key: cord-0948038-24mi50rv
authors: Aaroe, Ashley; Majd, Nazanin; Weathers, Shiao-Pei; de Groot, John
title: Potential Neurologic and Oncologic Implications of the Novel Coronavirus
date: 2020-04-16
journal: Neuro Oncol
DOI: 10.1093/neuonc/noaa096
sha: 7d53d74791d09eb8e62ae32593c730d88a5012f7
doc_id: 948038
cord_uid: 24mi50rv

nan

such as age and cardiovascular comorbidities, but we do not yet know the extent to which cancer is an independent poor prognostic indicator. We also do not know if neurologic manifestations will be a significant feature of the disease. To provide a framework for approaching COVID-19 from a neuro-oncology perspective, we have collated several recent reports.

SARS-CoV2 is an enveloped single-stranded RNA coronavirus that has caused the COVID-19 pandemic. It is one of seven coronaviruses that are known to infect humans, along with SARS-CoV1, MERS-CoV, and four endemic species that cause cold-like symptoms (229E, OC43, NL63 and HKU1). Common symptoms of COVID-19 include fever, cough, and shortness of breath. In an early report, all COVID-19 patients had abnormalities on chest CT, and the authors noted high serum cytokine levels as well (such as IL1B and IFNγ) [1] . Patients requiring ICU admission had higher concentrations of GCSF, IP10, MCP1 and TNFα than those who did not. It has been hypothesized that a cytokine release syndrome (similar to that seen in patients treated with immunotherapy) is implicated in patients who decompensate. Immunomodulatory agents such as hydroxychloroquine and tocilizumab are currently under investigation. Neurological symptoms have been described in association with many respiratory viruses [2] . Across all, the most common neurological manifestations are headache, encephalopathy, seizure, and encephalitis. There are several potential underlying mechanisms. Metabolic dysfunction and hypoxia, for example, can both contribute to encephalopathy and seizures. Human coronavirus species have been detected in CNS samples of patients with MS as early as the 1980s in autopsy studies [3] , and also in the CSF of children with acute disseminated encephalomyelitis. Consequently, there is a speculated association with demyelination. Human coronaviruses are also known to cause encephalitis. In one study, 22 of 183 children hospitalized with suspected encephalitis were infected with coronavirus [4] . Serum lymphocyte counts in children with CNS coronavirus infection were lower when compared with respiratory-infected patients. A similar phenomenon may be evident in SARS-CoV2, as an estimated 63% of COVID-19 patients develop lymphopenia, and recent data shows a trend to worsened lymphopenia in patients with CNS symptoms compared with those without [5] . SARS-CoV1, which is more structurally similar to SARS-CoV2 than other human coronaviruses, has also been demonstrated in the CSF of SARS patients in the early 2000s [6] .

There are many hypothesized routes of CNS invasion. These include hematogenous spread, in which viremia leads to either transcytosis across the blood brain barrier or infection of endothelial cells or leukocytes, and spread along peripheral nerves. Other human coronaviruses are thought to penetrate the CNS through the olfactory bulb. One group reported that upon infection of mice with human coronavirus OC43, viral antigens were first detected solely in the olfactory bulb [7] . Four days later virus was detected throughout the brain, with infection of both glial and neuronal cells. Interestingly, there are emerging reports of anosmia as a new presenting feature of SARs-CoV2, which may potentially be related to olfactory nerve involvement. Once Literature concerning the neurological manifestations of SARS-CoV2 is evolving quickly. A preliminary report describes a case of acute myelitis following SARS-CoV2 infection [9] . There is also a report a of survivor who experienced transient central hypoventilation (also known as Ondine's curse) [10] . Regarding larger data sets, one observational study from Wuhan reported that of 214 COVID-19 patients, 78 (36.4%) patients had neurologic manifestations [5] . 53 (24.8%) had CNS symptoms (predominantly dizziness and headache), and 19 (8.9%) had peripheral nervous system symptoms (predominantly hypogeusia and hyposmia). CNS symptoms were particularly severe in patients with worse respiratory involvement. As noted above, patients with neurological symptoms had lower serum lymphocytes than those without.

Another report found that, of 221 patients with COVID-19, 11 (5%) developed acute ischemic stroke, 1 (.5%) developed cerebral venous sinus thrombosis, and 1 (.5%) developed intracranial hemorrhage [11] . The patients with cerebrovascular disease were older, had more vascular risk factors, and were felt to have an increased inflammatory response as evidenced by higher Ddimer and C-reactive protein.

Another consideration of critical importance to neuro-oncologists is how patients with cancer will be affected by COVID-19. This demographic is known to have higher mortality from pneumonia caused by other human coronavirus species. In one cohort from Wuhan of 1590 COVID-19 cases, 18 had a history of cancer [12] . Two patients had unknown treatment status, four had chemotherapy or surgery in the past month, and twelve were long term survivors. This subset of cases was observed to have a higher risk of severe events (admission to ICU, need for A c c e p t e d M a n u s c r i p t 5 intubation, and death) compared to patients without a history of cancer (7/18 patients versus 124/1572 patients). However, the majority of patients were on surveillance, without active disease or immunosuppression. Also, the age of this group was higher which is a known independent poor prognostic factor. Nevertheless, a recent study from Italy corroborates that there is likely an increased risk of mortality in oncologic patients, finding that 20.3% of patients who died from COVID-19 had active cancer [13] . It is our hope that this summary is valuable as a starting point for further investigations and discussion.

A c c e p t e d M a n u s c r i p t

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Neurologic Alterations Due to Respiratory Virus Infections

Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children

Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. 2/22/2020

Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome

Human respiratory coronavirus OC43: genetic stability and neuroinvasion

Acute myelitis after SARS-CoV-2 infection: a case report. 3/16/20

The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients

Acute Cerebrovascular Disease Following COVID-19: A single Center, Retrospective, Observational Study. 3/3/2020

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy