COVID-19 and brain damage: Many open questions remain

Several clinical studies have reported persistent neurological and cognitive damage even after remission, whose incidence, duration, and the underlying mechanism are not yet known. The role of mechanical ventilation and hippocampal damage has been suggested.

A SARS-CoV-2 infection could directly lead to neurological deficits

The remission of respiratory symptoms today indicates clinical recovery from SARS-CoV-2 infection. However, several clinical studies have reported persistent neurological and cognitive damage, whose incidence, duration, and the underlying mechanism are not yet known. The role of mechanical ventilation and hippocampal damage has been suggested.

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Acute respiratory distress syndrome (ARDS), ventilation and cognitive disorders

Previous research on artificially ventilated patients - for whatever reason - has already shown that, in the long term, deficits in attention, memory, verbal fluidity, etc. may occur. One study reported that 78% of patients had such problems one year after discharge from the hospital and about half of the patients had them until two years later.

Furthermore, in the specific case of ARDS, it has already been observed that memory problems can persist for up to five years. For example, a link between the duration of hypoxia and attention or verbal memory levels has been demonstrated.

Finally, the inflammatory response to ARDS and its consequences may also aggravate neurological damage and promote chronic cognitive dysfunction. Cognitive disorders may, therefore, result directly or indirectly from ARDS. However, in the specific case of coronaviruses, the possibility of a direct action of the pathogen on the central nervous system (CNS) cannot be excluded.

Coronavirus-induced damage to the central nervous system

Coronaviruses are considered potentially neurotrophic. Several studies have already shown that they can enter the CNS in less than a week and be detected in the cerebrospinal fluid. A series of autopsies on SARS victims in 2003 showed sequences of the SARS-CoV genome throughout the cortex and hypothalamus. Diffuse lesions were also identified in different areas of the brain in patients infected with MERS-CoV, including the white matter and subcortical areas of the frontal, temporal and parietal lobes.

How can the central nervous system be invaded? Two hypotheses have been made. During a coronavirus infection, the permeability of the blood-brain barrier - partly composed of microvascular cells of the cerebral endothelium - could be compromised. Another possibility is an infection of peripheral neurons or olfactory sensory neurons that allow the virus to access the central nervous system via axonal transport.

Coronaviruses are responsible for acute central nervous system symptoms such as headaches, seizures, loss of consciousness, motor, or cognitive impairment. Although no direct causality has been established, this neuropathogenicity is increasingly recognized. Certain strains of coronavirus have been detected in the brains of patients with multiple sclerosis. Finally, the presence and persistence of coronaviruses in the brain appear to aggravate chronic neurological disorders such as Parkinson's disease. With regard to COVID-19, cases of loss of speech and understanding, encephalopathy, and Guillain-Barré syndrome have been reported.

Is the hippocampus a sort of “Achilles' heel”?

Studies conducted on animal models highlight the fragility of the hippocampus, which would be altered during respiratory infections. In mice, the influenza virus can, for example, induce morphological and functional changes in this area of the brain, which plays an important role in memory. Long-term deterioration of visual-spatial memory has already been observed. Is the SARS-CoV-2 virus responsible for such changes in the hippocampus in some patients? If so, are they a direct consequence of the viral infection? Further research is needed to find the answers.

Another area for future research is the impact of coronavirus infection on the development or aggravation of Alzheimer's disease, characterized by neuronal degeneration that begins in the hippocampus. Animal studies have already shown that the inflammation associated with viral infection significantly worsens the deterioration of visual-spatial memory, one of the main clinical features of Alzheimer's disease.

To date, no comprehensive neuropsychological evaluation of COVID-19 patients has been performed. It should include hippocampal function tests.

Psychological disorders, uncertain etiology

Cognitive problems are often linked to psychological problems resulting from coronavirus infection. A study of 90 cases of SARS showed high levels of psychological distress, with 59% of psychiatric disorders diagnosed and continued prevalence of 33% at 30-months follow-up. The severity of psychological symptoms was correlated here with the severity of the disease and functional impairment. Exposure to traumatic events in the context of an epidemic (death of loved ones, loss of income) was not the only explanation found.

In fact, the hypothesis of psychiatric disorders of viral origin is not excluded. A study of 40 patients suspected of being infected with MERS-CoV and quarantined, had revealed psychiatric disorders - including psychotic events - in 70.8% of them. All of these were subsequently positive, while the suspected cases that tested negative had none of these disorders. This may suggest a particularly strong psychological impact following the diagnosis of MERS-CoV, but also the existence of a viral mechanism.

The road ahead

The current pandemic - or the possible resurgence of coronavirus epidemics - is likely to lead to an increase in the prevalence of cognitive impairment, more or less directly associated with the infection itself. It seems necessary to carry out studies to precisely identify the nature of these disorders, their characteristics, the underlying mechanism, and the effectiveness of available treatments (pharmacological or psychological).

In patients cured of COVID-19, the cognitive deficit may last well beyond the end of respiratory symptoms and take subclinical forms that are difficult to detect. These "mild" memory and language disorders can be mistakenly attributed to the trauma of the epidemic. Emerging cognitive disorders or the worsening of pre-existing disorders, even after infection, should, therefore, alert the general practitioner.

K Ritchie, D Chan, T Watermeyer, The cognitive consequences of the COVID-19 epidemic: collateral damage?, Brain Communications, fcaa069,