There is extensive literature on endemicity, clinical symptomatology, immunology and proposed pathogenetic mechanisms that underlie neurologic disorders among patients afflicted with COVID-19 (SARS-CoV-2) infections [1 - 3]. What appears lacking is an in depth understanding of possible structural brain changes that could underlie the complex neurologic symptoms that persist in patients infected with COVID-19.
The prevalence of Neurologic and Psychiatric morbidity has been detailed in a retrospective study in which electronic health records of 236,379 patients were reviewed [4]. One third of those patients surviving COVID-19 had substantial neurological and psychiatric morbidity 6 months following their infection [4]. An analysis 841 COVID-19 patients from Spain and 214 patients from Wuhan, China, found that 57% and 24.8% respectively, had involvement of the central nervous system [5, 6]. A meta-analysis and review of 43 studies assessed 12 or more weeks following COVID diagnosis disclosed that 22% exhibited cognitive dysfunction with considerable functional impairment [7].
Among 103 patients hospitalized with COVID-19, 91.3% had at least one neurologic symptom [7]. Neurologic syndromes in the acute phase have included encephalopathy, encephalitis, macro/microhemorrhages, central venous thrombosis, acute disseminated encephalomyelitis (ADEM), myelitis, Guillain-Barré syndrome, Miller Fisher variant, persistent fatigue, seizure and neuromuscular disorders [7 - 11]. There are reports of acute COVID-19 patients developing ischemic stroke resulting from hypercoagulability, inflammation, cardiac dysfunction, and endothelial inflammation [9 - 13]. The COVID-19 virus can infect cerebrovascular endothelium as a result of circulating antiphospholipid autoantibodies inducing cell activation and dysfunction leading to thrombosis [14].
An autopsy study of 10 post-COVID-19 patients identified the accumulation of tau proteins and neurofibrillary tangles similar to the neuropathology typical of Alzheimer’s disease [15]. The same laboratory further demonstrated modifications of ryanodine receptors which control intracellular passage of calcium, and which in Alzheimer’s disease accumulates tau proteins and the production of neurofibrillary tangles [15]. Another post-mortem study identified pathological changes with β-amyloid aggregation and plaque formation accompanying tauopathy, neuronal degradation and cell death [16].
There is much speculation on whether and how COVID-19 affects neurons in the brain [18]. Among the proposed etiologies are immune mediated processes that are induced by the infection, direct infiltration of the central nervous system and virus-induced hyperinflammatory and/or hypercoagulable states inducing thrombosis [3, 18, 19].
Several hypotheses regarding the mechanism of action have been proposed as to how COVID-19 infection exerts its effect on central nervous system. Once the virus enters the systemic circulation, it could invade neural tissue by means of neurotropism related to the interaction of membrane-bound angiotensin converter 2 receptors (ACE-2) on vascular endothelium [20]. As a result of the intense inflammatory response there can occur increased permeability of the BBB which allows infected cells, cytokines and viremia from the COVID-19 virus itself, to enter the central nervous system [6, 10, 21]. Indirect mechanisms related to “immune dysregulation” have been cited as a putative source for brain damage by inducing a “cytokine storm” triggered by the infection [22, 23]. A postmortem study identified cytotoxic T lymphocytes and microglial activation as being present in cranial nerves, brainstem and cerebellar tissue following COVID-19 infection [24].
A second proposed mechanism is entry of the virus through the cribriform plate and olfactory bulb which would explain anosmia and ageusia that can develop acutely in some patients infected with COVID-19 [25]. Loss of taste and smell affected 47% of COVID-19 patients in one retrospective study [26]. Pathologic changes have been detected in the olfactory bulbs of patients who died from their COVID-19 infection, and viral specific RNA has been extracted from their olfactory tracts [25].