Neurology Perspectives 1 (2021) S16–S24 NEUROLOGY PERSPECTIVES www.journals.elsevier.com/neurology-perspectives REVIEW Cognitive symptoms after COVID-19 ⁎ M. Altuna 1,2 , Mª.B. Sánchez-Saudinós 1,2 , A. Lleó 1,2, 1 Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau – Biomedical Research Institute Sant Pau – Universitat Autònoma de Barcelona, Barcelona, Spain 2 Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain Received 2 September 2021; accepted 27 October 2021 KEYWORDS Abstract Brain fog; Introduction: SARS-CoV-2 infection frequently causes neurological symptoms. Cognitive Cognitive symptoms; alterations are among the most frequent symptoms, and may persist beyond the acute phase COVID-19; of infection. SARS-CoV-2 Methods: We conducted a narrative review of the literature. Results: Hospitalised patients, and especially critically ill patients, are at greater risk of developing cognitive symptoms. Post–COVID-19 cognitive symptoms, unlike those associated with other viral illnesses, have been observed in patients with mild infection, and present some atypical features. Cognitive symptoms may last longer in COVID-19 than in other infectious processes, and more frequently affect young people. Post–COVID-19 cognitive symptoms share common features with those described in chronic fatigue syndrome, including a similar profile with affective symptoms. Brief screening tests for cognitive impairment present suboptimal diagnostic performance, and standardised criteria are needed to ensure correct diagnosis. Post–COVID-19 cognitive impairment can have a significant impact on the patient's quality of life and functional independence, regardless of other post–COVID-19 symptoms. Currently, no specific treatments have been approved for post–COVID-19 cognitive impairment, although cognitive stimulation may be useful in some patients. Conclusions: Post–COVID-19 cognitive symptoms are common and are often associated with other systemic symptoms. Neuropsychological evaluation may be useful for diagnosis and to quantify their severity and long-term prognosis. Detailed, and individualised assessment of cognitive impairment may enable the design of treatment plans. n 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ⁎ Corresponding Author: Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau – Biomedical Research Institute Sant Pau – Universitat Autònoma de Barcelona, Barcelona, Spain. E-mail address: alleo@santpau.ca (A. Lleó). https://doi.org/10.1016/j.neurop.2021.10.005 2667-0496/n 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Neurology Perspectives 1 (2021) S16–S24 PALABRAS CLAVE Síntomas cognitivos post-COVID Niebla cerebral; Síntomas cognitivos; Resumen COVID-19 Introducción: La infección por SARS-Cov2 con frecuencia causa síntomas neurológicos. Los síntomas cognitivos se encuentran entre los síntomas más frecuentes y pueden persistir más allá de la fase aguda de la infección. Metodología: Revisión narrativa de la literatura. Resultados: El riesgo de padecer síntomas cognitivos es mayor en pacientes hospitalizados, especialmente en pacientes críticos. Los síntomas cognitivos post-COVID, a diferencia de los que aparecen en otros cuadros virales, se han observado en pacientes con infección leve y presentan algunos rasgos atípicos. La duración de la sintomatología cognitiva puede ser superior a otros procesos infecciosos y afectar con mayor frecuencia a personas jóvenes. Los síntomas cognitivos post-COVID comparten rasgos comunes con los descritos en el síndrome de la fatiga crónica, incluyendo un perfil similar de síntomas afectivos asociados. Los tests rápidos de cribado de deterioro cognitivo tienen un rendimiento diagnóstico subóptimo y son necesarios criterios estandarizados para un correcto diagnóstico. El deterioro cognitivo post-COVID puede ocasionar un impacto significativo en la calidad de vida y en la autonomía funcional del paciente, de forma independiente al resto de síntomas post- COVID. En la actualidad no existen tratamientos específicos aprobados para el deterioro cognitivo post-COVID, aunque la estimulación cognitiva puede ser útil en algunos pacientes. Conclusiones: Los síntomas cognitivos post-COVID son frecuentes, y con asiduidad se asocian a otros síntomas sistémicos. Una evaluación neuropsicológica puede ser de utilidad para el diagnóstico y para cuantificar su severidad y pronóstico a largo plazo. Una caracterización detallada e individualizada del deterioro cognitivo permite establecer medidas de tratamiento. n 2021 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. Este es un artículo Open Access bajo la licencia CC BY (http://creativecommons.org/licenses/by/4.0/). Introduction As the pandemic has progressed, neurological sequelae have been found not to be present exclusively in hospitalised SARS-CoV-2 infection can be associated with a wide range of patients with severe COVID-19, but also in patients with neurological complications, including encephalitis, cerebrovas- milder forms of the disease, who may also present such cular events, delirium, and neuromuscular symptoms. (1) The persistent neurological symptoms as headache, anosmia, neurological complications reported in the early months of ageusia, and cognitive, mood, and behavioural disorders. A 2020 were highly variable neurological symptoms, observed in recent study has shown that up to one-third of patients patients who were hospitalised, mainly in intensive care units present neurological or psychiatric symptoms within 6 (ICU), due to severe COVID-19. months of diagnosis of COVID-19. (10) Several mechanisms of neurological damage have been Cognitive symptoms were recognised as a typical symp- proposed, including direct viral invasion of the central tom of COVID-19 later in the course of the pandemic, gaining nervous system (CNS), and others not related with direct more importance in 2021, when numerous patients began to viral invasion such as injury of the vascular endothelium, present these sequelae. (11,12) These alterations may severe peripheral inflammation, and a prothrombotic state have an impact on functional independence, performance (Fig. 1). (2,3) SARS-CoV-2 has been shown to invade the CNS at work, (13) and quality of life. (14) Early and accurate through the olfactory mucosa (4) and olfactory nerve fibres, as diagnosis of these symptoms is therefore essential. well as via the haematogenous and lymphatic pathways. (3,5,6) This review focuses on post–COVID-19 cognitive impair- The SARS-CoV-2 spike protein binds to the angiotensin- ment, describing its characteristics, biological correlates, converting enzyme 2 (ACE2) receptor, which is abundantly and treatment. expressed in neurons, astrocytes, and oligodendrocytes, enabling the virus to enter cells, inducing mitochondrial Material and methods dysfunction. (7,8) Although SARS-CoV-2 viral proteins have been detected in the lower cranial nerves and brainstem We performed a literature search of the MEDLINE database neurons, their presence or absence does not seem to be to locate articles published until 1 October 2021, using the correlated with symptom severity; in fact, autopsy studies of following search strategy: ((SARS-Cov2) OR (COVID) OR brain tissue more frequently detect inflammatory changes than (COVID19)) AND ((cognitive symptoms) OR (brain fog) OR presence of the virus itself. (9) Furthermore, the peripheral (cognitive impairment)). We included original articles, case inflammatory activity observed in the context of SARS-CoV-2 series, systematic reviews, and meta-analyses written in infection translates into a marked increase in cytokine levels in English, Spanish, or French, and whose abstracts could be the blood, causing cytokine-mediated tissue damage in several accessed on MEDLINE. The search yielded a total of 1053 organs, including the nervous system. articles. After reading the titles and abstracts, we read the 17 M. Altuna, M.ªB. Sánchez-Saudinós, and A. Lleó Fig. 1 SARS-CoV-2 infection causes multisystem involvement. Neurological damage results from a combination of different indirect mechanisms, rather than exclusively by direct viral infection. Patients frequently present cognitive symptoms either in isolation or combined with other neurological symptoms. full texts of 154 articles that addressed the presence of SARS-CoV-2 infection. They often copresent with mood cognitive symptoms during acute infection or after COVID- disorders such as anxiety, emotional lability, and dysphoria. 19, and/or the cognitive impact of SARS-CoV-2 infection on Post–COVID-19 cognitive symptoms resemble those associ- patients with a prior diagnosis of cognitive impairment of ated with chronic fatigue syndrome. (18) No correlation has neurodegenerative origin. We subsequently performed a been observed between sex and likelihood of developing critical analysis of the content to restrict the number of cognitive symptoms after COVID-19; however, women do studies included in our review. We excluded case reports and present a greater risk of developing fatigue. (16) Fatigue and case series when other articles with a higher level of affective, anxious, and depressive symptoms may influence evidence provided the same information. Reviews and patients’ perception of their own cognitive performance. original articles were only included if they provided specific (18,19) Presence of these symptoms may also have a information on cognitive symptoms rather than generic negative impact on patients’ quality of life and socioeco- information on these alterations within the spectrum of nomic and employment status. post–COVID-19 neurological symptoms. Hospitalised patients with severe COVID-19 Brain fog and cognitive impairment Most patients with severe COVID-19 present severe respiratory The generic term “brain fog” has been used to refer to a distress. The presence of cognitive impairment in patients with series of mild cognitive symptoms of varying aetiology. This respiratory distress of all causes is well described in the term is not exclusive to SARS-CoV-2 infection, and has literature. (20,21) The prevalence of cognitive impairment previously been used in the context of other post-infectious after respiratory distress at the time of hospital discharge processes and/or such other conditions as chronic fatigue ranges from 70% to 100%, and may reach 80% at 1 year and 20% syndrome. During the COVID-19 pandemic, this term has at 5 years; and it is also associated with functional limitations. been used to describe difficulty concentrating, memory Respiratory distress may have a wide range of causes, and the problems, and sometimes confusion, (15,16) hypersensitivity pathogenic factors involved in cognitive impairment may vary to light and sound, and tinnitus. (17) Together with fatigue, depending on the aetiology, with the most relevant factors cognitive symptoms frequently persist beyond 4 weeks after being hypoxia, inflammation, delirium, hypoperfusion, and 18 Neurology Perspectives 1 (2021) S16–S24 blood–brain barrier disruption. (21) In these cases, special hospitalised patients, and especially those admitted to the emphasis should be placed on modifiable risk factors, seeking ICU, are at greater risk of presenting cognitive symptoms, to achieve good control with sedatives and mechanical they may also present in patients with mild COVID-19 and ventilation, to prevent haemodynamic instability, and to even in initially asymptomatic individuals. (16) provide early treatment for delirium. In the case of COVID-19, In recent months, cases have been reported of persistent delirium may appear during the acute phase in up to 30% executive dysfunction and, to a lesser extent, memory of hospitalised patients, and is more frequent in critically ill dysfunction (for at least 3 months after acute infection) in patients. (22) The higher frequency of delirium during young patients with mild COVID-19 not requiring hospital acute infection may be linked to direct viral invasion of the admission and presenting no other comorbidities. (30,31) CNS, inflammatory changes, systemic hypoperfusion, mechan- Several studies have compared post–COVID-19 cognitive ical ventilation and prolonged immobilisation requiring symptoms with other post-viral syndromes (eg, after sedoanalgesia, and greater social isolation. (23) It is well Epstein-Barr virus infection). SARS-CoV-2 infection pre- known that the duration of delirium in patients with respiratory sents some peculiar characteristics, since the presence of distress or shock is a major factor in the subsequent cognitive symptoms does not have a clear temporal development of long-lasting cognitive symptoms. (24) relationship with such other symptoms as affective disor- Most of the published case series of cognitive impairment ders and fatigue, or with their severity. In patients with after COVID-19 describe patients requiring hospitalisation or SARS-CoV-2 infection, cognitive symptoms may persist for even ICU admission due to severe COVID-19. (25) These longer than the remaining symptoms, and their progression series use different cognitive assessment tools, ranging from is independent. (32) surveys to telephone assessments, which makes it difficult to A recent study including data from over 3700 online determine the true prevalence of cognitive impairment surveys evaluated the prevalence of post–COVID-19 cogni- after COVID-19 in this population. The time of symptom tive symptoms and their progression. The survey was assessment also varies greatly between studies, with some distributed to young patients aged 30–60 years, half of case series performing these evaluations during the acute whom had presented mild COVID-19. Brain fog was reported phase, when patients were admitted to hospital. In any case, by 85.1% of participants, starting the first week after acute cognitive symptoms are frequent in the case series pub- infection and peaking at 3 months. Symptoms persisted for 7 lished, even affecting 100% of patients in some series. (25) months in 55.5% of participants. A total of 86.2% reported Patients requiring oxygen therapy or ICU admission have poorer work performance. (33) Likewise, a population-based been reported to present more severe impairment. (26) Up study including cognitively healthy adults older than 40 to 69% of patients with COVID-19 admitted to the ICU years reported poorer scores on the Montreal Cognitive present agitation at the time of extubation, and 65% of these Assessment (MoCA) after mild COVID-19. (34) present confusional symptoms after extubation and with- In summary, unlike other post-infectious syndromes, drawal of neuromuscular blocking agents; this rate is higher post–COVID-19 cognitive symptoms are more frequent in than those reported for patients with acute respiratory patients with history of mild COVID-19, and may persist for distress of other causes. (27) A recent study analysing the long periods of time, negatively impacting functional status electronic medical histories of a large number of individuals and work performance. confirms that the frequency of dementia within 6 months of acute COVID-19 is higher compared toother respiratory infections, both in hospitalised and non-hospitalised pa- Profile of post–COVID-19 cognitive impairment tients. (10) In that study, 2.6% of patients were diagnosed with dementia within 6 months of acute COVID-19, rising to The available evidence on post–COVID-19 cognitive impair- 4.7% in those presenting COVID-19–related encephalopathy. ment is heterogeneous due to differences in inclusion Patients admitted to the ICU due to acute respiratory criteria, time and methodology of assessment, and whether distress are more likely to present post-traumatic stress a control group was included (many studies did not include a syndrome, anxiety, and depressive symptoms (34%, 34%, and control group). A systematic review of 33 studies analysing 29%, respectively); these symptoms, in turn, have a direct the cognitive and psychiatric sequelae of COVID-19 con- impact on cognitive function. (28,29) Psychotic symptoms cluded that the neuropsychological evaluation of these seem not to be more prevalent in patients with SARS-CoV-2 patients should be standardised and emphasises the need infection than in patients with other severe viral infections. for longitudinal studies. (35) The most frequent profile of In summary, the prevalence of cognitive impairment is high post–COVID-19 cognitive impairment involves executive among patients with severe COVID-19 and negatively affects function and may be detected from 4 weeks after diagnosis their functional status and job performance. In fact, up to (subacute or convalescent phase) and even after 12 weeks one-third of patients with COVID-19 requiring mechanical (persistent symptomatology). (36) Most published studies ventilation at the ICU have not returned to active work at 1 use cognitive screening tests (eg, the MoCA or Mini–Mental year after admission. (24) State Examination), administered either in person (37–39) or by telephone; (40) and some include the Continuous Performance Test (a computerised assessment of sustained Patients with mild COVID-19 attention). (41) The studies included in the review used both objective assessments (26) and self-reported data. (42) In 80%–85% of cases, SARS-CoV-2 infection is asymptomatic These studies have identified attention and planning or presents with mild flu-like symptoms. Although difficulties, decreased information processing speed, and 19 M. Altuna, M.ªB. Sánchez-Saudinós, and A. Lleó deficits in short-term memory, abstraction, and orientation; Table 1 Profile of cognitive, mood, and behavioural (32) other alterations include anomia and difficulty under- symptoms in patients with post–COVID-19 cognitive standing spoken and written language, with the latter impairment (the most frequent symptoms are marked with problem being more frequent among patients who required asterisks). ICU admission. (43) Language problems may negatively impact patients’ social interaction and return to work. Cognitive symptoms Studies conducting massive online surveys also report Global cognitive function executive function as the most severely impaired cognitive Concentration* domain in these patients, although up to 50.5% of patients Memory* report memory problems at 7 months after acute infection. Working memory* (33) Impaired visuospatial function is also reported in these Verbal episodic memory patients, although the evidence is less robust (Table 1). Visual memory (36) One limitation of some of these studies is that they Executive function* administer cognitive screening tests to young patients, Sustained attention* although no normative data are available for that age Information processing speed* range. (32) Visuospatial processing In addition to cognitive symptoms, COVID-19 survivors Language have been found to present significantly higher rates of Affective symptoms psychiatric sequelae. (10) That same study reports that Anxiety* history of mental disorders is a risk factor for COVID-19 Depression* factors (1.65 times greater for all age groups and both Post-traumatic stress disorder sexes), probably linked to lifestyles and independently of Behavioural symptoms known physicalrisk. (10) The risk of developing depression Irritability and cognitive impairment has been linked to poor functional Sleep disorders status (as measured with the Post–COVID-19 Functional Other symptoms Status Scale) at 6 weeks from hospital discharge after Fatigue* COVID-19. (13) hypometabolism in the olfactory gyrus, limbic structures, hippocampus, brainstem, and cerebellum. (50) In a recent Correlation between cognitive symptoms and study including 15 hospitalised patients with neurological biomarkers symptoms, 10 presented neuroimaging alterations, with a pattern of predominantly frontoparietal hypometabolism, Several studies have quantified biomarkers of neurological which was correlated with performance in the MoCA. (51) In damage in patients with COVID-19. Some authors have found a 6-month longitudinal study, neuroimaging findings im- that patients with COVID-19 admitted to the ICU show proved over the follow-up period, although some of these elevated levels of glial fibrillary acidic protein and neurofil- patients presented residual hypometabolism. (51) ament light protein (NfL) in the blood, (44,45) and that high NfL levels are associated with poorer prognosis. (44,46,47) A recent study including 142 hospitalised patients found that Treatment even patients with no neurological symptoms presented high NfL levels, and that high levels were associated with poor Establishing the most appropriate treatment requires correct outcomes. (47) Another study reported elevated plasma identification of cognitive symptoms and evaluation of their levels of IL-4 and markers of neuronal damage in neuronal- severity. Experience with medium- and long-term management enriched extracellular vesicles in patients with neurological of post–COVID-19 cognitive symptoms is very limited. The symptoms. (48) However, few studies have analysed bio- recommendations currently available are the same as those markers in patients undergoing cognitive assessment. An- issued for other entities associated with similar profiles of other recent study including 29 patients with mild COVID-19 cognitive impairment, such as chronic fatigue syndrome. found no association between