Potential neurologic and oncologic implications of the novel coronavirus.

Along with medical providers across the world, we have watched the spread of the novel coronavirus SARS-CoV2 with deep concern. While much has been learned through the work of scientists and physicians on the front lines of the pandemic, there remain many unknowns. We are beginning to elucidate the underlying vulnerabilities that portend a worse clinical course, such as age and cardiovascular comorbidities, but we do not yet know the extent to which cancer is an independent poor prognostic indicator. Neurologic manifestations may 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.

Severe acute respiratory syndrome–coronavirus 2 (SARS-CoV2) is an enveloped single-stranded RNA coronavirus that has caused the COVID-19 pandemic. It is one of 7 coronaviruses that are known to infect humans, along with SARS-CoV1, MERS (Middle East Respiratory Syndrome)-CoV, and 4 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 interleukin 1B and interferon gamma).[1] Patients requiring admission to the intensive care unit (ICU) had higher concentrations of granulocyte colony stimulating factor, interferon gamma-induced protein 10, monocyte chemoattractant protein 1, and tumor necrosis factor alpha 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.

Neurologic symptoms have been described in association with many respiratory viruses.[2] Across all, the most common neurologic 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. Another unique question for COVID-19 is if the posited cytokine release syndrome causes neurologic complications. Lastly, while coronaviruses are not considered to have the same flagrant neurovirulence as polio and West Nile, they are nevertheless neuroinvasive.

Human coronavirus species have been detected in CNS samples of patients with multiple sclerosis as early as the 1980s in autopsy studies,[3] as well as 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 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 show 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, was also 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 viral particles have entered the CNS, SARS-CoV2 utilizes protein spikes to gain entry into cells. These spikes bind to the angiotensin converting enzyme 2 receptor which is expressed in both neurons and glia.[8]

Literature concerning the neurologic 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 of a survivor who experienced transient central hypoventilation (also known as Ondine’s curse).[10] Regarding larger datasets, one observational study from Wuhan reported that of 214 COVID-19 patients, 78 (36.4%) 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 neurologic 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 (0.5%) developed cerebral venous sinus thrombosis, and 1 (0.5%) 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 D-dimer 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, 4 had chemotherapy or surgery in the past month, and 12 were long-term survivors. This subset of cases was observed to have a higher risk of severe events (admission to ICU, need for intubation, and death) compared with patients without a history of cancer (7/18 patients vs 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] The impact of COVID-19 on the field of neuro-oncology is unknown. Patients on alkylating agents may be at greater risk of infection due to its lymphodepleting effects. As hospitals restrict access to protect patients from this viral pandemic, clinicians from all areas are weighing the risks of viral exposure with the importance of aggressive therapy for notoriously aggressive tumors of the brain. This pandemic forces us to reflect on our current practices and offers an opportunity for innovation. It is our hope that this summary is valuable as a starting point for further investigations and discussion.