Cognitive Screening After COVID-19 Tools Are Needed for the Assessment of Neurologic and Neuropsychologic Sequelae of Infection with the SARS-Cov-2 Virus

SPECIAL REPORT Cognitive Screening After COVID-19 Tools are needed for the assessment of neurologic and neuropsychologic sequelae of infection with the SARS-CoV-2 virus. By Sarah H. Gulick, PsyD; Steven Mandel, MD; Edward A. Maitz, PhD, ABN; and Christopher R. Brigham, MD, MMS

There is an emerging body of Cognitive Symptoms Reported After COVID-19 literature indicating that a sub‑ Many people report cognitive symptoms in the weeks set of people who experienced and months following diagnosis of COVID‑19 (Table).1-11 As SARS‑CoV‑2 infection have many as 75% of people who were hospitalized with COVID‑19 neurocognitive symptoms for report persistent symptoms even 6 months later.2 The terms weeks or even months afterwards. post-acute sequelae of SARS-CoV-2 (PASC), COVID syndrome, Approximately a third of people long COVID, and long haulers have all been used to describe with COVID‑19 report neurologic people who report persistent cognitive, psychologic, and symptoms.1 Although cognitive somatic symptoms after COVID‑19.5 Brain fog is used to symptoms can occur secondary describe a sense that thinking is slowed, concentration is fuzzy, to systemic disease, and a small and mental abilities are not as sharp as they once were. There number of individuals have had may be other lingering symptoms, including fatigue, body meningoencephalitis and vascular events (eg, stroke) during aches, inability to exercise, headache, and difficulty sleeping. COVID‑19, some do not present with any known objective The underlying pathophysiology of long COVID is unclear. evidence of neurologic insult. Many who have cognitive com‑ Symptoms may be similar to myalgic encephalomyelitis or plaints have normal neurologic and physical examinations, chronic fatigue syndrome (ME/CFS) and autonomic dysfunc‑ lab results, and neuroimaging. This review addresses reported tion. Symptoms may be attributed to mitochondrial dysfunc‑ symptoms weeks or months after infection, how and when tion and metabolic changes; however, the pathophysiology neurologists and other physicians might be able to assess is often unknown.12,13 Chronic symptoms are also suggestive these, and whether cognitive screening will inform ability to of postural orthostatic tachycardia syndrome (POTS).14 A return to work and treatment recommendations. For individ‑ hypothesis regarding etiology of cognitive decline is that the uals who are experiencing persistent symptoms after infection, virus may enter the brain via nasal passages and the olfactory we must define current best practices, recognizing that our bulb to directly invade the hippocampus.15 Some preliminary understanding is evolving. A timeline for when maximal medi‑ research suggests risk factors for developing long COVID, and cal improvement can be expected remains to be determined. early research suggests that increased age, specific symptoms Although this research is being done, it is occurring primarily in the first week of infection, higher body mass index (BMI), in tertiary medical centers and teaching hospitals, and much and female sex carry a higher risk of persistent symptoms.16 of the information has not yet entered clinical practice. We A recent article explored self reports of cognitive symptoms, anticipate that physicians will have patients who present with including persistent memory loss (34%) and concentration brain fog, a not uncommon symptom in this population. deficits (28%), 110 days after people were discharged from a This article aims to provide a preliminary approach to hospital ward vs an intensive care unit (ICU), and no significant screening cognitive symptoms after COVID‑19. Physicians differences were found regarding reported cognitive symptoms may choose cognitive screening as an efficient way to evaluate between the 2 groups.4 Another study reported poor concen‑ those reporting cognitive issues, and these may inform both tration and attention, poor memory, executive functioning treatment recommendations and decisions of whether to refer deficits, and brain fog at least 28 days after COVID-19.3 a patient for more comprehensive neuropsychologic testing. Preliminary research with neuropsychologic assessment There are several important limitations of cognitive screening shows that people with COVID‑19 exhibit deficits in several tests in this context that are discussed at the end of the article. cognitive domains. In a series of 2 cases, individuals recovering