cognitive function and plasma Multidisciplinary management of the non-pharmacological concentrations of different cytokines, although patients treatment seems reasonable for these patients. Treatment with COVID-19 did present executive dysfunction. (41) should be tailored to each patient’s needs; however, when Few studies include neuroimaging assessment of patients cognitive alterations cause significant functional impact, with post–COVID-19 cognitive impairment. MRI scans of treatment may include cognitive stimulation, language reha- COVID-19 patients after hospital discharge have detected bilitation (particularly in patients undergoing prolonged such findings as increased signal intensity and increased orotracheal intubation), and occupational therapy combined mean diffusivity in the thalamus, as well as periventricular with physical therapy or graded exercise therapy. (52) Gradual white matter hyperintensity. (38) In our experience, dilation incorporation or adaptation to work should also be considered of perivascular spaces in the hippocampus and basal ganglia in some cases, as this may improve the work integration of is occasionally observed in these patients (Fig. 2). These these patients. To date, no pharmacological treatment has findings may correspond to perivascular inflammation in been approved for post–COVID-19 cognitive symptoms. Like- histopathological studies. (49) wise, no studies have specifically addressed the use of Brain FDG-PET studies of patients with COVID-19 and micronutrients or dietary supplements, although a recent cognitive symptoms have revealed a pattern of study suggests that the natural flavonoid luteolin may be 20 Neurology Perspectives 1 (2021) S16–S24 Fig. 2 MRI scan of a young patient with post–COVID-19 cognitive impairment. A) Mild loss of cerebellar volume. B) and C) Prominent perivascular spaces in the bilateral hippocampus (B) and basal ganglia (C). beneficial due to its anti-inflammatory and neuroprotective such other proteins as tau, TDP-43, and α-synuclein. (7) It has properties. (53) The impact of vaccination against COVID-19 also been suggested that the virus may induce functional on such long-term post–COVID-19 symptoms as cognitive inhibition of acetylcholine receptors and promote dysregulation alterations is still unknown. Likewise, pharmacological treat- of the excitatory-inhibitory balance, which may be explained by ment of affective symptoms should be complemented with the expression of ACE2 in glutamatergic and GABAergic neurons. non-pharmacological treatments, which may provide signifi- (8) It has been postulated that retrograde or anterograde cant benefits for cognition, functional status, and quality of synaptic and axonal transport of SARS-CoV-2 may result in slow, life. Management of these patients may occasionally require diffuse spread throughout the entire CNS, months or even years the participation of clinical psychologists and psychiatrists. after infection. (8) However, insufficient data are available to confirm this hypothesis. Medium- and long-term follow-up of individuals with history of SARS-CoV-2 infection should include Impact of the COVID-19 pandemic on patients longitudinal neuropsychological assessments and analysis of with dementia multimodal biomarkers, which would help us to determine whether the infection increases the risk of developing neuro- Individuals with such neurodegenerative dementias as degenerative diseases. Alzheimer disease are at particularly high risk of developing severe COVID-19. Mortality in this patient group is consider- ably higher, in part due to their older age, presence of Conclusions and future lines of research comorbidities, and ineligibility for ventilatory support due to their functional status prior to SARS-CoV-2 infection. COVID- The current evidence suggests that cognitive sequelae are 19 survivors have been observed to present cognitive and frequent after COVID-19, even in mild cases not requiring functional worsening, with severity varying according to the hospitalisation or ICU admission. These cognitive alterations severity of the infection. Greater apathy, agitation, and include executive dysfunction and, to a lesser extent, aberrant motor behaviour have been observed in individuals memory impairment, which progressively improves in most with mild cognitive impairment and Alzheimer's disease cases. No specific treatment has been established for these dementia in the context of the COVID-19 pandemic, regard- patients, although tailored cognitive stimulation is recom- less of whether they actually presented SARS-CoV-2 infection. mended when symptoms cause functional limitations. (54) Even individuals who were not infected with the virus Long-term follow-up studies should be conducted to presented cognitive and functional decline, probably due to determine the prevalence of post–COVID-19 cognitive social isolation and the inability to attend centres providing impairment, its impact on public healthcare systems, and cognitive stimulation. (25,55) This has had a major negative the resources needed to treat these patients. This informa- impact on these patients’ global quality of life. tion will enable us to quantify the global impact of these sequelae from a clinical, economic, and work-related SARS-CoV-2 infection as a possible risk factor perspective. (57) Several international