#15,593
Nearly 8 months ago, in JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease, we looked at the first major report on the neurological impact of COVID-19, one which found more than 1/3rd of a study group (n=214) hospitalized in Wuhan, China showed signs of neurological involvement.Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.).
Since then we've seen numerous other studies describing neurological manifestations in COVID patients - with some warning of potential long-term sequelae - including an enhanced risk of Parkinson's disease.
- In mid-June, in The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?, we revisited the mysterious neurological epidemic that began around the time of the 1918 pandemic, and continued on for a decade.
- A couple of weeks later, in The Lancet: Yet Another Study On Neurological Manifestations In Severe COVID-19 Patients, we looked at report published in The Lancet Psychiatry, that described 153 COVID-19 cases treated in UK hospitals which found a wide range of neurological and psychiatric complications affecting both younger and elderly patients.
- In July I blogged on a 63-page report from the Journal Brain called The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
- In August, in J. Neurology: COVID-19 As A Potential Risk Factor For Chronic Neurological. Disorders, we revisited the growing concerns over the long-term neurological impacts of COVID-19 infection.
- In September (see Parkinsonism as a Third Wave of the COVID-19 Pandemic?) we looked at a Review Article, published in the Journal of Parkinson's Disease, that examined the parallels between COVID-19 and epidemics of the past, and the potential for seeing a new wave of neurological disorders.
- And in October, we looked at a report called Frequent Neurologic Manifestations & Encephalopathy‐Associated Morbidity in Covid‐19 patients which presented the first detailed study of neurological manifestations in hospitalized COVID patients in the United States.
While neurological manifestations are well documented in a significant percentage of COVID-19 cases, exactly how the virus manages to get into the brain has remained a mystery.
Yesterday, in a study published in Nature Neuroscience, researchers report they have at documented least a partial answer; tracing the virus's route via nerve cells in the olfactory mucosa from the nasopharynx to the brain. They caution, however, this may not be the only route of entry.
First a link to the Nature Study, followed by excerpts from a far less technical press release from Charité - Universitätsmedizin Berlin.
Published: 30 November 2020
Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19
Jenny Meinhardt, Josefine Radke, […]Frank L. Heppner
Nature Neuroscience (2020) Cite this article
Abstract
The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely.
By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism.
SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
Press release
30.11.2020
How SARS-CoV-2 reaches the brain
Using post-mortem tissue samples, a team of researchers from Charité – Universitätsmedizin Berlin have studied the mechanisms by which the novel coronavirus can reach the brains of patients with COVID-19, and how the immune system responds to the virus once it does. The results, which show that SARS-CoV-2 enters the brain via nerve cells in the olfactory mucosa, have been published in Nature Neuroscience*. For the first time, researchers have been able to produce electron microscope images of intact coronavirus particles inside the olfactory mucosa.
It is now recognized that COVID-19 is not a purely respiratory disease. In addition to affecting the lungs, SARS-CoV-2 can impact the cardiovascular system, the gastrointestinal tract and the central nervous system. More than one in three people with COVID-19 report neurological symptoms such as loss of, or change in, their sense of smell or taste, headaches, fatigue, dizziness, and nausea. In some patients, the disease can even result in stroke or other serious conditions.
Until now, researchers had suspected that these manifestations must be caused by the virus entering and infecting specific cells in the brain. But how does SARS-CoV-2 get there? Under the joint leadership of Dr. Helena Radbruch of Charité’s Department of Neuropathology and the Department’s Director, Prof. Dr. Frank Heppner, a multidisciplinary team of researchers has now traced how the virus enters the central nervous system and subsequently invades the brain.
As part of this research, experts from the fields of neuropathology, pathology, forensic medicine, virology and clinical care studied tissue samples from 33 patients (average age 72) who had died at either Charité or the University Medical Center Göttingen after contracting COVID-19. Using the latest technology, the researchers analyzed samples taken from the deceased patients’ olfactory mucosa and from four different brain regions. Both the tissue samples and distinct cells were tested for SARS-CoV-2 genetic material and a ‘spike protein’ which is found on the surface of the virus. The team provided evidence of the virus in different neuroanatomical structures which connect the eyes, mouth and nose with the brain stem. The olfactory mucosa revealed the highest viral load. Using special tissue stains, the researchers were able to produce the first-ever electron microscopy images of intact coronavirus particles within the olfactory mucosa. These were found both inside nerve cells and in the processes extending from nearby supporting (epithelial) cells. All samples used in this type of image-based analysis must be of the highest possible quality. To guarantee this was the case, the researchers ensured that all clinical and pathological processes were closely aligned and supported by a sophisticated infrastructure.
