Journal Identification = NRP Article Identification = 0637 Date: June 16, 2021 Time: 4:24 pm
doi:10.1684/nrp.2021.0637
REVUE DE NEUROPSYCHOLOGIE
NEUROSCIENCES COGNITIVES ET CLINIQUES
67
Short review
Rev Neuropsychol
2020 ; 12 (S1) : 67-9
Are there any neuropsychological
sequelae of SARS-CoV-2? * L’infection au SARS-CoV-2 entraîne-t-elle des troubles neuropsychologiques ?
Philippe Voruz1,2, Frédéric Assal2,3, Julie Péron1,2
1Clinical and Experimental Neuropsychology Laboratory, Faculty of Psychology and Education Science, Geneva University, 40 bd du Pont d’Arve,
1205 Geneva, Switzerland
2Cognitive Neurology Unit, Neurology Department, University Hospitals of Geneva, Switzerland
<julie.peron@unige.ch>
3Faculty of Medicine, Geneva University, Switzerland
To cite this article: Voruz P, Assal F, Péron J. Are there any neuropsy- chological sequelae of SARS-CoV-2?
Rev Neuropsychol 2020;12(S1):67-9 doi:10.1684/nrp.2021.0637
Abstract Initially characterized as a severe acute respiratory coron- avirus syndrome (SARS-CoV-2), new clinical observations in the acute phase of infection suggest that COVID-19 is also associated with the presence of neurological disorders. These observations are supported by recent cohort studies that indicate the presence of neurological disorders in patients with severe COVID-19 infection, in some cases even before the usual respiratory symptoms appear. Mao, et al.[1]found that 36.4 percent of COVID-19 infected patients had neurological symptoms, involving the cen- tral nervous system, the peripheral nervous system, and skeletal muscles. Encephalopathy is the most common neurological manifestation observed during the acute phase among patients followed in intensive care, but stroke has also been observed. At the neuropsycho- logical level, confusion, severe executive dysfunction, and major attention fluctuations are the most common features observed[2]. As we will see in this article, although the etio- logical hypotheses are compatible with the presence of neuropsychological disorders, and rare observations suggest the presence of the virus in the endothelium of the brain and in particular of the frontal lobe, we do not yet know if there are any cognitive sequelae directly related to COVID-19. If there were, these disorders would have a major impact in individual and societal terms. However, we do not know the predictive factors, nor the duration, the nature, or their kinetics.
Key words: cognition·neuropsychological sequelae·COVID-19·neuroimmunology
COVID-19: presence of neurological symptoms
Although neurological disorders were not initially included in the set of symptoms displayed in the course of infection with SARS-CoV-2, clinical observations, corrobo- rated by recent cohort studies[1], indicate that neurological symptoms are actually present in a high percentage of stud-
∗This article is an English language translation of the following article:
Voruz P, Assal F, Péron J. L’infection au Covid-19 entraîne-t-elle des troubles neuropsychologiques ?Rev Neuropsychol2020 ; 12 (2) : 187-90. doi:10.1684/nrp.2020.0567.
Correspondence:
J. Péron
ied patients. Maoet al.[1]found them in 36.4% of a cohort of patients (N = 214) infected with COVID-19. In some cases, they even preceded the respiratory symptoms. Cur- rent clinical data indicate that a proportion of patients have neurological symptoms similar to those observed in the wake of central nervous system (CNS) or peripheral nervous system lesions, including headache, epilepsy, disorders of consciousness, anosmia, ageusia[3], and sometimes even encephalopathy[4]. In addition to these clinical observa- tions, numerous pathological studies focusing on the CNS have found that this virus is capable of inducing encephali- tis [5] and stroke [6], with potentially severe cognitive consequences. A neuropathological study using electron microscopy even tracked the virus down in the endothelium of frontal lobe blood vessels in a patient with COVID-19 who had a clinical picture of encephalopathy[7].
Journal Identification = NRP Article Identification = 0637 Date: June 16, 2021 Time: 4:24 pm
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COVID-19: etiological hypotheses for neurological damage
Some viruses can directly invade the nervous system [8]. There are several hypotheses as to how SARS-CoV-2 reaches it [9]. One of them concerns the possible medi- ating role played by the immune system [10]. A severe inflammatory response syndrome has been observed in many patients, leading to multi-organ failure. A cytokine storm syndrome has also been evidenced in a subgroup of severely affected patients[11], with extremely high inflam- matory parameters, including C-reactive protein (CRP) and pro-inflammatory cytokines (IL-6, TNF-␣, IL-8, etc.) [12].