studies currently underway aim to for neurodegenerative disease provide large-scale clinical and biomarker data. Cooperation will enable high-quality research, involving scientists from In addition to causing cognitive impairment during the acute multiple fields. (58) Some of these studies, such as those led and subacute phases, or exacerbating existing cognitive by Yale University (COVID Mind Study) and the American impairment, it has been suggested that SARS-CoV-2 infection Association of Alzheimer Disease, include imaging and may be a risk factor for the development of neurodegener- biofluid markers. This information will be crucial in ative diseases in healthy individuals. (56) determining the extent of post–SARS-CoV-2 cognitive im- The cerebral hypoperfusion observed in the context of SARS- pairment and its prognosis in the long term. CoV-2 infection may accelerate amyloid-β aggregation and deposition, (3) and the aggregation and abnormal folding of 21 M. Altuna, M.ªB. Sánchez-Saudinós, and A. Lleó Acknowledgements COVID-19 patients: a multidisciplinary approach. EClinicalMedicine. 2021 Feb;32:100731 Available from: https://doi.org/10.1016/j. eclinm.2021.100731. Miren Altuna is the recipient of a Río Hortega grant from the 14. Townsend L, Dowds J, O’Brien K, Sheill G, Dyer AH, O’Kelly B, Carlos III Institute (CM19/00066). et al. Persistent poor health after COVID-19 is not associated with respiratory complications or initial disease severity. Ann Appendix A. Supplementary data Am Thorac Soc. 2021 Jun;18(6):997–1003 Available from: https://doi.org/10.1513/AnnalsATS.202009-1175OC. 15. Stefano GB, Ptacek R, Ptackova H, Martin A, Kream RM. Supplementary data to this article can be found online at Selective neuronal mitochondrial targeting in SARS-CoV-2 https://doi.org/10.1016/j.neurop.2021.10.005. infection affects cognitive processes to induce “brain fog” and results in behavioral changes that favor viral survival. Med Sci Monit: Int Med J Exp Clin Res. 2021;Vol. 27:e930886 Available References from: 10.12659/MSM.930886. 16. Garg M, Maralakunte M, Garg S, Dhooria S, Sehgal I, Bhalla AS, 1. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, et al. The conundrum of “long-COVID-19”: a narrative review. Spudich S. Neuropathogenesis and neurologic manifestations of Int J Gen Med. 2021;14:2491–506 Available from: https://doi. the coronaviruses in the age of coronavirus disease 2019: a org/10.2147/IJGM.S316708. review. JAMA Neurol [Internet]. 2020 Aug 1;77(8):1018–27 17. Moghimi N, Di Napoli M, Biller J, Siegler JE, Shekhar R, Available from: https://doi.org/10.1001/jamaneurol.2020.2065. McCullough LD, et al. The neurological manifestations of post- 2. Solomon T. Neurological infection with SARS-CoV-2 — the story acute sequelae of SARS-CoV-2 infection. Curr Neurol Neurosci so far. Nat Rev Neurol [Internet]. 2021;17(2):65–6 Available Rep. 2021 Jun;21(9):44 Available from: https://doi.org/10.1007/ from: https://doi.org/10.1038/s41582-020-00453-w. s11910-021-01130-1. 3. Miners S, Kehoe PG, Love S. Cognitive impact of COVID-19: 18. Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, looking beyond the short term. Alzheimers Res Ther. 2020 Dec;12 et al. Persistent neurologic symptoms and cognitive dysfunction (1):170 Available from: https://doi.org/10.1186/s13195-020- in non-hospitalized Covid-19 “long haulers”. Ann Clin Transl 00744-w. Neurol. 2021 May;8(5):1073–85 Available from: https://doi. 4. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes org/10.1002/acn3.51350. R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of 19. Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A, Gouze H, central nervous system entry in individuals with COVID-19. Nat et al. Post-discharge persistent symptoms and health-related Neurosci. 2021 Feb;24(2):168–75 Available from: https://doi. quality of life after hospitalization for COVID-19. J Infect. 2020; org/10.1038/s41593-020-00758-5. Vol. 81:e4–6 Available from: https://doi.org/10.1016/j. 5. Chen X, Laurent S, Onur OA, Kleineberg NN, Fink GR, Schweitzer jinf.2020.08.029. F, et al. A systematic review of neurological symptoms and 20. Herridge MS, Moss M, Hough CL, Hopkins RO, Rice TW, Bienvenu complications of COVID-19. J Neurol. 2021 Feb;268(2):392–402 OJ, et al. Recovery and outcomes after the acute respiratory Available from: https://doi.org/10.1007/s00415-020-10067-3. distress syndrome (ARDS) in patients and their family care- 6. Al-Sarraj S, Troakes C, Hanley B, Osborn M, Richardson MP, givers. Intensive Care Med. 2016 May;42(5):725–38 Available Hotopf M, et al. Invited review: the spectrum of neuropathology from: https://doi.org/10.1007/s00134-016-4321-8. in COVID-19. Neuropathol Appl Neurobiol. 2021 Feb;47(1):3–16 21. Sasannejad C, Ely EW, Lahiri S. Long-term cognitive impairment Available from: https://doi.org/10.1111/nan.12667. after acute respiratory distress syndrome: a review of clinical 7. Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID- impact and pathophysiological mechanisms. Crit Care. 2019 19. J Alzheimers Dis. 2020;76(1):3–19 Available from: https:// Nov;23(1):352 Available from: https://doi.org/10.1186/s13054- doi.org/10.3233/JAD-200581. 