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TABLE. SUBJECTIVE AND OBJECTIVE COGNITIVE article, and future research is needed to continue examining IMPAIRMENT AFTER COVID-19 differences between those who had COVID‑19 and were or were not hospitalized, as well as between people with mild vs Domain Population Studied severe symptoms during COVID‑19. Subjective Concentration >28 days after symptom onset3 cognitive and attention and ≤110 days after hospital Cognitive Screening Tests impairment discharge3 Assessing cognitive complaints objectively during the short Memory >28 days after symptom onset3 time of a typical office visit can be challenging, but screening and ≤10 days after hospital tests can be done by a primary care physician or neurologist discharge4,5 to determine whether more comprehensive cognitive testing is indicated. Several cognitive screening tests have been devel‑ Executive >28 days after symptom onset3 oped and used in a variety of populations. It is important to functioning note, however, that literature directly comparing the 3 cogni‑ Slowed >28 days after symptom onset3 tive screening tests discussed in this article with each other is thinking or and ≤3 months after hospital somewhat limited. There is also no literature yet regarding use brain fog discharge6,7 of cognitive screening tests in a COVID‑19 population. Objective Concentration 2 people after acute phase8 cognitive and attention and severe COVID-19; inpatient Saint Louis University Mental Status (SLUMS) Examination impairment post-critical acute stage9 The SLUMS exam was created to detect mild cognitive impairment (MCI) in veterans,17 age 18 years and up; however, Memory 2 people after acute phase8 research regarding use in younger adults is limited. The SLUMS and severe COVID-19; inpatient exam takes approximately 7 minutes to administer and is avail‑ post-critical acute stage9 able in multiple languages. It is free to the public, with a brief 10 Executive 37 and 149 days after COVID‑19; training video available on the developers’ webpage. functioning mixed participant group,11 severe COVID-19, inpatient MoCA 9 postcritical acute stage MoCA was developed as a rapid screening measure to detect Visual mixed participant group11 mild cognitive dysfunction18 and has been validated for use attention in individuals ages 55 to 85. MoCA has been used as a screen‑ Visuospatial severe COVID-19, inpatient ing tool in multiple populations, including people with a large functioning post-critical acute stage9 range of neuropsychiatric conditions from Alzheimer disease (AD) to HIV-related dementia. Multiple versions are available from COVID‑19 (ages 33 and 56), who were not hospitalized, to allow for serial testing in approximately 100 languages. The had screening and neuropsychologic testing 37 and 149 days MoCA takes about 10 minutes to administer and is available after symptom onset. Cognitive screening with the Montreal digitally. The MoCA is available to the public, although the Cognitive Assessment (MoCA) and the Mini-Mental State publishers require completion of brief (1 hour) training and Examination (MMSE) was unremarkable, but more comprehen‑ certification, which costs $125, before administering the MoCA. sive tests revealed deficits in executive functioning and work‑ ing memory.9 Neuropsychologic tests were administered to MMSE matched groups, age 30 to 64, who had recovered from vs not The MMSE was developed to screen for cognitive impair‑ had COVID-19. Tests included the Trail Making Test (TMT), ment19 and is validated for use in ages 18 to 85 years. The Sign Coding Test (SCT), Continuous Performance Test (CPT), MMSE takes approximately 10 minutes to administer and is and Digital Span Test (DST). No differences were seen on the available in about 70 languages. Before 2001, the MMSE was TMT, SCT, or DST, but individuals who had recovered from free, but in 