Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barre syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barre syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.

Neurological Associations of COVID-19

Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review.

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Dusseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS-CoV-2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS-CoV-2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS-CoV-2 and emphasize that brain organoids could model CNS pathologies of COVID-19.

https://www.embopress.org/doi/epdf/10.15252/embj.2020106230

SARS-CoV-2 targets neurons of 3D human brain organoids.

Neurological manifestations and complications of COVID-19: A literature review.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.

COVID-19: A Global Threat to the Nervous System.

Guillain-Barré Syndrome associated with SARS-CoV-2 infection.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) remains a serious issue for global health, given widespread infectivity and a high contagion rate. A tremendous amount of data has been generated since it was first identified in December 2019. It is vital to keep up with these data from across the world at a time of uncertainty and continuously evolving guidelines and clinical practice. This review provides an update on recent developments concerning epidemiology, clinical presentation, treatment options, and scientific advancements to combat the COVID-19 pandemic.

COVID-19: An Update on the Epidemiological, Clinical, Preventive, and Therapeutic Management of 2019 Novel Coronavirus Disease.

First successfully described in 1967, acute respiratory distress syndrome has since garnered much interest and debate. Extensive studies and clinical trials have been carried out in efforts to address the associated high mortality; however, it remains a significant burden on health care. Despite the heterogeneous etiologies that lead to the development of acute respiratory distress syndrome, this rapidly progressing form of respiratory failure, characterized by severe hypoxemia and nonhydrostatic pulmonary edema, has a recognizable pattern of lung injury. In this chapter, we will review the clinical manifestations, definitions, causes, and a brief overview of the pathophysiology of this complex syndrome.

Acute Respiratory Distress Syndrome Definition, Causes, and Pathophysiology.

As the confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to grow with over 1 million documented infections in the United States alone, researchers and health care workers race to find effective treatment options for this potentially fatal disease. Mortality remains high in patients whose disease course requires mechanical ventilation and admission to intensive care units. While focusing on therapies to decrease mortality is essential, we must also consider the logistical hurdles faced with regard to safely and effectively delivering treatment while limiting the risk of harm to hospital staff and other noninfected patients. In this article, we discuss aspects of surge planning, considerations in limiting health care worker exposure, the logistics of medication delivery in a uniform and consolidated manner, protocols for delivering emergent care in a rapidly deteriorating coronavirus disease-2019 (COVID-19) patient, and safe practices for transporting infected patients.

Institutional COVID-19 Protocols: Focused on Preparation, Safety, and Care Consolidation.

Acute respiratory distress syndrome (ARDS) was first described in 1967. Since then, several landmark studies have been published that have greatly influenced the way we diagnose and treat patients with ARDS. Despite extensive research and advancements in ventilator strategies, moderate-severe ARDS has been associated with high mortality rates. Current treatment remains primarily supportive with lung-protective ventilation strategies. Pharmacological therapies that reduce the severity of lung injury in vivo and in vitro have not yet translated into effective clinical treatment options. Currently, the mortality rate of severe ARDS remains in the range of 30% to 40%. To review, the mainstay of ARDS management includes mechanical ventilation with low tidal volumes to decrease barotrauma, prone ventilation, conservative fluid management, and neuromuscular blockade. ARDS survivors tend to have long-term and potentially permanent neuromuscular, cognitive, and psychological symptoms, affecting patient's quality of life posthospitalization. These long-term effects are likely secondary to prolonged hospitalizations, prolonged mechanical ventilation, utilization of prone strategies, utilization of paralytic drugs, and occasionally steroids. Therefore, several novel therapies outside the realm of advanced ventilation and prone positioning methods are being studied. In this article, we discuss a few of these novel therapies including prophylactic aspirin, inhaled nitric oxide, mesenchymal stem cells, and intravenous β-agonists. Steroids and extracorporeal membrane oxygenation have been discussed in a previous article.

Ahmed Virani

Papers

Guillain-Barré Syndrome associated with SARS-CoV-2 infection.

COVID-19: An Update on the Epidemiological, Clinical, Preventive, and Therapeutic Management of 2019 Novel Coronavirus Disease.

Acute Respiratory Distress Syndrome Definition, Causes, and Pathophysiology.

Institutional COVID-19 Protocols: Focused on Preparation, Safety, and Care Consolidation.

Acute Respiratory Distress Syndrome Novel Therapies.