Long COVID-19 syndrome has recently been recognised as a complex chronic clinical entity in subjects who have experienced SARS-CoV-2 infection. It is currently defined as the presence of symptoms for more than twelve weeks developed during or after SARS-CoV-2 infection which are not explained by an alternative diagnosis, usually presenting with clusters of symptoms that can affect any body system in the body, including the central nervous system.1 The prevalence of Post Acute Sequalae of SARS-CoV-2 infection (PASC) has shown significant variation among studies ranging from 33% in community-based studies2 to 75% in hospital-discharged subjects.3–5 Several important risk factors for PASC have been recognised including not only hospitalisation itself, but also increased age and obesity.1 Further, observational studies indicate a higher risk of PASC among middle-aged women,3–5 subjects with type 2 diabetes, subjects with the presence of autoantibodies during infection, and subjects that experienced more than five symptoms during the first week of initial infection.6–7 A recent study suggested the presence of PASC in 52% of young adults who were isolated at home during the infection, indicating the occurrence of PASC appears to be independent of the severity of the initial illness.8

Pathophysiological Processes Involved in Neurological Manifestations of PASC

It is well known that coronavirus enters the host cell using clathrin mediated endocytosis (CME) that is triggered by the binding of the virion to host receptors, such as angiotensin-converting enzyme 2 (ACE2), and to host proteases, such as transmembrane serine protease 2 (TMPRSS2)9 or furin10 that are present in the secretory pathway and CME compartments. Exactly how SARS-CoV-2 invades the central nervous system (CNS) is not clear and needs to be established, but possible neuroinvasive mechanisms include hematologic spread, retrograde transport from the peripheral nervous system (PNS), and blood-brain barrier (BBB)-mediated spread.11 Studies on CoVs strongly favour retrograde neuronal transport as a viable route for viral invasion of the CNS.12–13

A characteristic feature of PASC is the emergence of new symptoms that fluctuate over time. Several hypotheses have been put forward to explain this including (a) the presence of a defective immune response which would favour viral replication for a longer time; (b) the existence of systemic damage secondary to an excessive inflammatory response or an altered immune system (cytokine storm syndrome); c) the presence of physical impairment or mental/ psychosocial sequelae (anxiety, depression, post-traumatic stress disorder, effects of confinement or social isolation); and unfortunately d) reinfection with the same or a different variant of SARS-CoV-2.14–15

The immunological mechanisms of neurocognitive presentation of PASC include immune exhaustion leading to chronic inflammation, autoimmunity, and mast cell activation syndrome.16 Patients with PASC may develop a dysfunctional immune response, with increased interferon-γ, interleukin-2, B-cell, CD4+ and CD8+ T-cells, and appear to have effector T-cell activation with pro-inflammatory features.17 Post-mortem analysis of COVID-19 patients show hypertrophic astrocytes and activated microglia18 and astrocytes likely play a pivotal role in the neuropathology of COVID-19, being involved in the virus’ CNS spread, immune responses, and neuronal function.19 Both neuroinflammation and neurodegeneration in PASC are associated with reactive astrocytosis leading to failure of synaptic functions particularly in glutaminergic, GABA-ergic and glycinergic neurons followed by disruption of short-term or/and long-term synaptic plasticity contributing to the development and perpetuation of neurocognitive symptoms.20 Microglia also play an important role in the development of PASC through the direct effects of microglia activation as initiators of reactive astrogliosis; via realisation of ATP from the distressed cell (through hyperactivation of P2X7 receptors),21 and subsequent activation of NF-kB in microglia and astrocytes; increasing reactive oxygen species (ROS) production; activation of NRLP3 inflammasomes, and upregulation of proinflammatory cytokines.22 This hyperinflammatory stage is associated with high energy demand leading to a high degree of mitochondrial stress and eventually to cell death. COVID-19 patients with dysfunctional mitochondria are likely to exhibit a prolonged hyperinflammatory phase of sepsis, which may cause increased production of proinflammatory cytokines also resulting in increased cell death.23 This ROS-induced mitochondrial stress negatively affects mitochondrial metabolism and ATP synthesis and increases mitochondrial fragmentation.24 Cells with dysfunctional mitochondria may also have impaired immune-tolerant phase repair responses, as well as reduced responsiveness to treatment.23 Thus, the interplay between inflammation and mitochondrial ROS-dependent oxidative stress is important for regulating inflammatory and antiviral immune responses.11