2001, the test was licensed to a commercial com‑ COVID‑19 scored lower on several aspects of the CPT, indicat‑ pany, PAR, through which MMSE must now be purchased. ing sustained attention deficits.8 Although cognition is an important factor for assessing Evidence for Use of Cognitive Screening Tests overall functioning and employment potential, other factors, Evidence for the MoCA such as medical and psychologic history, may also affect func‑ In a minireview of studies that used the MoCA to assess tioning. Fatigue, medication effects, possible dissimulation, people with traumatic brain injury (TBI),20 it was found to reli‑ and current psychologic functioning need to be considered. A ably detect cognitive impairment in people with mild TBI com‑ detailed discussion of these factors is outside the scope of this pared with normal controls. The MoCA is also said to differen‑

20 PRACTICAL NEUROLOGY MAY 2021 SPECIAL REPORT tiate cognitive disturbances between mild and severe TBI. Still, SLUMS raw score change over a year did not correlate with more research is needed to determine if the the MoCA can any functional measures.29 In a population of veterans (mean differentiate functional cognitive differences in mild vs moder‑ age 75) the SLUMS and the MMSE had similar sensitivity and ate TBI. Use of the MMSE has been compared with use of the specificity in detecting dementia.17 In a nonveteran group of MoCA in TBI for prediction of outcome at discharge from an 170 individuals age 60 or more who were administered the acute care setting, and both were found to have similar predic‑ MMSE and the SLUMs as well as the more comprehensive tive abilities compared with the Disability Rating Scale.21 In a neuropsychologic TMT, Rey Auditory Verbal Learning Test, study of 130 individuals over age 55 without severe cognitive and the Wisconsin Card Sorting Test, the SLUMS correlated impairment who were administered 2 cognitive assessments more strongly with the TMT than the MMSE.30 The SLUMS between 2 and 4 months apart, the MoCA was more reliable outperformed MMSE in predicting cognitive performance than the MMSE, but all measures, including the MoCA, MMSE, across all measures and demographic variables, with the excep‑ and Color Trails Test (CTT) showed within-person variability.22 tion of perseverative errors on the Wisconsin Card Sorting Test. Subtests of the MMSE and the MoCA have been compared, Significant differences between the MMSE and the SLUMS and the MoCA has more sensitivity for detecting executive were also been observed in people who resided in assisted- vs dysfunction. In a study comparing Chinese-language versions independent-living environments (n=118, age 41 to 96).31 of the MMSE and the MoCA in 1,222 individuals who had A study of 136 veterans (median age 78) administered the experienced a stroke, MoCA trail-making and abstraction sub‑ SLUMS, the Short Test of Mental Status (STMS), and the tests were more sensitive to executive dysfunction than the MoCA in random order and the Clinical Dementia Rating MMSE 3-step command test. The MoCA digit span forwards (CDR) scale at a separate session showed all 3 screening tests and backwards test, however, was less sensitive to executive correlated with the CDR. All had adequate specificity, sensitiv‑ dysfunction than the MMSE 3-step command subtest.23 ity, and positive and negative predictive value. The authors also point out that compared with the MMSE, the SLUMS has bet‑ Evidence for the MMSE ter sensitivity and specificity for detecting both dementia and In a meta-analysis of cognitive screening to assess MCI, MCI when compared with DSM-IV criteria.32 Addenbrooke Cognitive Examination Revised (ACE-R), Consortium to Establish a Registry for Alzheimer’s Disease Working Model and Decision Tree (CERAD), MoCA, and the Quick Mild Cognitive Impairment As described in a New York Times article, “. . .a veteran nurse (Qmci) screen were found to have similar diagnostic accuracy, practitioner at an urgent care clinic who fell ill with the virus whereas the MMSE had lower sensitivity.24 The MMSE has in July, finds herself forgetting routine treatments and lab tests, high sensitivity for dementia and is the most frequently stud‑ and has to ask colleagues about