A Review of Neurological Symptoms in COVID-19 Patients
By Rupali Gund, Ph.D.
As authorities are preparing to ease lockdown measures and try a staggered reopening, it is important to realize that we haven’t won the pandemic yet. A second wave of infection is expected, but the continued implementation of strict personal hygiene and social distancing would potentially curtail the spike. Until we develop an effective cure, a thorough review of existing knowledge would primarily aid in our efforts to at least coexist with the SARS-CoV-2 virus. To that end, we decided to focus on some of the lesser-discussed symptoms of COVID-19 involving neurological manifestations.
According to the Centre for Disease Control and Prevention (CDC), infected people develop symptoms that vary from mild to severe, usually 2-14 days after exposure. This includes a broad spectrum of symptoms ranging from fever, dry cough, sore throat, headache, and fatigue to more severe ones such as difficulty in breathing and chest pain2. Recent observations suggest that, besides the respiratory illness, COVID-19 can also have life-threatening effects on the nervous system. Patients manifest neurological conditions that include dizziness, taste and smell impairment, impaired consciousness, or fatal cerebral ischemic stroke or hemorrhage2.
COVID-19 Causes Multi-Organ Failure Including the Nervous System
A study conducted in Wuhan suggests that approximately 40% of patients develop neurological manifestations3. These are more common in severely infected, elderly patients (age>65 years) who have an existing medical condition. CDC identifies patients with hypertension, diabetes, asthma, obesity, heart, liver or kidney disease, and patients with a compromised immune system due to cancer treatment, AIDS or organ transplantation, as a high-risk group. Children were initially considered low-risk; however, new reports indicate that younger children can develop a hyperinflammatory condition resembling Kawasaki disease4.
A gender-based difference is also observed, wherein due to the higher levels of the ACE2 (Angiotensin I converting enzyme 2) receptor, more number of men, especially with heart failure, get infected than women. The ACE2 receptor, which is required for viral attachment and entry into the host cells, is expressed in multiple tissues, including the gastrointestinal tract, kidneys, and liver. As a result, the virus can cause systemic infection and result in multi-organ failure. It can infect alveolar cells in the lungs as well as in small intestines. Patients develop numerous complications, including kidney failure, cardiovascular damage, and blood coagulation disorder.
Also, dermatological conditions with skin rashes are observed several days before other signs are noted. Difficulty in breathing and low oxygen saturation due to respiratory illness could result in bluish lips and face. Patients also exhibit necrosis in fingers and toes; a condition now termed as “COVID-19 toes”.
Neurological Disorders Associated with COVID-19
Severe COVID-19 patients present several symptoms that could arise due to the impact of coronavirus on the nervous system. A retrospective study conducted on hospitalized patients in Wuhan found that patients developed neurological symptoms with central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste, smell and/or vision impairment and nerve pain), and skeletal muscle injury manifestations3.
Severely infected patients also manifest impaired consciousness. COVID-19 was found to negatively impact the level (causing drowsiness and coma) and content of consciousness (causing confusion and delirium). In relatively older patients with severe infection, acute cerebrovascular complications lead to ischemic stroke or cerebral hemorrhage. Most neurological presentations are observed within 1-2 days after hospitalization. Interestingly, some patients only manifest neurological symptoms without showing typical symptoms of fever, cough, anorexia, or diarrhea.
In addition to infecting lung cells, the virus can affect the brain tissue setting off an inflammatory reaction causing viral encephalitis. Nerve tissue damage caused by inflammation in the brain can lead to symptoms such as headache, fever (mainly high fever), vomiting, convulsions, and consciousness disorders.
Systemic infection and respiratory damage associated hypoxia (low oxygen) negatively impair the brain function causing hypoxic encephalopathy5. The pathological change in this condition involves fluid accumulation in the brain, causing cerebral edema. Patients with a mild course of the disease may develop headache, uneasiness, drowsiness, and delirium. Severely affected patients may experience disoriented consciousness, coma, and paralysis. Besides, a subset of patients have blood coagulation disorder and develop fatal cerebrovascular conditions resulting in ischemic stroke and hemorrhage.
