COVID-19 is one of the most severe crises of the last decades, with unprecedented and unpredictable losses. COVID-19 is mainly a disease with respiratory symptoms, but cardiovascular and neurological complications are more and more reported and should not be ignored. Some patients with COVID-19 experience delirium during hospitalization, with confusion, agitation and disorientation. The neurological complications are insufficiently known and they may alter the prognosis of these patients. The researchers struggle to understand why these neurological signs appear, who is at higher risk and how they should be managed. Two hypotheses have been advanced: the first one is related to the direct viral invasion and infection of the brain and the second one to an overstimulation of the immune system. The appropriate treatment of the neurological signs depends on the correct knowledge and understanding of the pathophysiological mechanisms.
In the first systematic nationwide UK surveillance study of the acute neurological complications of COVID-19, performed by Varatharaj et al, published in June 2020 in Lancet Psychiatry, 125 patients with COVID-19 with neurological or psychiatric complications have been evaluated. 62% of these patients developed ischemic or hemorrhagic strokes, and 31% presented confusion, unconsciousness, psychosis, or other signs of encephalitis(1). Not all the patients who developed neurological signs had severe forms of the disease. Another study on 43 patients with neurological complications from COVID-19 has found that the most severe neurological complications appeared in patients with mild respiratory symptoms, resembling that the brain pathology is the main disease(2). The neurological complications include stroke, encephalitis, peripheral nerve damage (typical of Guillain-Barré syndrome), anxiety disorder, post-traumatic stress disorder(2).
A Chinese study performed in Wuhan on 214 patients with COVID-19 has found that 36.4% of them developed neurological complications, more significant in patients with severe disease(3). 24.8% of the patients presented central nervous system manifestations and 8.9% of them peripheral nervous system clinical signs(3). A study conducted in France identified neurological complications in 84% of patients admitted to the intensive care unit with acute respiratory failure secondly to COVID-19(4). These neurological manifestations consisted in headache, dizziness, impaired consciousness, acute cerebrovascular disease, encephalopathy, delirium, skeletal muscle injury, ataxia, and seizures(3),(4).
Loss of smell and taste, as early symptoms of COVID-19, have been evaluated by many studies. These symptoms may appear also in otherwise asymptomatic patients infected with SARS-CoV-2. A study performed in four European countries on 417 patients with COVID-19 has found that more than 85% have loss of smell and taste(5). The pathophysiological mechanism is not yet completely understood, the main hypotheses being related to the nasal tract inflammation or alterations of the sensory neurons from the olfactory bulb.
The pathophysiological mechanisms of neurological complications have been investigated. In a preprint publication, an electron microscopy study has shown that SARS-CoV-2 can infect neurons, leading to neuronal destruction(6). The virus levels in the brain were low, not consistently detectable, and clustered around the blood vessels(6).
SARS-CoV-2 is hard to detect in the brain, compared with other organs. Tests like real time-polymerase chain reaction (RT-PCR) often fail to detect the virus in the brain(7), possibly because the ACE2 receptor, that the virus uses to entry, is not expressed enough in brain cells(7). This is the reason why many researchers consider that the most probable explanation of neurological complications in patients with COVID-19 is the immunologic response of the human body to the coronavirus infection(7). Other hypothesis that should not be ignored is related to the medications used for the treatment of COVID-19: tocilizumab and chloroquine may frequently induce headache as a side effect. Also, case reports about multifocal cerebral thrombotic microangiopathy and demyelinating disorders associated to tocilizumab treatment have been published(8),(9). Seizures, peripheral neuropathy, dizziness, paresthesia and hypoesthesia may be side effects of chloroquine and hydroxychloroquine(10). Hypoxia may further impair the neurological functions.
The long-term neurological consequences of COVID-19 are uncertain and most probably will be revealed in the years to come.
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