terminology she used to know ied instrument used in assessing the US Hispanic population automatically.”33 If a patient presents to a physician’s office according a meta-analysis, but ethnicity and education were with these cognitive symptoms, the physician could consider significant confounders.25 This was also found for people over administering a cognitive screening measure (eg, MoCA, age 60.26 In 93 individuals hospitalized for heart failure who had MMSE, or SLUMS) in order to obtain more information and reported neurocognitive problems, scores on the MoCA and facilitate decision making (Figure). Additionally, the physician MMSE were compared. The MoCA classified 41% as cognitively may ask the patient how long they have been experiencing impaired who were not detected with the MMSE.27 In a study cognitive symptoms, and they may be interested in knowing if comparing the MoCA and the MMSE 1 week and 3 months others have also noticed cognitive changes (Box). Ultimately, after stroke in a group of 60 people (mean age 72), the MoCA it is up to the physician to decide which cognitive screening scores were lower and the MMSE skewed more towards test tool to utilize in clinical practice. If no cognitive impairment ceiling (the point at which items become too difficult to is apparent on the cognitive screening test, no action may be answer). In this study, the MoCA was more sensitive than the necessary at that time. If symptoms re-emerge at a later date, MMSE, but the MoCA had poorer specificity. The MMSE was the physician may choose to readminister a cognitive screen. also found to be valid in this population.28 We propose that if there is evidence of impairment during screening, the physician may choose to monitor the patient Evidence for the SLUMS and reevaluate in 3 months. If impairment is still apparent on In a study comparing the SLUMS and the MMSE in 304 par‑ a cognitive screen at reassessment, and the patient continues ticipants age 70 and older, the MMSE and the SLUMS correlat‑ to report cognitive symptoms, a referral for comprehensive ed with each other and with 2 functional measures; however, neuropsychologic assessment may be necessary. A neuropsy‑ the MMSE and the SLUMS categorized the same individual chologist can assess the validity and nature of the cognitive differently. The 1-year change in MMSE raw scores correlated symptoms, along with severity of impairment and whether with changes in 3 functional domains and age. In contrast, the psychologic factors may be contributing to the presentation.

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tool will facilitate physician decision-making and guide refer‑ rals to obtain appropriate assessment and treatment. The cognitive screening tools discussed in this review are proposed as screening tests for cognitive impairment, not psy‑ chologic distress. It is important to recognize that psychologic and cognitive symptoms may occur simultaneously. It can be challenging to determine the etiology of symptoms and if a person is experiencing true cognitive impairment or impair‑ ment secondary to psychologic distress. A neuropsychologist can assist in making this differential diagnosis. A cognitive screening tool does not define a patient’s impairment, func‑ tion, or disability. This determination requires a more com‑ prehensive evaluation. The determination of disability often requires a thorough understanding of the patient’s medical, psychosocial, educational, and vocational history; an updated medical evaluation; objective measures of symptom validity; a comprehensive objective assessment of the individual’s cogni‑ tive and psychologic functioning; and an understanding of the requirements and demands of their job.