Possible Mechanisms of Nervous System Damage
Direct Viral Invasion into the Brain
The effect on the nervous system could occur through direct or indirect pathways. Direct invasion of coronavirus into the brain tissue could damage the nerve tissue. This entry is hypothesized to happen through blood and/or transport along the peripheral nerves. Once the virus infects and kills the infected cells at the point of entry, virus particles release into the blood, causing systemic infection and damage the blood-brain barrier to access the brain tissue.
Additionally, viruses can infect peripheral nerves and travel along the nerves to enter the brain tissue. One possible hypothesis for the neuronal route could be the transport through olfactory neurons in the nasal cavity6. Coronavirus is known to be transmitted through air droplets (generated by sneezing and coughing), and it infects the respiratory system through the nasal tract. The unique location of olfactory nerves and olfactory bulb in the nasal cavity makes it an accessible channel for the virus between nasal epithelium and brain. As a consequence, the virus can migrate into the brain through the olfactory tract in the early stages of infection. The actual route of entry into the brain (via blood/neurons) is not experimentally proven yet and demands further investigation. Damage in the olfactory neurons perhaps could be responsible for the impairment in the sense of smell in COVID-19 patients, which intriguingly develops in the absence of nasal congestion.
Hypoxia and Inflammatory Cytokine Induced Cerebral Damage
Coronavirus severely compromises respiratory function because virus particles infect the cells lining the walls of air sacs called alveoli and blood capillaries in the lungs. Infected cells become virus-producing factories that produce new virus particles that rapidly infect the neighboring cells. Eventually, infected cells die and accumulate in the alveoli along with the fluid leaking from damaged blood capillaries. This tissue damage and inflammation result in the thickening of the alveolar wall, which makes gas exchange difficult and leads to shortness of breath, causing respiratory illness pneumonia.
Trouble in breathing causes hypoxia, which promotes anaerobic metabolism and elevates levels of acidic metabolic by-products in the brain tissue. To improve blood flow, cerebral blood vessels dilate, but that is negatively accompanied by leakage of fluid in brain interstitium, causing swelling and edema. Cerebral edema is a serious complication as swelling can obstruct blood flow and result in hemorrhage. If hypoxia persists, brain activity deteriorates gradually and drowsiness, and even coma sets in paralyzing COVID-19 patients.
Coronavirus also induces an elevated proinflammatory cytokine storm that can negatively impact the brain function. The virus can perhaps directly infect microglia and astrocytes (shown in experimentally cultured cells only) and induce Interleukin-6 (IL-6) that further aggravate COVID-19 symptoms.
ACE-2 related Cerebrovascular Disorder
Ischemic stroke, cerebral thrombosis, and cerebral hemorrhage are some of the acute cerebrovascular conditions. Critically ill patients have elevated levels of D-dimer (an indicator of blood clot formation and breakdown) and severe platelet reduction, causing blood coagulation issues. Clot formation in blood vessels can block blood circulation in the affected tissue causing an ischemic stroke or bursting of blood vessels leading to hemorrhage.
Besides, the inflammatory cytokine storm caused by systemic infection and hypoxia caused by respiratory damage further aggravates the medical condition in patients and enhances the tendency for the cerebrovascular disorder. ACE-2 is a critical enzyme that controls blood pressure. Virus attachment to ACE2 prevents its normal function, causing an increase in blood pressure and elevates the chances of hemorrhagic strokes Thus, a combination of coagulation disorders and increased blood pressure in patients with underlying hypertensive condition aggravates disease prognosis with the occurrence of ischemic or hemorrhagic strokes in severe COVID-19 patients.
In summary, COVID-19 is not just a respiratory illness but affects multiple organs, including the nervous system. Severe infected elderly patients are particularly a high-risk group for developing neurological manifestations due to their underlying medical conditions. The loss of sense of smell or taste develops early during infections in asymptomatic individuals who are potential carriers. Therefore, it must be considered as an early tell-tale sign for coronavirus infection in the absence of other symptoms7. Such individuals should strictly practice self-isolation to limit transmission. Other neurological manifestations in patients could be as benign as a headache or can escalate to a life-threatening condition such as cerebral stroke/hemorrhage. Health care providers should be closely monitoring brain function and activity in COVID-19 patients. Conversely, patients hospitalized solely for neurological disorders should be tested for COVID-19.
Editor: Rajaneesh K. Gopinath, Ph.D.
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