A Disease Hidden in Plain Sight: Pathways and Mechanisms of Neurological Complications of Post-acute Sequelae of COVID-19 (NC-PASC)

The global impact of coronavirus disease 2019 (COVID-19) marked by numerous pandemic peaks is attributed to its high variability and infectious nature, transforming it into a persistent global public health concern. With hundreds of millions of cases reported globally, the illness is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite its initial classification as an acute respiratory illness, recent evidence indicates that lingering effects on various bodily systems, such as cardiovascular, pulmonary, nervous, gastrointestinal (GI), and musculoskeletal, may endure well beyond the acute phase. These persistent manifestations following COVID-19, commonly known as long COVID, have the potential to affect individuals across the entire range of illness severity, with a tendency to be more prevalent in mild to moderate cases. At present, there are no established criteria for diagnosing long COVID. Nonetheless, it is conceptualized as a multi-organ disorder encompassing a diverse array of clinical manifestations. The most common, persistent, and debilitating symptoms of long COVID may be neurological, known as neurological complications of post-acute sequelae of COVID-19 (NC-PASC). More than one-third of individuals with a prior SARS-CoV-2 infection show involvement of both the central nervous system (CNS) and peripheral nervous system (PNS), as evidenced by an approximately threefold higher incidence of neurological symptoms in observational studies. The persistent neurological symptoms of long COVID encompass fatigue, headache, cognitive decline, "brain fog", dysautonomia, neuropsychiatric issues, loss of smell (anosmia), loss of taste (ageusia), and peripheral nerve problems (peripheral neuropathy). Reported pathogenic mechanisms encompass viral persistence and neuro-invasion by SARS-CoV-2, neuroinflammation, autoimmunity, coagulopathy, and endotheliopathy. Raising awareness of potential complications is crucial for preventing and alleviating the long-term effects of long COVID and enhancing the prognosis for affected patients. This review explores the hypothetical pathophysiological mechanisms and pathways of NC-PASC with a sole aim to increase awareness about this crippling disease.