Summary To summarize, the following cognitive symptoms following COVID‑19 have been reported: memory loss,3-5 attention and concentration decline,3,4 executive functioning decline,3 and slowed thinking/brain fog.3,6,7 The objective studies discussed show cognitive decline in memory,10 attention and concen‑ Figure. A Working Clinical Model for Cognitive Screening After tration,8,10 executive functioning,9-11 visuospatial function‑ COVID-19. Goals of this working model are to provide individuals ing,10 and visual attention.11 It is expected that physicians will with reasonable necessary diagnosis and efficacious treatment to encounter patients who are reporting some of these persis‑ the degree possible and help them return to the highest possible tent cognitive symptoms weeks or months after COVID‑19 level of functioning. diagnosis, including some individuals who never had a positive Additionally, a neuropsychologist can provide treatment rec‑ SARS‑CoV‑2 test. Physicians may choose to utilize cognitive ommendations and facilitate return to work. screening tools in their practice as a quick and practical way to identify symptoms and guide decision making. n Limitations 1. Pilotto A, Masciocchi S, Volonghi I, et al. Clinical presentation and outcomes of severe acute respiratory syndrome Cognitive screening tools to assess individuals for cognitive coronavirus 2-related encephalitis: the ENCOVID multicenter study. J Infect Dis. 2021;223(1):28-37. symptoms after COVID‑19 have limitations; there are none to 2. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-232. date designed specifically for use in a COVID‑19 population. 3. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their Thus, cognitive screening tests developed for other patient impact [preprint]. SSRN. 2020;10.2139/ssrn.3820561. doi:10.1101/2020.12.24.20248802 4. Garrigues E, Janvier P, Kherabi Y, et al. Post-discharge persistent symptoms and health-related quality of life after populations must be implemented. Cognitive screening tools hospitalization for COVID-19. J Infect. 2020;81(6):e4-e6. doi:10.1016/j.jinf.2020.08.029 do not assess symptom validity or psychologic factors, for 5. Lambert N, Survivor Corps, El-Azab SA, et al. COVID-19 survivors’ reports of the timing, duration, and health impacts of post- acute sequelae of SARS-CoV-2 (PASC) infection [preprint]. medRxiv. 2021;03.22.21254026. doi:10.1101/2021.03.22.21254026 which comprehensive neuropsychologic evaluation is needed. 6. Rubin R. As their numbers grow, COVID-19 “long haulers” stump experts. JAMA. 2020;324(14):1381-1383. Cognitive screening tests do not replace a comprehensive 7. Savarraj JPJ, Burkett AB, Hinds SN, et al. Three-month outcomes in hospitalized COVID-19 patients [preprint]. medRxiv. 2020;10.16.20211029; doi:10.1101/2020.10.16.20211029 neuropsychologic assessment; however, a cognitive screening 8. Zhou H, Lu S, Chen J, et al. The landscape of cognitive function in recovered COVID-19 patients. J Psychiatr Res. 2020;129:98-102. 9. Hellmuth J, Barnett TA, Asken BM, et al. Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients. J Neurovirol. 2021;27(1):191-195. BOX. Clinical Questions to Consider 10. Beaud V, Crottaz-Herbette S, Dunet V, et al. Pattern of cognitive deficits in severe COVID-19. J Neurol Neurosurg Psychiatry. 2021;92(5):567-568. 11. Chamberlain SR, Grant JE, Trender W, Hellyer P, Hampshire A. Post-traumatic stress disorder symptoms in COVID-19 survivors: 1. How long have you been experiencing cognitive symptoms? online population survey. BJPsych Open. 2021;7(2):e47. doi:10.1192/bjo.2021.3 12. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/ chronic fatigue syndrome: a possible approach to SARS-CoV-2 ‘long-haulers’?. Chronic Dis Transl Med. 2021;7(1):14-26. 2. Have others noticed or commented on cognitive changes? 13. Tancheva L, Petralia MC, Miteva S, et al. Emerging neurological and psychobiological aspects of COVID-19 infection. Brain Sci. 2020;10(11):852. 3. What setting do you experience cognitive changes in? 14. Johansson M, Ståhlberg M, Runold M, et al. Long-haul post–COVID-19 symptoms presenting as a variant of postural orthostatic tachycardia syndrome: the Swedish experience [published online ahead of print, 2021 Mar 10]. JACC Case Rep. 2021;3(4):573-580. 15. Ritchie K, Chan D, Watermeyer T. The cognitive consequences of the COVID-19 epidemic: collateral damage? Brain Com-

