“If someone has weakness in their left arm, and they don’t use their left arm as much, it’s not going to get stronger if they don’t receive physical therapy. The same happens in the brain. People need to receive brain rehabilitation in order to recover from COVID-19 symptoms.” –Majid Fotuhi, Johns Hopkins University
In the midst of the coronavirus pandemic, with more than 14 million cases and over 600,000 deaths worldwide, clinicians are grappling with the fact that the virus can, in fact, lead to complications beyond the respiratory system like the lungs: Neurological symptoms such as stroke, encephalopathy (brain damage) and even a rare condition of brain inflammation condition may emerge.
A growing number of reports are detailing a host of brain disorders among COVID-19 patients. While these neurological complications are rare, researchers are alerting clinicians to be on the lookout for patients’ symptoms such as fatigue, numbness and memory problems.
“We want clinicians to recognise the range and timing of potential neurological complications of SARS COV-19. This will hopefully improve early diagnosis and treatment and potentially reduce the burden of long-term neurological disability,” Ross Paterson, a senior research fellow and honorary consultant neurologist at the Dementia Research Centre at University College London, wrote in an email to Being Patient.
People recovering from the coronavirus should also be aware of such symptoms, researchers say, as neurological disorders may increase a person’s risk for accelerated aging, mental health disorders and possibly neurodegenerative diseases.
Accordingly, researchers are urging those in recovery to see a neurologist if they are experiencing cognitive issues like processing information more slowly or trouble focusing six to eight months after their hospital discharge.
“This virus has the potential to damage multiple organs, either directly or indirectly, and this may have lasting implications for health beyond the immediate COVID-19 infection,” Paterson said.
A Concerning Number of Patients Suffering from a Rare Brain Condition
In a study published last week in the journal Brain, Paterson and colleagues documented the symptoms of more than 40 COVID-19 patients in the UK. A dozen suffered from inflammation in the central nervous system. Among them were nine patients with acute disseminated encephalomyelitis (ADEM) which is a rare condition typically seen in children, caused by a brief but widespread inflammation in the brain and spinal cord.
The researchers saw an alarming increase in the number of patients with ADEM. While the team usually treats about one adult patient with ADEM monthly, that number has increased to at least one per week.
Some patients received steroids while others received therapies to alter their immune responses, Paterson said, with some responding well to treatment. Though he noted that the results should be interpreted with caution as the study involved a small number of patients, using purely observational data. Since there was not a control group, the researchers would not have known how patients’ conditions would have changed without treatment.
While the team usually treats about one adult patient with ADEM monthly, that number has increased to at least one per week.
Other Neurological Symptoms of COVID-19 Patients
The group also documented a host of other neurological symptoms among COVID-19 patients. Eight patients from the cohort suffered strokes. Another eight suffered from peripheral neurological disorders caused by damage to the nerves outside of their brain and spinal cord. Ten patients had encephalopathies (brain damage) along with delirium or psychosis.
One of the patients described in the study was a 65-year-old female with a history of cognitive decline, and she was presumed to have early onset Alzheimer’s. Six days after experiencing fever, cough and muscle ache, her vision deteriorated. She had a hard time speaking and reading. Hallucinations emerged as she reported seeing people inside her house and objects flying around the room.
The patient received steroids for a presumed case of encephalitis (brain inflammation) two weeks after the onset of neurological symptoms. While her symptoms remained during the team’s research, her cognition and visual symptoms improved.
Whether Alzheimer’s disease may increase people’s risk for COVID-19 remains unclear. Paterson said the team is hoping to better understand whether COVID-19 may interfere with the inflammatory pathways in the central nervous system of people with neurodegeneration. He pointed to the fact that brain inflammation plays an important role in neurodegenderation. For instance, the gene TREM2 which increases the risk for developing Alzheimer’s, is involved in regulating inflammation and plays a role in a host of neurodegenerative diseases.
Also, people with dementia have less cognitive reserve, Paterson said, and the variety of diseases or physiological stresses can lead to the decline in their cognition, changes that might be temporary.
Immune Response to COVID-19
Scientists are still figuring out whether the virus directly attacks the brain to cause neurological illnesses, though findings from the recent study suggested that may not be the case: The virus was not found in infected patients’ brain and spinal cord fluid. Instead, researchers found evidence that the body’s immune response to the virus may, in some cases, have led to brain inflammation.