As cytokine-producing cells are known to play a regu- latory role in the immune response [13], these markers suggest the presence of an excessive immune response that in some cases may severely damage the CNS, thus reducing cognitive capacity. A second hypothesis, not incompatible with the first one, concerns the blood circulation in the brain. Many patients in a very serious condition present symptoms imitating vasculitis and thrombosis [12]. This clinical observation has been corroborated by the presence of virus in endothelial cells in the vascular beds of different organs in a series of patients with COVID-19, possibly via the angiotensin-converting enzyme 2 (ACE2) expressed by these cells[14].
COVID-19: neuropsychological symptoms
During the acute phase, the most commonly observed neuropsychological characteristics in patients in intensive care are confusion, major executive dysfunction, and wide fluctuations in attention. If patients have a stroke during this phase, they may display additional deficits, depending on the location of the lesion. Although these deficits can be attributed to intubation and sedation, what is striking is the duration of this confusion, compared with non-COVID patients in the same intensive care conditions. Moreover, these neuropsychological disorders also appear to occur in patients with more moderate forms of the disease.
Neuropsychological studies conducted in a neuroim- munological context have flagged up the presence of long-term and sometimes permanent cognitive deficits (e.g., memory and executive or emotional function disorders) linked to specific immunological modulations in several other pathologies, including HIV [15], multiple sclero- sis [16], and encephalitis [17]. We obviously do not yet have sufficient data on neuropsychological disorders dur- ing infection with SARS-CoV-2. Moreover, the relevant epidemiological variables have yet be identified, even if several avenues are currently being explored. Neverthe- less, if we transpose these findings to SARS-CoV-2 and consider neuroimmunological and vascular hypotheses,
we can postulate that infection with COVID-19 has a direct effect on executive and attentional functions, as result of either damage to integrative networks involving cortico-subcortical regions, or neuropathological lesions involving frontal regions, basal ganglia, and the cerebellum [18, 19].
COVID-19: epidemiological risk factors and neuropsychiatric consequences
A recent meta-analysis by Yang et al. [20] including 1576 patients showed that the most common risk factors for a severe form of the disease were arterial hyperten- sion, respiratory illness, cardiovascular disease, age, and sex (older men present the most serious severe forms). Based on statistics updated on a daily basis by the Federal Pub- lic Health Office (OFSP), these observations also appear to be valid in Switzerland. Regarding comorbidities, studies have also shown that a high body mass index can be a risk factor[21].
In addition to these risk factors, it is crucial to consider the possible neuropsychiatric problems that may be trig- gered by public health measures such as lockdowns, or quite simply by the fear of becoming infected. Research has shown that lockdown can trigger or exacerbate anxiety and depression[22, 23], resulting in major posttraumatic stress disorder symptoms among 96% of the individuals con- cerned[24]. Several emotions, including fear, are known to influence cognitive functions, and recent neuroimmunol- ogy research has highlighted the influence of emotional factors on cognitive reserve and cognitive decline in indi- viduals with multiple sclerosis[25].
Based on these observations, we can surmise that SARS- CoV-2 has an indirect neuropsychiatric impact on executive and attentional functions. Studies have highlighted reduced connectivity of intrinsic networks in neuropsychiatric pathologies such as depression[26], anxiety[27], and post- traumatic stress disorder[28]. This reduction in connectivity may lead to a reduction in cognitive reserve, with potentially harmful effects on executive and attentional functions.
Conclusion
In the current pandemic, it is legitimate to ask whether infection with COVID-19 has neuropsychological seque- lae. Cognitive dysfunction resulting from brain lesions has a heavy cost, both economic and human, especially for the patients and their families. If COVID-19 does indeed have a short- and/or long-term impact on cognitive functions, there will be major social and individual consequences. To date, we still do not know enough about either the cognitive and affective consequences of infection with COVID-19, or the risk and protective factors. The possible presence of cog- nitive disorders in the wake of infection with COVID-19 is
Journal Identification = NRP Article Identification = 0637 Date: June 16, 2021 Time: 4:24 pm
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key to establishing an accurate clinical description of this pathology, as well as its potential societal and individual impact.
Conflict of interest None.
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