INTRODUCTION
The COVID-19 pandemic was announced in March 2020 [1]. The new disease is caused by coronavirus SARS-CoV-2 (SARS – severe acute respiratory syndrome) [2] with a typical symptomatology including fever, cough, fatigue and muscle pain [3]. Contrary to the initial perceptions, SARS-CoV-2 does not only attack lungs and the respiratory system, but also many other important organs, including the CNS [2]. Outcomes of neuroimaging studies conducted by various research centers around the world confirm the prevalence of brain abnormalities, linked to the course of infection in patients with COVID-19 [4]. Brain structural abnormalities, associated with COVID-19 (after cautious exclusion of other causes) were found in 124 out of 361 (34%) patients examined. The most frequent brain abnormalities were noted as white matter (WM) hyperintensities (on MRI scans) or hypodensities (on CT scans). These changes indicate decreased WM density in COVID-19 patients, compared to the normal range of WM density. This type of brain abnormalities accounts for approx. 76% of all brain structural changes described [4]. So far, these abnormalities are described as diffused, that is not specific to any particular brain structure, and are observed in bilateral medial temporal lobes [5]; frontal, occipital, parietal and temporal lobes [6-10]; insular cortex, cingulate gyri [8]; cerebral peduncle and internal capsule [11]; thalamus [5, 7, 12]; midbrain [5]; pons [7, 11]; parahippocampal gyri and basal ganglia [12]; splenium of corpus callosum [11, 13]; olfactory nerves/ bulb [14, 15]; and gyrus rectus [5]. Even though it remains uncertain whether these brain changes persist over time, their observed prevalence, scope and localization allow for speculation about the risk of various neuropsychological dysfunctions in patients who underwent COVID-19.
An additional challenge with the long-term neurological and neuropsychological consequences of COVID-19 is the evidence that infection-induced parenchymal inflammation may increase the long-term risk of developing Alzheimer’s disease [16] or Parkinson’s disease [17].
The recognition of risks associated with COVID-19 impacted and mobilized the neuropsychology community worldwide. Numerous published appeals call for urgent systematic neuropsychological research and development of clinical practice, i.e., diagnostics, neuro-psychological rehabilitation and psychotherapy, in order to provide professional care to people who may need it after COVID-19 [18-21].
In response to these needs, the article aims to review the current state of knowledge regarding neuropsycho-logical deficits that may result from SARS-CoV-2 infection and the related disease, and to formulate initial recommendations for clinical practice. It also includes a description of COVID-19-specific and non-specific risk factors of brain changes and neuropsychological dysfunction, the results of up-to-date research and recommendations for neuropsychological diagnosis and rehabilitation for COVID-19 survivors. A critical review of empirical research and reviews related to the CNS complications of COVID-19, published before March 2021, was conducted by searching PubMed, PubMedCentral, Google Scholar and bioRxiv.
RISK FACTORS OF NEUROPSYCHOLOGICAL CHANGES IN COVID-19
COVID-19 is a disease with many risk factors of brain dysfunction and neuropsychological disorders in both acute and chronic phases and with potential chronic disability [22]. These factors can be divided into specific and non-specific to COVID-19.
Specific risk factors
Risk factors specific to COVID-19 that can lead to dysfunction or death of neurons within the CNS, and consequent neuropsychological disorders include:
Cerebral hypoxia
SARS-CoV-2 enters the body through the respiratory tract, attacks bronchi and lungs, leading to severe changes in these organs and, consequently, to hypoxia of the entire organism, including the brain [23]. Additionally, the severe course of COVID-19 infection often affects people with concomitant bronchopulmonary diseases, which is associated with the intensification of pulmonary changes and systemic hypoxia.
Notably, severe course of the COVID-19 infection is often observed in individuals with comorbid broncho-pulmonary diseases, which is associated with intensified pulmonary changes and systemic hypoxia. Hypoxia resulting from various conditions (e.g., progressive obstructive pulmonary disease, obstructive sleep apnea, cardiac arrest or cerebral arteries occlusion) is known to be linked to the CNS changes and cognitive consequences (e.g., distorted focus, memory, thinking, visuospatial orien tation) that may be further accompanied by emotional disorders, such as anxiety, depression, symptoms of posttraumatic stress disorder [24, 25]. Cognitive difficulties can persist over two years after the hypoxic event, regardless of the patient’s emotional state [26]. Neuro-psychological deficits following hypoxia typically require long-term neuropsychological rehabilitation and can present various intensity and scope, from severe, generalized to selective, cognitive deficits [27]. Similar cognitive impairments and emotional disorders are currently observed in patients in the early phase and up to 3 months after severe respiratory disorders due to COVID-19 [28].