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munications. 2020;2(2):fcaa069. doi:10.1093/braincomms/fcaa069. 16. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. Nat Med. 2021;27(4):626-631.[ Sarah H. Gulick, PsyD 17. Tariq SH, Tumosa N, Chibnall JT, Perry MH 3rd, Morley JE. Comparison of the Saint Louis University mental status examina- Neuropsychology Post-Doctoral Fellow tion and the mini-mental state examination for detecting dementia and mild neurocognitive disorder--a pilot study. Am J Geriatr Psychiatry. 2006;14(11):900-910. Clinical Neuropsychology Associates 18. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive Philadelphia, PA impairment [published correction appears in J Am Geriatr Soc. 2019;67(9):1991]. J Am Geriatr Soc. 2005;53(4):695-699. 19. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. 20. Mishra K, Purohit D, Sharma S. Montreal Cognitive Assessment Score: a screening tool for cognitive function in traumatic brain Steven Mandel, MD injury (TBI) population. J Neurol Neuromedicine. 2020;5:35-39. Clinical Professor of Neurology 21. de Guise E, Leblanc J, Champoux MC, et al. The mini-mental state examination and the Montreal Cognitive Assessment after traumatic brain injury: an early predictive study. Brain Inj. 2013;27(12):1428-1434. Zucker School of Medicine at Hofstra-Northwell 22. Feeney J, Savva GM, O’Regan C, King-Kallimanis B, Cronin H, Kenny RA. Measurement error, reliability, and minimum detect- Adjunct Professor of Medicine, New York Medical College able change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among community living middle-aged and older adults. J Alzheimers Dis. 2016;53(3):1107-1114. New York, NY 23. Fu C, Jin X, Chen B, et al. Comparison of the Mini-Mental State Examination and Montreal Cognitive Assessment executive subtests in detecting post-stroke cognitive impairment. Geriatr Gerontol Int. 2017;17(12):2329-2335. 24. Breton A, Casey D, Arnaoutoglou NA. Cognitive tests for the detection of mild cognitive impairment (MCI), the prodromal Edward A. Maitz, PhD, ABN stage of dementia: Mmeta-analysis of diagnostic accuracy studies. Int J Geriatr Psychiatry. 2019;34(2):233-242. 25. Arévalo SP, Kress J, Rodriguez FS. Validity of cognitive assessment tools for older adult Hispanics: a systematic review. J Am Clinical Neuropsychologist Geriatr Soc. 2020;68(4):882-888. Clinical Neuropsychology Associates 26. Ciesielska N, Sokołowski R, Mazur E, Podhorecka M, Polak-Szabela A, Kędziora-Kornatowska K. Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini-Mental State Examination (MMSE) in mild cognitive impairment Adjunct Clinical Assistant Professor, Widener University (MCI) detection among people aged over 60? Psychiatr Pol. 2016;50(5):1039-1052. 27. Cameron J, Worrall-Carter L, Page K, Stewart S, Ski CF. Screening for mild cognitive impairment in patients with heart Philadelphia, PA failure: Montreal cognitive assessment versus mini mental state exam. Eur J Cardiovasc Nurs. 2013;12(3):252-260. 28. Cumming TB, Churilov L, Linden T, Bernhardt J. Montreal Cognitive Assessment and Mini-Mental State Examination are both valid cognitive tools in stroke. Acta Neurol Scand. 2013;128(2):122-129. Christopher R. Brigham, MD, MMS 29. Howland M, Tatsuoka C, Smyth KA, Sajatovic M. Detecting change over time: a comparison of the SLUMS examination and Department of Medicine the MMSE in older adults at risk for cognitive decline. CNS Neurosci Ther. 2016;22(5):413-419. 30. Feliciano L, Horning SM, Klebe KJ, Anderson SL, Cornwell RE, Davis HP. Utility of the SLUMS as a cognitive screening tool among Affiliate Faculty, Leadership in Preventive Medicine a nonveteran sample of older adults. Am J Geriatr Psychiatry. 2013;21(7):623-630. doi:10.1016/j.jagp.2013.01.024. 31. Buckingham DN, Mackor KM, Miller RM, et al. Comparing the cognitive screening tools: MMSE and SLUMS. Pure Insights. Residency/Fellowship Program, Maine Medical Center 2013;2(1):3. https://digitalcommons.wou.edu/pure/vol2/iss1/3 Portland, ME 32. Cummings-Vaughn LA, Chavakula NN, Malmstrom TK, Tumosa N, Morley JE, Cruz-Oliver DM. Veterans Affairs Saint Louis University Mental Status examination compared with the Montreal Cognitive Assessment and the Short Test of Mental Status. J Am Geriatr Soc. 2014;62(7):1341-1346. Disclosures 33. Belluck P. “I feel like I have dementia”: brain fog plagues covid survivors. The New York Times. Published October 11, 2020. Updated January 8, 2021. https://www.nytimes.com/2020/10/11/health/covid-survivors.html SHG, SM, EAM, and CRB report no disclosures

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