By Ulrike W. Kaunzner, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Kaunzner reports no financial relationships relevant to this field of study.

SYNOPSIS: Known coronaviruses (CoV) can enter the central nervous system by different pathophysiologic mechanisms. Neurological presentations linked to the novel SARS-CoV-2 include encephalopathy, encephalitis, cranial neuropathies, Guillain-Barré syndrome and other neuropathies, and ischemic and hemorrhagic strokes.

SOURCES: Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun 2020; March 30. doi: 10.1016/j.bbi.2020.03.031. [Online ahead of print].

Ye M, Ren Y, Lv T. Encephalitis as a clinical manifestation of COVID-19. Brain Behav Immun 2020; April 10. doi: 10.1016/j.bbi.2020.04.017. [Online ahead of print].

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), a single-stranded ribonucleic acid (RNA) virus, which is the seventh known coronavirus. Typical presentation includes respiratory and systemic symptoms. However, a significant percentage of COVID-19 patients have neurological symptoms, including headache, anosmia, paresthesia, altered mental status (AMS), stroke, and encephalitis. The study by Wu et al discusses different peripheral and central nervous system (CNS) diseases that have been linked to well-studied coronavirus infections in the past. SARS-CoV, which caused SARS in 2003, has been associated with encephalitis, polyneuropathy, and strokes. Middle East respiratory syndrome (MERS), caused by MERS-CoV, also can lead to neurological symptoms, such as stroke, AMS, Guillain-Barré syndrome (GBS), and other neuropathy occurring two to three weeks after the initial respiratory presentation.

The pathophysiologic mechanisms of known coronaviruses affecting the CNS include direct entrance of the virus into the brain, which can occur either via an opening of the blood-brain barrier, or anterograde or retrograde neuronal transport. Angiotensin-converting enzyme 2 (ACE2) receptors on neuronal surfaces and capillary endothelium have been described as targets for different viruses in the past, including coronaviruses, and can be a potential entrance for SARS-CoV-2. Decreased oxygenation from lung infection, causing hypoxic changes in the brain and affecting mitochondria, may lead to anaerobic metabolism and cerebral edema. And activation of the immune system may lead to systemic inflammation affecting the brain or causing direct activation of residential CNS immune and glia cells. The case report by Ye et al describes a patient who presented with typical symptoms of COVID-19, including fever, shortness of breath, and myalgia, and tested positive for SARS-CoV-2. He developed confusion, and cerebrospinal fluid (CSF) analysis was negative for SARS-CoV-2 RNA as well as CSF immunoglobulin M (IgM) and immunoglobulin G (IgG) for SARS-CoV-2. The authors concluded that the patient had COVID-19-related encephalitis and, given the negative polymerase chain reaction (PCR) and serological titers, the presentation might have been related to the immune response. The patient improved with mannitol and supportive measures, returned to his baseline, and eventually was discharged.

COMMENTARY

These publications increased awareness of COVID-19-associated CNS disease at an early stage of the COVID-19 pandemic. The review of coronavirus-related pathophysiology is important, since it facilitates the understanding of possible CNS entry routes and disease mechanisms associated with SARS-CoV-2. As the pandemic emerges, new neurological disorders are being observed, such as ataxia, seizures, venous sinus thrombosis, Miller-Fisher syndrome, GBS, and cerebral hemorrhage. Knowledge of CNS involvement of coronaviruses is important.

The case of encephalitis highlights the fact that neither PCR nor serological testing were able to detect SARS-CoV-2 in CSF. The authors commented that bacterial infection and tuberculosis were ruled out, and it would be useful to know that other CSF viral panels were tested as well. The CSF profile does not show a classic pattern of infection, and the authors concluded that an immune/inflammatory response was the most likely etiology.

When this case report was published, only a few cases of encephalitis had been described. However, there now is increasing evidence that SARS-CoV-2 can cause meningitis and encephalitis, and some cases show the presence of viral RNA. These different cases demonstrate that encephalopathy or encephalitis needs to be considered in the presence or absence of SARS-CoV-2 in the CSF. However, whether mechanisms other than direct infection or inflammation contribute to an encephalitis-like picture also needs to be established. Fortunately, only a small number of COVID-19 patients have presented with encephalitis so far. However, many patients have prolonged encephalopathy, and more data are needed. Since viral clearance from the CNS is dependent on T-cells and neuronal apoptosis, as Wu and colleagues discussed, it will be important to see if patients with proven CNS involvement will have long-term sequelae or secondary inflammatory response from their infection.

Overall, establishing the extent of neurological symptoms associated with COVID-19 will be essential to determine if these symptoms are directly related to virus infection or secondary to other immune mechanisms. CSF analysis and autopsy data will show the range of neurotropism of SARS-CoV-2 and inflammatory response. CNS disease also has been considered an indicator of poor prognosis. Therefore, early recognition and treatment will be important. Documentation of neurological symptoms, close follow-up of respective cohorts, and comprehensive clinical databases will help to assess for the prevalence of neurological diseases in COVID-19 patients.