Vascular changes
Patients with COVID-19 may further experience inflammatory changes in blood vessels and arterio-venous thrombotic complications that may involve CNS. Hyper-coagulation alone poses an increased risk of stroke which, in turn, leads to neurological and neuropsychological symptoms [29, 30]. Hypercoagulability and hyperinflammation observed in patients with severe course of COVID-19 may contribute to delirium and other disturbances of consciousness that are associated with chronic cognitive difficulties, following the recovery from the disease [2, 31].
Neuronal damage
The intranasal route via the olfactory nerves is hypothesized as one of the main neuronal pathways for SARSCoV-2 for direct entry into the brain [3, 32]. The anatomical organization of olfactory nerves and the olfactory bulb in the nasal cavity and forebrain effectively make it a channel between the nasal epithelium and the CNS. Previous studies conducted after the respiratory corona-virus infected nasal cells concluded that it could reach the entire brain and CSF through the olfactory nerve and olfactory bulb causing inflammation, demyelinating reactions and neuronal death. It is suggested that through the olfactory bulb, SARS-CoV-2 may target the deeper parts of the brain, including the thalamus and brainstem, causing the collapse of the respiratory and cardiorespiratory centers [14]. The resulting inflammation (encephalitis) can lead to delirium, generalized cognitive deficits, and severe long-term neuropsychological changes [31, 32]. Empirical data suggest that through direct neural pathways SARS-CoV-2 can also enter hippocampus amygdala, causing memory impairment and emotional dysfunctions [33, 34].
Nonspecific risk factors
The group of nonspecific risk factors, nonetheless related to COVID-19, includes iatrogenic factors and other risks related to the patient’s individual characteristics.
Iatrogenic factors
Numerous studies show that long-term cognitive impairment may occur as a result of the critical condition of a patient requiring hospitalization at the intensive care unit (ICU) in the course of any severe somatic disease [26]. Even though intensive care treatment (e.g., ventilator, large quantities of strong sedative medication) saves lives of critically ill patients, it also carries the risk of complications, such as cognitive difficulties that persist post-recovery. Social isolation, particularly the lack of direct contact with relatives and being cut off from emotional support which is known to facilitate recovery, are yet another adverse iatrogenic factor. Unfortunately, ensuring such contact is particularly difficult during the pandemic [22, 35]. Importantly, many indications point out to neuropsychological deficits being underdiagnosed even in hospitalized patients. It is, after all, strongly emphasized in case of encephalopathy or stroke victims that the fact that they do not present any visible deficits, being capable of “walking and talking” at the time of discharge from the hospital, does not necessarily translate into their neuropsychological functioning being fully intact [29, 36].
Individual characteristics
Demographic and health-related factors comprise a distinct class of risk factors of neuropsychological impairment in the COVID-19 survivors. Among them of particular importance are older age, high blood pressure, diabetes, obesity, smoking tobacco/cigarettes, and co-morbid conditions such as oncological, coronary, neurological or psychiatric [22]. This class of factors in itself is an indicator of a higher risk of developing mild cognitive impairment – MCI [37]. At the same time, these factors are also the risks linked to a more severe course of the COVID-19 disease [38].
Older age and premorbid neurodegenerative conditions (such as Alzheimer’s disease, mild cognitive impairment and Parkinson’s disease) are especially linked to a possible lasting cognitive impairment in the COVID-19 survivors [39]. One mechanistic explanation common to the effects of old age preexisting dementia, and SARS- Cov-2 infection is the suppressed neurotrophic expression of the angiotensin-converting enzyme 2 (ACE-2) which plays a protective role, inhibiting cognitive impairment [40]. Thus, the intersecting effects of old age and chronic, pre-existing medical conditions, especially from the dementia spectrum, can be hypothesized in COVID-19 survivors [39]. There is also an accumulating epidemio-logical evidence suggesting that SARS-CoV-2 survivors without premorbid dementia are at a higher risk of the subsequent development of neurological diseases, particularly Alzheimer’s disease [16]. In response to the urgent need to understand the chronic neuropsychiatric sequelae in COVID-19 survivors, the Alzheimer’s Association with the guidance from WHO, and representatives from over thirty countries, formed an international consortium with special attention given to the underlying biological factors that may contribute to post-COVID-19 dementia development [41]. While these research efforts are in progress, the literature available suggests that the possible acceleration in cognitive manifestations, long-term cognitive decline and the underlying pathogenic mechanisms are likely multifactorial, and remain to be determined in older adults with or without neurodegenerative conditions who survived COVID-19 infection [39].
