle appears unlikely because these muscle cells do not express high levels of ACE-2.  High CPK appears to result from skeletal muscle injury by vasculitis (blood vessel inflammation) and other insults common to the intensive care unit (ICU.)

Skeletal muscles are weakened by the immobilization of serious illness and more so by the induced paralysis necessary to intubation and mechanical ventilation.  This results in severe weakness after recovery; rehabilitation to regain strength is often prolonged.

Other Organs Likely to be Severely Affected by COVID-19

The cells that express the most ACE-2 on their surfaces are endothelium (the lining of blood vessels big and small), respiratory epithelium from the nose to the trachea, bronchi, and smaller tubes leading to the alveoli (tiny sacs in the lung where oxygen is absorbed into the blood), the lining of the digestive tract (mouth, throat, esophagus, small and large intestine– skipping the stomach itself which has a specialized lining that resists high levels of acid), the lining of the urinary tract (genitourinary endothelium– bladder, kidneys, and tubes in between), and smooth muscle cells (the heart and blood vessels, among others.)  Damage from severe COVID-19 appears in all these organs, although it is most critical in the lungs (that fill with fluid, impairing oxygenation) and heart (where pump weakness and irregular beats lead to circulatory failure.)  The brain clearly is involved in this cascade of disasters, whether directly or indirectly.

Patients Who Recover From COVID-19 Are Still Suffering Afterwards

I hope that this gives you a better idea of the spectrum of neurological and psychiatric symptoms associated with COVID-19.  There is clearly a neurological basis for post-traumatic stress disorder, impaired memory, depression, and anxiety following the virus.

There are medical reasons why a previously highly organized and optimistic ER doctor would take her own life at 49 after appearing to recover from COVID-19 and returning to work.  This case was reported on April 27.  I won’t get into it in too much detail (here— NY Times,  here–CNN,  here–NBC,  and here–NPR, are some news accounts), but there are reasons why someone with no predisposing psychological problems would kill herself– it’s the pernicious effects of the virus combined with the unreasonable and unrealistic demands that were placed upon her as an emergency room physician and director.