019-2626-z. 8. Wang F, Kream RM, Stefano GB. Long-term respiratory and 22. Nakamura ZM, Nash RP, Laughon SL, Rosenstein DL. Neuropsy- neurological sequelae of COVID-19. Med Sci Monit Int Med J Exp chiatric complications of COVID-19. Curr Psychiatry Rep. 2021 Clin Res. 2020 Nov;26:e928996 Available from: 10.12659/ Mar;23(5):25 Available from: https://doi.org/10.1007/s11920- MSM.928996. 021-01237-9. 9. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder 23. Kotfis K, Williams Roberson S, Wilson JE, Dabrowski W, Pun BT, AS, Edler C, et al. Neuropathology of patients with COVID-19 in Ely EW. COVID-19: ICU delirium management during SARS-CoV-2 Germany: a post-mortem case series. Lancet Neurol. 2020 pandemic. Crit Care. 2020 Apr;24(1):176 Available from: Nov;19(11):919–29 Available from: https://doi.org/10.1016/ https://doi.org/10.1186/s13054-020-02882-x. S1474-4422(20)30308-2. 24. Hosey MM, Needham DM. Survivorship after COVID-19 ICU stay. 10. Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6- Nat Rev Dis Prim. 2020 Jul;6(1):60 Available from: https://doi. month neurological and psychiatric outcomes in 236 379 org/10.1038/s41572-020-0201-1. survivors of COVID-19: a retrospective cohort study using 25. Alonso-Lana S, Marquié M, Ruiz A, Boada M. Cognitive and electronic health records. The Lancet Psychiatry. 2021 May;8 neuropsychiatric manifestations of COVID-19 and effects on (5):416–27 Available from: https://doi.org/10.1016/S2215- elderly individuals with dementia. Front Aging Neurosci. 0366(21)00084-5. 2020;12:588872 Available from: https://doi.org/10.3389/ 11. Lleó A, Alcolea D. The cognitive aftermath of COVID-19. Brain fnagi.2020.588872. Commun [Internet]. 2020 Jul 1;2(2). https://doi.org/10.1093/ 26. Almeria M, Cejudo JC, Sotoca J, Deus J, Krupinski J. Cognitive braincomms/fcaa072 Available from. profile following COVID-19 infection: Clinical predictors leading 12. Ritchie K, Chan D, Watermeyer T. The cognitive consequences of to neuropsychological impairment. Brain, Behav Immun - Heal. the COVID-19 epidemic: collateral damage? Brain Commun. 2020 Dec;9:100163 Available from: https://doi.org/10.1016/j. 2020;2(2):fcaa069 Available from: https://doi.org/10.1093/ bbih.2020.100163. braincomms/fcaa069. 27. Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, 13. de Graaf MA, Antoni ML, Ter Kuile MM, Arbous MS, Duinisveld Kummerlen C, et al. Neurologic features in severe SARS-CoV-2 AJF, Feltkamp MCW, et al. Short-term outpatient follow-up of 22 Neurology Perspectives 1 (2021) S16–S24 infection. New Engl J Med. 2020;Vol. 382:2268–70 Available J Psychiatr Res. 2020 Oct;129:98–102 Available from: https:// from: https://doi.org/10.1056/NEJMc2008597. doi.org/10.1016/j.jpsychires.2020.06.022. 28. Nikayin S, Rabiee A, Hashem MD, Huang M, Bienvenu OJ, 42. Weerahandi H, Hochman KA, Simon E, Blaum C, Chodosh J, Duan Turnbull AE, et al. Anxiety symptoms in survivors of critical E, et al. Post-discharge health status and symptoms in patients illness: a systematic review and meta-analysis. Gen Hosp with severe COVID-19. J Gen Intern Med [Internet]. 2021;36(3): Psychiatry. 2016;43:23–9 Available from: https://doi.org/ 738–45 Available from: https://doi.org/10.1007/s11606-020- 10.1016/j.genhosppsych.2016.08.005. 06338-4. 29. Rabiee A, Nikayin S, Hashem MD, Huang M, Dinglas VD, Bienvenu 43. RA E. Potential for cognitive communication impairment in OJ, et al. Depressive symptoms after critical illness: a COVID-19 survivors: a call to action for speech-language systematic review and meta-analysis. Crit Care Med. 2016 pathologists. Am J Speech-Language Pathol [Internet]. 2020 Sep;44(9):1744–53 Available from: https://doi.org/10.1097/ Nov 12;29(4):1821–32 Available from: https://doi.org/ CCM.0000000000001811. 10.1044/2020_AJSLP-20-00147. 30. Hellmuth J, Barnett TA, Asken BM, Kelly JD, Torres L, Stephens 44. Sutter R, Hert L, De Marchis GM, Twerenbold R, Kappos L, ML, et al. Persistent COVID-19-associated neurocognitive Naegelin Y, et al. Serum neurofilament light chain levels in the symptoms in non-hospitalized patients. J Neurovirol. 2021 intensive care unit: comparison between severely ill patients Feb;27(1):191–5 Available from: https://doi.org/10.1007/ with and without coronavirus disease 2019. Ann Neurol. 2021 s13365-021-00954-4. Mar;89(3):610–6 Available from: https://doi.org/10.1002/ 31. Blomberg B, Mohn KG-I, Brokstad KA, Zhou F, Linchausen DW, ana.26004. Hansen B-A, et al. Long COVID in a prospective cohort of home- 45. Cooper J, Stukas S, Hoiland RL, Fergusson NA, Thiara S, Foster isolated patients. Nat Med. 2021 Sep;27(9):1607–13 Available D, et al. Quantification of neurological blood-based biomarkers from: https://doi.org/10.1038/s41591-021-01433-3. in critically ill patients with coronavirus disease 2019. Crit Care 32. Woo MS, Malsy J, Pöttgen J, Seddiq Zai S, Ufer F, Hadjilaou A, Explor. 2020 Oct;2(10):e0238 Available from: https://doi.org/ et al. Frequent neurocognitive deficits after recovery from mild 10.1097/CCE.0000000000000238. COVID-19. Brain Commun. 2020;2(2):fcaa205 Available from: 46. Aamodt AH, Høgestøl EA, Popperud TH, Holter JC, Dyrhol-Riise https://doi.org/10.1093/braincomms/fcaa205. AM, Tonby K, et al. Blood neurofilament light concentration at 33. Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. admittance: a potential prognostic marker in COVID-19. J Characterizing long COVID in an international cohort: 7 months of Neurol. 2021 Mar:1–10 Available from: https://doi.org/ symptoms and their impact. EClinicalMedicine. 2021 Jul;101019. 