Furthermore, psychiatric symptoms such as depression, adaptation or anxiety disorders and post-traumatic stress disorder (PTSD),which are intensified amid the COVID-19 pandemic, may also contribute to cognitive problems [42-44]. Especially, in the light of the current debate on bidirectional causality between PTSD and neurocognitive impairment [45], one can speculate about an increased prevalence and/or adverse maintenance of PTSD symptoms in the COVID-19 survivors that present neurocognitive decrements. This possible feedback loop hypothesis could further suggest elevated risk of neuro-cognitive difficulties in COVID-19 survivors suffering from PTSD symptoms. As neurocognitive deterioration constitutes one of the core features of PTSD through its associations with altered brain connectivity [45], neuro-transmitter and neuroendocrine activity [46] these mecha nisms may pose additional challenge to differentiate the etiology of cognitive impairment in COVID-19 survivors [47] and may be expected to play additional role in long-term cognitive disturbances.
Additionally, individuals exhibiting smell and taste impairments in the course of COVID-19 are at an elevated risk of physiological dysregulation of ingestive behavior that can lead to poorer health outcomes, anorexia, weight loss and low albumin levels [48]. Even though the role of the SARS-CoV-2 neuroinfection vs. malnutrition in direct neuropsychological dysfunction remains to be “elucidated”, evidence from other neuroinfectious and neurodegenerative diseases suggests a more direct link with cognitive deterioration, where anosmia and ague-sia are proposed as possible early biomarkers of disease progression and severity [49]. Amidst COVID-19-related lockdowns and quarantine restrictions, increased disparities in food security, food literacy, diet quality (especially in terms of immuno-supportive nutrients) and management of food intake can contribute to nutrition-related risks, with adverse consequences for neuropsychological consequences of the disease expected particularly in socioeconomically, educationally, and environmentally disadvantaged populations [50, 51].
DATA FROM CLINICAL RESEARCH
Initial scientific reports on the impact of COVID-19 on the CNS structure and function originated in China even before the announcement of the COVID-19 pandemic by the World Health Organization [14]. Shortly after, numerous reports confirmed the possibility of the COVID-19 patients presenting neurological and neuro-psychiatric syndromes or symptoms including encephalitis, meningitis, transverse myelitis, epileptic seizures, cerebral hemorrhagic and ischemic strokes, headache and dizziness, anosmia and ageusia, Guillain-Barré syndrome, as well as delirium, distorted consciousness, agitation, lethargy and frontal lobe syndrome, with symptoms such as verbal perseverance and imitation behavior [11-13].
According to the data provided by Helms et al. [9], 33% of patients who underwent the ICU treatment for COVID-19 (i.e., 15 out of 45 patients, on average 63 year old) at the time of discharge from the hospital presented symptoms from a spectrum of executive disorders, including attention deficits, disorientation, and difficulties with following verbal instructions. For example, these patients could not give the correct answer to a question like “Do two pounds weigh more than one pound?” or lift two fingers, first in one hand and then in the other.
Varatharaj et al. [52] discussed the results of dementia screening tests in the UK population of patients with COVID-19. Based on a sample of 125 hospitalized COVID-19 patients, the authors discussed the symptoms of neurological or neuropsychiatric disorders, with cerebral vascular changes (77/125 [62%]), other neurological symptoms (9/125 [7%]) or with altered mental status related to the CNS inflammation or neuropsychiatric syndromes (37/125 [29.6%]). Patients from this particular cohort ranged in age between 23 and 94 (mean = 71). Unfortunately, the neuropsychological functioning of this cohort, especially the patients with cerebral vascular lesions resulting from COVID-19, was not thoroughly evaluated on discharge from the hospital. Data revealed that the criterion of “dementia-like syndrome” was met by six patients that were classified into the subgroup with altered mental status and neuropsychiatric disorders (6/37 [26%]).
There is, however, a systematic increase in the number of neuropsychological studies indicating the presence of significant cognitive impairment in the COVID-19 survivors. For example, Zhou et al. [23] disseminated the results of their study in 29 hospitalized COVID-19 patients (mean age = 47 years) vs. 29 controls (mean age = 42), which excluded patients who could have presented cognitive disorders due to factors other than COVID-19 (e.g., previous neurological or mental disorder, other diseases, learning disabilities). The clinical group was assessed relatively soon post recovery, i.e., after the second negative SARS-CoV-2 test result. The authors implemented a battery of screening tests that enabled remote neuropsychological assessment. Outcomes of their study showed a statistically significant reduction in the ability of sustained attention in the COVID-19 survivors as compared to the control group. Severity of cognitive impairment in the COVID-19 survivors was positively correlated with the rate of inflammation at the time of hospital admission (as measured by the concentration of C-reactive protein CRP; r = 0.5-0.4) [23].