Other factors such as damage to the blood vessels, deprivation of oxygen and blood clots, Paterson said, may also lead to neurological complications and explain why some people experience neurological symptoms before or without respiratory symptoms.
While clinicians are trying to better understand how the immune system and other factors can lead to neurological illnesses of COVID-19 patients, researchers have stitched together a clearer picture of how the immune response of inflammation plays a role in the respiratory symptoms of infected patients.
In particular, other scientists have identified ACE2, a receptor found in tissues such as the lungs, heart, nose and mouth, as gateway for the virus. It’s also the entry point for SARS-CoV-1, the virus which causes severe acute respiratory syndrome (SARS).
“When the [SARS-CoV-2] interferes with the normal function of ACE2 … it’s priming your lung into a state where it thinks it’s experiencing severe lung injury so there is a rapid ramp up of inflammation,” said Krishna Sriram, a postdoctoral fellow at University of California San Diego, who is studying how these proteins and immune responses are affected by the virus.
“Excessive inflammation is actually what causes the injury,” he added. “This is why you’re seeing a huge emphasis on anti-inflammatory drugs.”
The virus binds onto ACE2 receptors and renders them less capable of regulating a crucial biochemical pathway. What falters when the virus invades the body is ACE2’s ability to modulate angiotensin II, a protein that can increase inflammation.
According to Sriram, that may in part explain why people with hypertension (high blood pressure) and diabetes are at a higher risk for COVID-19, as they already have elevated levels of inflammation and angiotensin signals. One study of 140 hospitalized patients who were infected showed that 30 percent of them had hypertension and more than 10 percent had diabetes.
Infections typically begin in the nose or mouth, Sriram said, which can eventually spread to the lungs. Cells that form the lining of the lungs die, and the lungs become more vulnerable to bacterial infection.
“It’s a feedback loop. All of these inflammatory cells are going nuts because they think your lungs are seriously injured,” Sriram said. “They secrete a bunch of factors which then exacerbates injury and causes cell death. When your cells begin to die, they drive inflammation even further.”
That’s why patients can experience other infections like pneumonia, Siram said. Air sacs of the lungs become inflamed and filled with fluid or pus, leading to fever, chills and difficulty breathing. And about 16 percent of people with COVID-19 develop a severe respiratory illness such as pneumonia or acute respiratory distress syndrome.
“Once an infection like pneumonia kicks in, your immune system is going to go even crazier because not only are your immune cells thinking that your lungs are severely injured, they now [also] have to deal with the secondary infection,” Sriram said.
As immune cells crowd into the lungs, he added, they secrete substances to battle the invading virus. They can release an excessive amount of inflammatory substances, including proteins called cytokines. The notorious cytokine storm occurs as the inflammatory proteins flood the body.
The array of immune responses may lead to the formation of blood clots in blood vessels, Sriram said, a process known as thrombosis. Strokes may then follow.
“It’s the formation of thrombotic clots within your lung, which if they spread to other parts of your body and lodge in a small vessel in your brain, [that may lead to] a stroke,” Sriram said. “That’s most likely what’s happening. The picture is still emerging because there’s ongoing debate about the direct effects of the virus on the blood vessels themselves.”
Treatment for COVID-19 Patients
Researchers are testing a variety of anti-inflammatory drugs to help people recover from the impacts of the virus. A clinical trial is underway to assess whether the anti-inflammatory medication baricitinib paired with remdesivir, an antiviral drug already proven to help hospitalized patients recover, can speed recovery time even further.
Preliminary findings show that dexamethasone, a drug used since the 1960s to treat inflammatory diseases and cancer, may reduce death rates by about a third among COVID-19 patients who require mechanical ventilation.
In the meantime, Dr. Aaron Ritter, associate staff of neuropsychiatry and behavioral neurology at Cleveland Clinic Lou Ruvo Center, urged people who may be at high risk for neurological diseases, such as older adults, those who have compromised immune systems, and people with underlying medical problems, to diligently follow social distancing and hygiene protocols.
According to Johns Hopkins University Affiliate Staff Majid Fotuhi, brain rehabilitation is crucial for restoring patients’ cognitive abilities after they experience neurological complications like stroke.
“If someone has weakness in their left arm, and they don’t use their left arm as much, it’s not going to get stronger if they don’t receive physical therapy,” he said. “The same happens in the brain. People need to receive brain rehabilitation in order to recover from COVID-19 symptoms.”