The development of long-term symptoms of
coronavirus disease 2019 (COVID-19) more than four weeks after primary
infection, termed "
long COVID" or post-acute sequela of
COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as
fatigue, "
brain fog",
headaches,
cognitive impairment,
dysautonomia, neuropsychiatric symptoms,
anosmia,
hypogeusia, and
peripheral neuropathy. Pathogenic mechanisms of these symptoms of
long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function.
SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged
cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2
protease activity and complement activation, can contribute to hypoxic neuronal injury and blood-brain barrier dysfunction, respectively. Current
therapeutics target pathological mechanisms by employing
antivirals, decreasing
inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of
long COVID and potential
therapeutics.