Another neuropsychological research into COVID-19 was presented by Almeria et al. [28]. The authors presented a cohort of 35 hospitalized COVID-19 patients (mean age = 47, SD = 8.9), including 20% of patients who required ICU medical care, 66% received oxygen, while the remaining 14% of patients showed mild COVID-19 symptoms. The study excluded individuals over 60 years of age, patients with premorbid neurological or mental illnesses, cognitive impairment or other risk factors of cognitive disturbances. Qualified participants were examined using a standardized neuropsychological tests battery in face-to-face contact between 10 and 35 days after hospital discharge. Results below 2 standard deviations from the mean (that indicate significant reduction compared to the norm) were found in 19 out of 25 neuropsychological indices. Problems were most frequently noted on the following tests: the Trail Making Test Part B, the Digit Symbol Modalities Test, and the Phonetic Fluency Test. These tests requires engagement of attention, working memory, executive functions, visuospatial orientation, motor skills, and verbal memory [28].
The analysis of data from the nationwide online intelligence test on a sample of over 48,000 people that was carried out by the British Broadcasting Corporation in the UK also suggests that the functioning of the COVID-19 survivors in multiple cognitive domains may be impaired as compared to individuals who were not infected with SARS-CoV-2 [53]. Significant decline was found in performing cognitive tasks of working memory and executive functions, primarily in patients with confirmed coronavirus infection (n = 361) who had been hospitalized (n = 147). Patients showing more severe respiratory disorders and in greater need of medical intervention due to the COVID-19 presented lower cognitive performance after the disease. However, Hampshire et al. (2020) hypothesize that cognitive disturbances related to the COVID-19 may also affect individuals who suffered from SARS-CoV-2 infection at home and did not require medical attention. The authors suggest the inflammatory origins of brain dysfunction. In fact, there are new studies suggesting possible neurological and cognitive complications in patients after mild COVID-19, without the need for hospitalization [54], but these data require further systematic investigations.
The presence of cognitive impairment even three months after recovery from mild to moderate COVID-19 in young people was described by Woo et al. [33]. The study included 18 middle-aged (mean age = 42), COVID-19 survivors, who did not reveal subsequent medical complications after recovery, and 10 control individuals (mean age = 38.4). The hospitalized patients comprised 61% of the clinical group and their condition was assessed as mild to moderate. Patients who needed the ICU treatment were not included in the study. The remaining 33% received medical care at home throughout the course of the COVID-19 disease, while 6% did not require any medical attention. Cognitive and emotional testing was performed using the over-the-phone interview and standardized neuropsychological screening tools, while controlling for the examination conditions to a maximum possible extent. The COVID-19 survivors performed worse on objective tests for short-term memory, attention, verbal learning, semantic memory, and word update readiness as compared to non-infected individuals. Most of the clinical group (78%) also reported fatigue, lack of energy, mood lability, difficulties in logical thinking, and sound aversion. Anxiety, depression and severity of the COVID-19 symptoms were not significantly related to cognitive outcomes [33].
More recent neuropsychological studies have confirmed these findings and further suggested that difficulties with memory, executive function, attention, inhibition, verbal fluency or visuospatial orientation persist in the COVID-19 survivors for many weeks after recovery [55-58]. Many individuals who recovered from COVID-19 report feeling symptoms of anxiety, depression, and difficulties in falling asleep even six months after the acute phase of SARS-CoV-2 infection [3]. The persistence of these disturbances and their possible impact on the quality of life in the COVID-19 survivors require further scientific exploration.
In summary, according to the data presented, it is possible that due to COVID-19 at least one third of patients whose condition was severe and who experienced neurological and/or neuropsychiatric disorders, especially the elderly and those with various comorbidities and individual risk factors, may suffer from long-term neuropsychological impairments that require neuropsychological assistance. The hypothesis that some people after mild COVID-19, who did not require hospitalization may also experience neurological changes and cognitive impairment should not be rejected. However, these conclusions need further in-depth investigations.