10.1007/s00415-021-10517-6. https://doi.org/10.1016/j.eclinm.2021.101019 Available from. 47. Prudencio M, Erben Y, Marquez CP, Jansen-West KR, Franco- 34. Del Brutto OH, Wu S, Mera RM, Costa AF, Recalde BY, Issa NP. Mesa C, Heckman MG, et al. Serum neurofilament light protein Cognitive decline among individuals with history of mild correlates with unfavorable clinical outcomes in hospitalized symptomatic SARS-CoV-2 infection: a longitudinal prospective patients with COVID-19. Sci Transl Med. 2021 Jul;13(602). study nested to a population cohort. Eur J Neurol. 2021 Oct;28 https://doi.org/10.1126/scitranslmed.abi7643 Available from. (10):3245–53 Available from: https://doi.org/10.1111/ 48. Sun B, Tang N, Peluso MJ, Iyer NS, Torres L, Donatelli JL, et al. ene.14775. Characterization and biomarker analyses of post-COVID-19 com- 35. Vanderlind WM, Rabinovitz BB, Miao IY, Oberlin LE, Bueno- plications and neurological manifestations. Cells. 2021 Feb;10(2). Castellano C, Fridman C, et al. A systematic review of https://doi.org/10.3390/cells10020386 Available from. neuropsychological and psychiatric sequalae of COVID-19: implica- 49. Lee M-H, Perl DP, Nair G, Li W, Maric D, Murray H, et al. tions for treatment. Curr Opin Psychiatry. 2021 Jul;34(4):420–33 Microvascular injury in the brains of patients with covid-19. N Available from: https://doi.org/10.1097/YCO.0000000000000713. Engl J Med [Internet]. 2020 Dec 30;384(5):481–3 Available 36. Daroische R, Hemminghyth MS, Eilertsen TH, Breitve MH, from: https://doi.org/10.1056/NEJMc2033369. Chwiszczuk LJ. Cognitive impairment after COVID-19—a review 50. Guedj E, Million M, Dudouet P, Tissot-Dupont H, Bregeon F, on objective test data [Internet]. Front Neurol. 2021;Vol. 12:1238 Cammilleri S, et al. (18)F-FDG brain PET hypometabolism in Available from: https://doi.org/10.3389/fneur.2021.699582. post-SARS-CoV-2 infection: substrate for persistent/delayed 37. Pistarini C, Fiabane E, Houdayer E, Vassallo C, Manera MR, disorders? Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):592–5 Alemanno F. Cognitive and emotional disturbances due to Available from: https://doi.org/10.1007/s00259-020-04973-x. COVID-19: an exploratory study in the rehabilitation setting 51. Blazhenets G, Schroeter N, Bormann T, Thurow J, Wagner D, [Internet]. Front Neurol. 2021;Vol. 12:500 Available from: Frings L, et al. Slow but evident recovery from neocortical https://doi.org/10.3389/fneur.2021.643646. dysfunction and cognitive impairment in a series of chronic 38. Raman B, Cassar MP, Tunnicliffe EM, Filippini N, Griffanti L, COVID-19 patients. J Nucl Med. 2021 Jul;62(7):910–5 Available Alfaro-Almagro F, et al. Medium-term effects of SARS-CoV-2 from: https://doi.org/10.2967/jnumed.121.262128. infection on multiple vital organs, exercise capacity, cognition, 52. Humphreys H, Kilby L, Kudiersky N, Copeland R. Long COVID and quality of life and mental health, post-hospital discharge. the role of physical activity: a qualitative study. BMJ Open. EClinicalMedicine. 2021 Jan;31:100683 Available from: https:// 2021 Mar;11(3):e047632 Available from: https://doi.org/ doi.org/10.1016/j.eclinm.2020.100683. 10.1136/bmjopen-2020-047632. 39. De Lorenzo R, Conte C, Lanzani C, Benedetti F, Roveri L, Mazza 53. Theoharides TC, Cholevas C, Polyzoidis K, Politis A. Long-COVID MG, et al. Residual clinical damage after COVID-19: a syndrome-associated brain fog and chemofog: luteolin to the retrospective and prospective observational cohort study. rescue. Biofactors. 2021 Mar;47(2):232–41 Available from: PLoS One [Internet]. 2020 Oct 14;15(10):e0239570 Available https://doi.org/10.1002/biof.1726. from: https://doi.org/10.1371/journal.pone.0239570. 54. Lara B, Carnes A, Dakterzada F, Benitez I, Piñol-Ripoll G. 40. Baig AM. Neurological manifestations in COVID-19 caused by Neuropsychiatric symptoms and quality of life in Spanish SARS-CoV-2. CNS Neurosci Therap. 2020;Vol. 26:499–501 Avail- patients with Alzheimer’s disease during the COVID-19 lock- able from: https://doi.org/10.1111/cns.13372. down. Eur J Neurol. 2020 Sep;27(9):1744–7 Available from: 41. Zhou H, Lu S, Chen J, Wei N, Wang D, Lyu H, et al. The https://doi.org/10.1111/ene.14339. landscape of cognitive function in recovered COVID-19 patients. 23 M. Altuna, M.ªB. Sánchez-Saudinós, and A. Lleó 55. Iodice F, Cassano V, Rossini PM. Direct and indirect neurolog- 57. Carod-Artal FJ. Post-COVID-19 syndrome: epidemiology, diag- ical, cognitive, and behavioral effects of COVID-19 on the nostic criteria and pathogenic mechanisms involved. Rev healthy elderly, mild-cognitive-impairment, and Alzheimer’s Neurol. 2021 Jun;72(11):384–96 Available from: 10.33588/ disease populations. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin rn.7211.2021230. Neurophysiol. 2021 Feb;42(2):455–65 Available from: https:// 58. Hall PA, Sheeran P, Fong GT, Cheah CSL, Oremus M, Liu- doi.org/10.1007/s10072-020-04902-8. Ambrose T, et al. Biobehavioral aspects of the COVID-19 56. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. pandemic: a review. Psychosom Med. 2021 May;83(4):309–21 Immediate and long-term consequences of COVID-19 infections Available from: https://doi.org/10.1097/PSY.0000000000000932. for the development of neurological disease. Alzheimers Res Ther. 2020 Jun;12(1):69 Available from: https://doi.org/ 10.1186/s13195-020-00640-3. 24