Table 1 Proposed mechanisms underlying neuropathogenesis in COVID-19.

Systemic dysfunction induced neurological injury

Patients suffering from severe COVID-19 can often experience hypoxemia, which can lead to encephalopathy, a condition of metabolic disruption due to organ failure or medicine side effects. However, those with astrocytic and neuronal injury do not typically present a characteristic pathogenesis when infected with moderate to severe COVID-19. Confusion and changes in consciousness are also common due to high concentrations of circulating proinflammatory cytokines. Brain vessel wall MRI scans of five patients revealed that ventilation therapy for COVID-19-related ARDS affects awakening. The scans showed abnormal contrast enhancement in the vascular wall of the basal skull arteries, possibly indicating the presence of endothelin.

Acute hypoxic ischemic damage was observed in the majority of neuropathologic patients infected with COVID-19, along with the presence of hemorrhagic and bland infarcts, microglial activation, and neuronophagia. The other group of patients had symptoms consistent with delayed post-hypoxic leukoencephalopathy, as seen in ARDS, but not related to COVID-19.

[55,56,57,58,59,60]

RAS dysfunction

The dysregulation of the RAS, due to its reliance on ACE2, may be a factor in the pathophysiology of COVID-19 infection. ACE2 serves to transform angiotensin II into angiotensin-(1-7), which is responsible for vasodilation, antiproliferation, and antifibrotic effects. The binding of SARS-CoV-2 to ACE2, however, can damage vascular endothelial cells by inhibiting mitochondrial and endothelial nitric oxide synthetase activity, leading to secondary cardio- and cerebrovascular effects.

[61,62,63]

Immune dysfunction

SARS-COV-2 is associated with an irregular systemic immune response including proinflammatory stimulation.

Proinflammatory state: In cases of severe COVID-19, systemic inflammation has been observed with lasting fever, increased inflammatory markers such as D-dimer and ferritin, and elevated proinflammatory cytokines and markers of inflammation like peripheral tumor necrosis factor (TNF) and interleukin-6 (IL-6). Additionally, thrombophilia, stroke and other thrombotic symptoms may be present due to a proinflammatory state, with complement activation potentially resulting in thrombotic microvascular injury.

Cytokines released in the brain can lead to microglial activation and a systemic inflammatory response, resulting in brain injury. There is no established correlation between viral invasion and microglial nodules or neuronophagia; however, microglial activation to phagocytose hypoxic neurons was observed in brain tissue of patients infected with a different virus.

Para-infectious and postinfectious triggers: In many COVID-19 cases, Guillain-Barré Syndrome appears to be a para-infectious rather than postinfectious complication, not at the start of the infection but in time. One reported case has revealed weakness to be more common than fever and respiratory symptoms. Additionally, there have been reports of a long period of time between the beginning of a viral illness and its accompanying weakness, which is in line with its status as a postinfectious complication.

[56, 64,65,66,67,68]

Viral invasion of the nervous system

SARS-CoV-2 has been found in a majority of brain specimens in post-mortem case series. However, this does not directly correlate with evidence of severe neuropathological conditions, indicating that SARS-CoV-2 may induce a systemic inflammatory response rather than the infection itself causing neural injury. The effects of SARS-CoV-2 on cerebral vessels remain largely unknown. Autopsy reports provide conflicting evidence, pointing to the potential of SARS-CoV-2 to cause direct endothelial invasion, which could be related to endotheliitis in the lung, heart, kidney, liver, and small intestine.

[69,70,71]