NEUROPSYCHOLOGICAL DIAGNOSIS AND REHABILITATION
COVID-19 is a major challenge for all clinicians, including neuropsychologists. The key is therefore the cooperation of various specialists caring for the patient, exchange of information and the results of specialist examinations. To prevent neuropsychological disorders, including late cognitive decline in population of COVID patients, treatment and controlling for neurological and other risk factors is urgently needed. The contribution of neuropsychology to the diagnosis and rehabilitation of the COVID-19 survivors should be considered in relation to the severity of the course of the disease, health-related consequences, and subsequent treatment phases. Contact with a neuropsychologist should be part of acute inpatient treatment if the patient’s condition allows for it. Also, after recovery from the active phase of the disease patients should be seen in rehabilitation departments, outpatient diagnostics and – in the case of possible complications – in other specialist departments, such as neurology or psychiatry.
It is recommended to diagnose the neuropsycho-logical status of people after COVID-19 with the risk of developing cognitive changes as soon as possible and, if required, introduce early rehabilitation interventions [59, 60]. When the patient’s condition and the epidemic situation allow it, a comprehensive in-person neuro-psychological assessment using standardized methods of examination, based on the Polish norms, is strongly recommended. Assessment should cover cognitive domains (general intellectual level, speed of information processing, attention, memory, executive functions, speech and language, motor and psychomotor skills, visual-spatial orientation, social cognition) and emotional functioning (depression, anxiety, PTSD). In a situation where a comprehensive evaluation is not possible, it is also recommended to use screening methods, bearing in mind their psychometric limits (e.g., low sensitivity and specificity of the Mini Mental State Examination) [61].
Listed below are standardized tests with the Polish norms selected from a much larger set of methods recommended for neuropsychological assessment in individuals after COVID-19 [62]: the Wechsler Adult Intelligence Scales, the California Verbal Learning Test, the Wisconsin Card Sorting Test, the Ruff Figural Fluency Test, the Verbal Fluency Test, the Color Trails Test, the Mini Mental State Examination, the Beck Depression Inventory. These methods are characterized by a high, well established value for neuropsychological evaluation of populations with brain disorders, including neuroinfectious diseases [63].
A comprehensive functional diagnosis should be the starting point for neuropsychological rehabilitation, tailored to the individual needs and capabilities of the patient. There are no methods of rehabilitation specific to the population of COVID-19 patients, therefore the approaches and techniques used in patients with brain injuries are recommended, especially after hypoxia, stroke and encephalopia [64, 65]. A holistic approach may be of particularly high value. It not only comprises the training in the area of a disturbed function, but also looks after the patient’s individual needs and goals, and accounts for addressing the impact of deficits on coping with activities of daily living. It also considers maladaptive beliefs, which becomes critical, as these may increase during the COVID-19 pandemic [64, 65].
In the COVID-19 pandemic, diagnostic testing and in-person rehabilitation are not always possible. Amid the pandemic, neuropsychologists took steps to incorporate remote methods, which have been more readily used in a broader medical services context (telemedicine) [65, 66]. Despite teleconsultation-related concerns, the use of audio- or videoconferencing for the purposes of neuropsychological assessment is advancing [67]. Guidance was sought from professional organizations and several of them issued recommendations for practice amid the COVID-19 pandemic, including the COVID-19 Pandemic Health System REsilience PROGRAM (REPROGRAM), Inter-Organizational Practice Committee (IOPC) [68], and the NeuroCOVID-19 International Neuropsychological Society Special Interest Group [62]1.
Due to the lack of a complete picture of neuropsycho-logical disorders related to COVID-19, it may be tempting to diminish the importance of patients’ subjective functioning or addressing them solely in terms of depressed mood, anxiety disorders, delusions or post-traumatic reactions. On the other hand, the possibility of psychopathological symptoms or syndromes that may coexist and be linked to objective cognitive difficulties should not be disregarded. In light of the above, clinical neuropsychologists should be more open to consider symptoms reported by patients and their families and to explore these rather than trying to fit them into the diagnostic criteria. Vigilance and openness to learning about the nature of the reported difficulties can facilitate the determination of the patient’s actual mental problems as well as the assessment of their impact on everyday functioning. Such approach also provides an opportunity to establish positive relationship with a patient and helps to prevent iatrogenic disorders e.g. mood disorders, reluctance toward using healthcare services due to sensed rejection, being misunderstood or underestimated which is often due to the lack of sufficient knowledge on the part of specialists or preconceived ideas about the nature of the patient’s difficulties or possible therapy options.
In conclusion, it should be highlighted that it is currently difficult to estimate the real extent and persistence of neuropsychological disorders in the population affected by COVID-19. In-depth epidemiological studies are needed to address this issue. However, we have the means and methods that can be readily used in the current health care system in order to provide individuals in need with access to professional neuropsychological help.