“These data support the notion that SARS-CoV-2 is able to use the olfactory mucosa as a port of entry into the brain,” says Prof. Heppner. This is also supported by the close anatomical proximity of mucosal cells, blood vessels and nerve cells in the area. “Once inside the olfactory mucosa, the virus appears to use neuroanatomical connections, such as the olfactory nerve, in order to reach the brain,” adds the neuropathologist. “It is important to emphasize, however, that the COVID-19 patients involved in this study had what would be defined as severe disease, belonging to that small group of patients in whom the disease proves fatal. It is not necessarily possible, therefore, to transfer the results of our study to cases with mild or moderate disease.”
The manner in which the virus moves on from the nerve cells remains to be fully elucidated. “Our data suggest that the virus moves from nerve cell to nerve cell in order to reach the brain,” explains Dr. Radbruch. She adds: “It is likely, however, that the virus is also transported via the blood vessels, as evidence of the virus was also found in the walls of blood vessels in the brain.” SARS-CoV-2 is far from the only virus capable of reaching the brain via certain routes. “Other examples include the herpes simplex virus and the rabies virus,” explains Dr. Radbruch.
The researchers also studied the manner in which the immune system responds to infection with SARS-CoV-2. In addition to finding evidence of activated immune cells in the brain and in the olfactory mucosa, they detected the immune signatures of these cells in the cerebral fluid. In some of the cases studied, the researchers also found tissue damage caused by stroke as a result of thromboembolism (i.e. the obstruction of a blood vessel by a blood clot). “In our eyes, the presence of SARS-CoV-2 in nerve cells of the olfactory mucosa provides good explanation for the neurologic symptoms found in COVID-19 patients, such as a loss of the sense of smell or taste,” explains Prof. Heppner. “We also found SARS-CoV-2 in areas of the brain which control vital functions, such as breathing. It cannot be ruled out that, in patients with severe COVID-19, presence of the virus in these areas of the brain will have an exacerbating impact on respiratory function, adding to breathing problems due to SARS-CoV-2 infection of the lungs. Similar problems might arise in relation to cardiovascular function.”
*Meinhardt J et al., Olfactory transmucosal SARS-CoV-2 invasion as port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2020. doi: 10.1038/s41593-020-00758-5
On this study
This study would not have been possible without the consent of the patients and/or their family members. The authors are immensely grateful to them. Post-mortem examinations performed by neuropathologists and pathologists on patients who have died of COVID-19 require the same level of personal protective equipment that is used when dealing with individuals with e.g. HIV or tuberculosis. Results from this study were published as a preprint (prior to peer review) on 4 June 2020. Following completion of the peer review process, the paper has now been published in Nature Neuroscience.
While many people continue to dismiss COVID-19 as a mild-to-moderate flu-like respiratory illness, the evidence continues to show that the virus can often have a far broader impact on human health, up to and including persistent or even permanent neurological damage.
Three weeks ago, in CDC: Late Sequelae of COVID-19 (Long COVID), we looked at the CDC's update on COVID cases who continue to experience complications even months after they have cleared the virus.
These complications include:
- Cardiovascular: myocardial inflammation, ventricular dysfunction (23-25)
- Respiratory: pulmonary function abnormalities (15, 32)
- Renal: acute kidney injury (22)
- Dermatologic: rash, alopecia (16)
- Neurological: olfactory and gustatory dysfunction, sleep dysregulation, altered cognition, memory impairment (1, 3, 13, 16, 19, 20)
- Psychiatric: depression, anxiety, changes in mood (3, 13, 16)
While most people survive COVID-19, and most of those appear to recover fully, that clearly isn't always the case. Meaning it may take years before we can properly gauge the long-term impact of this pandemic on public health.
