[메디게이트뉴스 배진건 칼럼니스트] There are patients who complain of’brain fog’ as a corona 19 sequelae. Brain fog refers to the appearance of vague symptoms as if they were clouded, like the feeling of words. Neurological symptoms such as cognitive impairment, mental distress and delirium that appear in corona19 patients are sometimes referred to as’COVID brains’. The medical term for Covid Brain or Brain Fog is encephalopathy (腦病症). It means a brain disease. It refers to brain lesions, diseases, as well as general dysfunction.
Could the coronavirus even invade the brain? The brain protects the brain from microbes and toxins, usually through a wall called the’blood brain barrier (BBB)’. This BBB is located inside the capillaries that penetrate the brain and spinal cord. If the Corona 19 virus can penetrate this barrier, it will be able to invade the central nervous system. Then, the’reservoir virus’, which remains hidden in the central nervous system without being removed after cure for Corona 19, can recur after several years.
Most doctors, including internal medicine, may not be aware of any neurological abnormalities. In other words, when a seizure occurs or when there is no tremor symptom, it can only appear to be in a vague state. In addition, the environment in the intensive care unit, such as equipment and sedatives, bed isolation, etc., can exacerbate delirium. So there are cases where the cause cannot be related to the virus. Although the effects of the virus on the lungs are the most immediate and scary, the lasting effects on the nervous system can be much larger and even more destructive.
On February 8th, a research team from Memorial Sloan Kettering (MSK), a famous cancer hospital in Manhattan, New York, presented at Cancer Cell entitled’Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients’. Published a thesis. Meninges are the connective tissue covering the brain and spinal cord and are also called meninges. It consists of a three-ply membrane, the outermost part of the dura mater, the middle part of the arachnoid, and the thinnest of the three layers, the leptomeningeal. The title of the paper is that this inflammatory soft meningeal cytokine leads to corona 19 brain lesions in cancer patients. The research team concluded that neurological abnormalities appear as an indirect result of an inflammatory reaction in the human body (the famous’cytokine storm’).
Why are cancer patients the target of the COVID-19 study? This is because cancer patients are in an immunocompromised state where their immunity has fallen to the bottom due to long-term chemotherapy and radiation therapy. Because they are cancer patients with a low baseline, when corona infection occurs, immune changes can be better observed, which is advantageous for research. This study began as a collaboration to treat patients’ conditions as MSK intensive care units asked how to solve the symptoms of delirium in people infected with Corona 19, becoming a joint task of people in various fields.
Brain fog symptoms can occur in mild symptoms such as headache, loss of smell, and paresthesia, as well as severe forms such as aphasia, stroke, and seizures. There have been reports from last year that some of the patients with severe Corona 19 suffer from complications such as delirium and that cognitive impairments, including confusion and memory loss, persist for some time after the acute symptoms disappear. When MSK encountered the first Covid Brain patient, it was thought that the coronavirus itself affected the brain, causing a delusion. It was still unclear whether it was a symptom as a result of the virus being able to directly infect the brain through the BBB, or a secondary result of persistent inflammation.
So, from May to July of last year, MSK medical staff first performed all the neurological examinations (e.g. brain scan MRI, CTs, EEG monitoring) of 18 corona19 respiratory infection cancer patients. However, when these neurological examinations failed to observe any particular abnormalities, the researchers collected and analyzed cerebrospinal fluid (CSF) through lumbar punctures from 13 patients. The median values of cancer patients were 57 days after confirmation of respiratory infection and 37 days after onset of brain lesions. In particular, the number of cells, protein, and glucose present in the CSF were normal as known. First, the presence of Corona 19 was confirmed by CSF through a PCR-based test followed by an antibody test, but no virus was detected. There is still no conclusive evidence that Corona 19 infects neurons or astrosites, which are brain cells.
The researchers solved clinical questions such as confusion and memory loss presented by patients with science through CSF analysis. Another reason MSK was able to do this well is that it has accumulated a lot of experience in CAR-T cell therapy for cancer patients. The biggest clinical problem of CAR-T treatment is’Cytokine release syndrome (CRS)’, which is immune hyperactivity. Cytokines are secreted by CAR-T to kill cancer cells, but this side effect is high fever, muscle pain, low blood pressure and respiration in some patients as T cells release excessive amounts of immune active substances. The method of co-administration is used. In addition, interleukin-6, an immunologically active substance, remains high, and the patient may die. So, when Corona 19 patients show CRS symptoms, MSK medical staff knew how to deal with it.
The researchers divided the patients into four groups to properly perform the CSF analysis. To compare with the cancer patient corona-positive group, the first group is the corona19-negative patients whose age and type of cancer match. The second group was those who received CAR-T treatment among cancer patients, and the third group was the patients with autoimmune encephalitis (AIE). Twelve different markers of inflammation were investigated in 4 cohorts of around 8 people each.
As a result of the analysis, the patients’ CSF showed persistent inflammation, and the amount of IFN-β and IL-8 cytokines was very high compared to blood. Markers of aging and typical markers of neurodegeneration were also high. In particular, neurofibrillary fibers produced by a gene named NEFL, and neurofibrillation (NfL), known as a biomarker of dementia, were also high. So far, there have been reports that these inflammatory symptoms are present in CSF in a very small number of patients with coronavirus. However, like this study, the patient group has never been as large as 18. Of course, results from more patient populations are needed to generalize the conclusions of this study. In general, the central nervous system (CNS) was thought to be an immune privilege area where an immune surveillance system by immune cells does not exist because of the brain barrier. However, every new discovery proves that the immune system and the brain are closely related.
In particular, the main researcher, Dr. Boire’s lab used several’molecular screens’ because they were studying how immune cells work inside the brain just as cancer cells spread to the brain from other organs in the body. The inflammatory markers of COVID-19 patients and those of CAR-T-treated patients also overlap, but did not match. In particular, after receiving CAR-T cell therapy, the time for inflammatory markers to appear is a little slower compared to COVID-19.
Through this study, the research team concluded that the pathogenesis of encephalopathy caused by Corona 19 infection in cancer patients is not caused by the penetration of the virus into the brain, but by persistent encephalopathy caused by the’type 2 interferon mediator’ and the resulting nerve damage. Therefore, it is an empirical prescription for CAR-T treatment that steroids such as dexamethasone can be a useful treatment.
In particular, the correlation between the amount of matrix metalloproteinase-10 (MMP-10) in the CSF of these patients and the degree of neurodegenerative disease progression was outstanding. A new role exists for the’extracellular matrix (ECM)’, which accounts for 20% of the brain cell volume, a study we were not aware of. Therefore, it will be more meaningful to study using MMP-10 as a prognostic biomarker for neurological dysfunction.
As the corona pandemic prolonged, awareness of people suffering long-term symptoms after infection increased. Although Brain Fog or Covid Brain expresses neurological symptoms, there is also a temporal expression. This condition, called’Long COVID’, becomes a persistent long-haulers, significantly reducing the quality of life for those who have experienced infection. Statistically, the number of severely ill male patients is higher than that of females and the mortality rate is higher. Conversely, why are there more’long-haulers’ in women? To ensure that people who are completely exhausted after experiencing COVID-19 can return to their normal lives after taking a short walk, further research will be needed to answer questions about various neurological disorders and immune systems.
※The column is the columnist’s personal opinion and may not match the editorial direction of this magazine.