Neurocovid: Study Shows That COVID-19 Brain Fog Caused By Inflammatory Molecules In The Cerebral Spinal Fluid

Neurocovid: A new study by researchers from Memorial Sloan Kettering Cancer Center has found that the common symptoms of “brain fog” and confusion as a result of COVID-19 infection and even in those ‘recovered’ irrespective if they were asymptomatic, mild, moderate or hospitalized severe cases, are caused by inflammatory molecules in the cerebral spinal fluid.

The study team suggests that anti-inflammatory drugs, such as steriods, could help alleviate the symptoms of COVID brain.
 
The SARS-CoV-2 coronavirus infection induces a wide spectrum of neurologic dysfunction that emerges weeks after the acute respiratory infection. To better understand this pathology, the study team prospectively analyzed of a cohort of cancer patients with neurologic manifestations of COVID-19, including a targeted proteomics analysis of the cerebrospinal fluid.
 
The study team found that cancer patients with neurologic sequelae of COVID-19 harbor leptomeningeal inflammatory cytokines in the absence of viral neuroinvasion. The majority of these inflammatory mediators are driven by type II interferon and are known to induce neuronal injury in other disease states. In these patients, levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks after convalescence from acute respiratory infection. These prolonged neurologic sequelae following systemic cytokine release syndrome lead to long-term neurocognitive dysfunction.
 
The study findings were published in the peer reviewed journal: Cancer Cell https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00051-9#%20
 
Because of the numerous neurological symptoms and conditions found in COVID-19 patients, experts have coined the term Neurocovid as a specific field of study to deal with these issues.
 
Of the dozens of unusual symptoms that have emerged in COVID-19 patients (Both infected and recovering including those facing ‘Long Haul’ symptoms) is a condition that’s informally called “COVID brain” or “brain fog.”
 
“COVID brain” is characterized by confusion, headaches, and loss of short-term memory. In severe cases, it can lead to psychosis and even seizures. It usually emerges weeks after someone first becomes sick with COVID-19.
 
The multidisciplinary study team from Memorial Sloan Kettering reports in the published study on the 8th of February 2021 that the underlying cause of “COVID brain” is the presence of inflammatory molecules in the liquid surrounding the brain and spinal cord (called the cerebrospinal fluid). The study findings suggest that anti-inflammatory drugs, such as steroids, may be useful for treating the condition, but the team warns that more research is needed.
 
Dr Jessica Wilcox, the Chief Fellow in neuro-oncology at Memorial Sloan Kettering and one of the first authors of the study told Thailand Medical News via phone, “We were initially approached by our colleagues in critical care medicine who had obser ved severe delirium in many patients who were hospitalized with COVID-19. That meeting turned into a tremendous collaboration between neurology, critical care, microbiology, and neuroradiology to learn what was going on and to see how we could better help our patients.”
 
Typically the medical term for COVID brain is encephalopathy. Members of Memorial Sloan Kettering’s Department of Neurology felt well-poised to study it, Dr Wilcox says, because they are already used to treating the condition in other systemic inflammatory syndromes.
 
It is a common side effect in patients who are receiving a type of immunotherapy called chimeric antibody receptor (CAR) T cell therapy, a treatment for blood cancer. When CAR T cell therapy is given, it causes immune cells to release molecules called cytokines, which help the body to kill the cancer. But cytokines can seep into the area around the brain and cause inflammation.
 
Initially when the research team first began studying COVID brain, though, they didn’t know that cytokines were the cause. They first suspected that the virus itself was having an effect on the brain.
 
The research in the Cancer Cell paper focused on 18 patients who were hospitalized at Memorial Sloan Kettering with COVID-19 and were experiencing severe neurologic problems. The patients were given a full neurology workup, including brain scans like MRIs and CTs and electroencephalogram (EEG) monitoring, to try to find the cause of their delirium.
 
However when nothing was found in the scans that would explain their condition, the researchers thought the answer might lie in the cerebrospinal fluid.
 
Memorial Sloan Kettering’s microbiology team devised a test to detect the COVID-19 virus in the fluid. Thirteen of the 18 patients had spinal taps to look for the virus, but it was not found. At that point, the rest of the fluid was taken to the lab of Memorial Sloan Kettering’s physician cum scientist Dr Adrienne Boire for further study.
 
Dr Jan Remsik, a research fellow in Dr Boire’s lab in the Human Oncology and Pathogenesis Program and the paper’s other first author, led the analysis of the fluid.
 
Dr Remsik said, “We found that these patients had persistent inflammation and high levels of cytokines in their cerebrospinal fluid, which explained the symptoms they were having.”
 
