Understanding the Mechanisms of Neurological Complications in COVID-19 with IsoPlexis’ Functional Proteomics

  • While coronaviruses generally cause respiratory illnesses, some COVID-19 patients have shown neurological symptoms, including headaches, confusion, and ischemic stroke. It is currently unclear what exactly causes neurological symptoms of COVID-19—whether symptoms are caused by the virus infiltrating the brain, by immune response-driven inflammation, or something else.
  • Based on experiences studying viruses such as HIV, SARS-CoV-1 and MERS, neurological manifestations of COVID-19 may potentially be caused by CNS inflammation, noting elevated levels of IL-6, IL-8, and IP-10 in patients’ CSF and plasma.
  • With IsoPlexis’ platform, researchers can identify cytokines released in the CNS and predict what immune cell types and pathways are associated with neurological symptoms.

IsoPlexis’ Unique Single-Cell Proteomics Helps Researchers Answer Critical Questions About the Effects of COVID-19

The Lancet Psychiatry  addressed the accumulating evidence of neurological symptoms in patients with COVID-19.1 Over the past several months, a portion of COVID-19 patients have experienced neurological symptoms, ranging from hallucinations, new-onset psychosis, and general neurocognitive decline, to ischemic stroke and intracerebral hemorrhage. Another common symptom of COVID-19, loss of smell or taste, may also be considered a mild neurological symptom.2 A publication in Brain noted the growing reports of neurological COVID-19 complications, even sometimes in the absence of other symptoms. With the growing need to understand these neurological symptoms, IsoPlexis’ platform has proven its ability to identify unique biomarker signatures in COVID-19 patients and in those experiencing neurological symptoms in an article published in BMC Neurology and another, forthcoming publication.

Acute disseminated encephalomyelitis (ADEM), a dangerous and sometimes fatal condition that is more often associated with viral infection in young children, is now being diagnosed in an increasing number of adult COVID-19 patients. In the study published in Brain, researchers recorded the neurological symptoms of 43 patients hospitalized with COVID-19 in London. The results were startling: of the 43 patients, 12 had inflammation of the CNS, including 9 cases of ADEM. An additional 10 patients experienced delirium or psychosis, eight patients had strokes, and another eight patients had peripheral nerve damage. Furthermore, at least two patients presented with symptoms that were likely neurological in origin after discharge, such as hallucinations, compulsive behaviors, and unusual drowsiness.3 Scientists are concerned that these symptoms could last for months or longer after infection, in some cases causing long-term cognitive deficiencies.2 In the decades after the 1918 Spanish flu pandemic, up to 1 million people develop encephalitis lethargica, a dangerous brain disorder causing fever, delayed physical and mental response, and lethargy. While the relationship between this disorder and the 1918 flu is unclear, many scholars argue that the brain disorder occurred as a complication of the flu.4

Analyzing CSF to Identify Potential Biomarkers of Neuroinflammation with IsoPlexis’ High-plex Automated Immunoassays

It is still unclear what exactly is driving neurological complications in the current pandemic­—factors such as the isolation of quarantine and decreased oxygen could create a “perfect storm to generate delirium.”2 While some researchers attribute neurological complications primarily to the infiltration of the SARS-CoV-2 virus into patients’ brains, there is no clear evidence as of yet that this is the case. While during the SARS-CoV-1, or SARS pandemic, the virus was present in some patients’ brains, this was not the case with MERS.2 So far, there has only been one reported instance of SARS-CoV-2 in the CSF, as reported in The Lancet Psychiatry There have been many more reports of CSF not testing positive for the virus.5 In a case study where a patient first presented with neurological symptoms, IsoPlexis’ highly multiplexed CodePlex cytokine assay, identified elevated levels of IL-6, IL-8, and IP-10 in the patients’ CSF and plasma as well as a unique MCP-1 signature only found in the CSF. This indicates that inflammation was likely driving these neurological complications.5 Available evidence is currently insufficient to suggest that SARS-CoV-2 can infiltrate the brains of those infected.

“One big question we have is whether the neurological issues we’re seeing, if they’re due to damage in the central nervous system (CNS), is that damage being incurred directly by the presence of the virus in the brain? Or is that a consequence of the human body having an aberrant or too strong immune reaction to the presence of the virus?” explained Dr. Shelli Farhadian of the Yale School of Medicine in a recent interview with IsoPlexis. According to Dr. Farhadian, who has conducted research on the effects of HIV on the brain, while some neurological complications of HIV are due to the virus’s direct presence in the nervous system, others are caused by the immune system sending an influx of immune cells into the CNS, causing damage and inflammation. The same may be true of neurological complications of COVID-19.

The next step, Dr. Farhadian says, is to gain a better understanding of the underlying mechanisms driving these neurological symptoms, through use of technology such as the CodePlex Secretome solution and the IsoLight system. With these tools, researchers can identify the secreted cytokines found in the CNS and begin to identify “the important immune cell types and immune cell pathways that may be contributing to neurological problems.”2 With these technologies providing critical insights into the effects of COVID-19 infection on different systems of the human body, scientists can make headway in developing targeted and individualized treatments for a diverse range of symptom presentations. Additionally, health professionals should make assessments of cognitive function a regular part of the screening or treatment of a COVID-19 patient, as early identification of neurological complications is critical to avoiding long-term damage.

To learn more about how IsoPlexis technology aids COVID-19 research, watch the “Improving COVID-19 Treatment & Vaccine Development by Modulating the Immune Response: Applying Single-Cell Proteomics” webinar below.



  1. Varatharaj A, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. The Lancet Psychiatry 7: P875-882, 2020.
  2. Winter, L, Severe Neurological Ailments Reported in COVID-19 Patients. The Scientist, 2020.
  3. Paterson RW, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological, and laboratory findings. Brain, 2020.
  4. Heidt, A, Dozens More Cases of Neurological Problems in COVID-19 Reported. The Scientist, 2020.
  5. Farhadian S, et al. Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19. BMC Neurology 20: 284, 2020.
Share This Article
Subscribe to Follow the Data

Weekly email to keep you at the forefront of single-cell & multiplexed proteomics.