He adds that some smaller case studies with only a few patients had reported similar findings, but this study is the largest one so far to look at this effect.
 
In the COVID-19-positive patient cohort, an increase in IFN-γ and its downstream effectors, CXCL-9, -10, and −11, is demonstrated in the cerebrospinal fluid (CSF) nearly 2 months after onset of SARS-CoV-2 infection.
 
As the major mediator against viral defenses in both intracranial and systemic processes, the systemic upregulation of the IFN-γ response is not unexpected in patients with a viral infection. However, IFN-γ demonstrates opposing roles in other neuroinflammatory conditions, regulating both pro-inflammatory and neuroprotectant properties in oligodendroglial cells, microglia, and astrocytes. Increased levels of intracranial CXCL chemokines have been described in a wide array of infectious and non-infectious CNS pathologies. The subsequent intracerebral accumulation of chemokines, monocyte-macrophages, and T lymphocytes downstream of IFN-γ propagates further neurologic injury. https://www.frontiersin.org/articles/10.3389/fimmu.2015.00539/full
 
https://pubmed.ncbi.nlm.nih.gov/29593804/
 
https://pubmed.ncbi.nlm.nih.gov/15111302/
 
https://pubmed.ncbi.nlm.nih.gov/16163626/
 
https://pubmed.ncbi.nlm.nih.gov/23831863/
 
Dr Boire added, “We used to think that the nervous system was an immune-privileged organ, meaning that it didn’t have any kind of relationship at all with the immune system. But the more we look, the more we find connections between the two.”
 
A key focus of Dr Boire’s lab is studying how immune cells are able to cross the blood-brain barrier and enter this space, an area of research that’s also important for learning how cancer cells are able to spread from other parts of the body to the brain.
 
Dr Boire further added, “One thing that was really unique about Dr Jan’s approach is that he was able to do a really broad molecular screen to learn what was going on. He took the tools that we use in cancer biology and applied them to COVID-19.”
 
Importantly the inflammatory markers found in the COVID-19 patients were similar, but not identical, to those seen in individuals who have received CAR T cell therapy.
 
Also as with CAR T cell therapy, the neurologic effects are sometimes delayed.
 
Interestingly the initial inflammatory response with CAR T cell treatment is very similar to the reaction called cytokine storm that’s often reported in individuals with COVID-19, Dr. Wilcox explains.
 
It was found that with both COVID-19 and CAR T cell therapy, the neurologic effects come days or weeks later. In CAR T cell patients, neurologic symptoms are treated with steroids, but doctors don’t yet know the role of anti-inflammatory treatments for people with neurologic symptoms of COVID-19.
 
Dr Wilcox added, “Many of them are already getting steroids, and it’s possible they may be benefitting.”
 
Dr Boire concluded,“This kind of research speaks to the cooperation across the departments at Memorial Sloan Kettering and the interdisciplinary work that we’re able to do. We saw people getting sick, and we were able to use our observations to ask big clinical questions and then take these questions into the lab to answer them.”
 
Just for additional information, Dr Boire is an inventor on a patent related to modulating the permeability of the blood-brain barrier and is an unpaid member of the scientific advisory board of EVREN Technologies.
 
The study was funded by National Institutes of Health grant P30 CA008748, the Pew Charitable Trusts, the Damon Runyon Cancer Research Foundation, and the Pershing Square Sohn Cancer Research Alliance GC239280. It was also supported by the American Brain Tumor Association Basic Research Fellowship, the Terri Brodeur Breast Cancer Foundation Fellowship, and the Druckenmiller Center for Lung Cancer Research.
 
The study team concluded, “Our findings have potentially important diagnostic and treatment implications. A prolonged encephalopathy of unknown etiology accompanies critical infections with COVID-19, and studies to date have not identified any obvious meningitic, ischemic, or ictal cause. This case series characterizes the increase in pro-inflammatory CSF cytokines in cancer patients in the weeks after respiratory illness. Similar to other encephalitides, these cytokines may result in neuronal damage in the absence of obvious radiographic abnormalities. Dexamethasone, a potent steroid and immunosuppressant, is the only intervention that has been shown in large-scale studies to reduce the incidence of death in hospitalized patients with severe COVID-19 infections. The impact of dexamethasone on COVID-19-related neurologic toxicity, specifically, has not been defined. Our data demonstrate that the neurologic toxicity associated with COVID-19 is biochemically similar to CAR T cell neurotoxicity. Clinical rubrics for the grading and management of CAR T cell neurotoxicity support early diagnosis and use of anti-inflammatory agents, including dexamethasone.”
 
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