Special Report: Cognitive Screening After COVID-19

There is an emerging body of literature indicating that a subset of people who experienced SARS-CoV-2 infection have neurocognitive symptoms for weeks or even months afterwards. Approximately a third of people with COVID-19 report neurologic symptoms.¹ Although cognitive symptoms can occur secondary to systemic disease, and a small number of individuals have had meningoencephalitis and vascular events (eg, stroke) during COVID-19, some do not present with any known objective evidence of neurologic insult. Many who have cognitive complaints have normal neurologic and physical examinations, lab results, and neuroimaging. This review addresses reported symptoms weeks or months after infection, how and when neurologists and other physicians might be able to assess these, and whether cognitive screening will inform ability to return to work and treatment recommendations. For individuals who are experiencing persistent symptoms after infection, we must define current best practices, recognizing that our understanding is evolving. A timeline for when maximal medical improvement can be expected remains to be determined. Although this research is being done, it is occurring primarily in tertiary medical centers and teaching hospitals, and much of the information has not yet entered clinical practice. We anticipate that physicians will have patients who present with brain fog, a not uncommon symptom in this population.

This article aims to provide a preliminary approach to screening cognitive symptoms after COVID-19. Physicians may choose cognitive screening as an efficient way to evaluate those reporting cognitive issues, and these may inform both treatment recommendations and decisions of whether to refer a patient for more comprehensive neuropsychologic testing. There are several important limitations of cognitive screening tests in this context that are discussed at the end of the article.

Cognitive Symptoms Reported After COVID-19

Many people report cognitive symptoms in the weeks and months following diagnosis of COVID-19 (Table).^1-11 As many as 75% of people who were hospitalized with COVID-19 report persistent symptoms even 6 months later.² The terms post-acute sequelae of SARS-CoV-2 (PASC), COVID syndrome, long COVID, and long haulers have all been used to describe people who report persistent cognitive, psychologic, and somatic symptoms after COVID-19.⁵Brain fog is used to describe a sense that thinking is slowed, concentration is fuzzy, and mental abilities are not as sharp as they once were. There may be other lingering symptoms, including fatigue, body aches, inability to exercise, headache, and difficulty sleeping.

The underlying pathophysiology of long COVID is unclear. Symptoms may be similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and autonomic dysfunction. Symptoms may be attributed to mitochondrial dysfunction and metabolic changes; however, the pathophysiology is often unknown.^12,13 Chronic symptoms are also suggestive of postural orthostatic tachycardia syndrome (POTS).¹⁴ A hypothesis regarding etiology of cognitive decline is that the virus may enter the brain via nasal passages and the olfactory bulb to directly invade the hippocampus.¹⁵ Some preliminary research suggests risk factors for developing long COVID, and early research suggests that increased age, specific symptoms in the first week of infection, higher body mass index (BMI), and female sex carry a higher risk of persistent symptoms.¹⁶

A recent article explored self reports of cognitive symptoms, including persistent memory loss (34%) and concentration deficits (28%), 110 days after people were discharged from a hospital ward vs an intensive care unit (ICU), and no significant differences were found regarding reported cognitive symptoms between the 2 groups.⁴ Another study reported poor concentration and attention, poor memory, executive functioning deficits, and brain fog at least 28 days after COVID-19.³

Preliminary research with neuropsychologic assessment shows that people with COVID-19 exhibit deficits in several cognitive domains. In a series of 2 cases, individuals recovering from COVID-19 (ages 33 and 56), who were not hospitalized, had screening and neuropsychologic testing 37 and 149 days after symptom onset. Cognitive screening with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) was unremarkable, but more comprehensive tests revealed deficits in executive functioning and working memory.⁹ Neuropsychologic tests were administered to matched groups, age 30 to 64, who had recovered from vs not had COVID-19. Tests included the Trail Making Test (TMT), Sign Coding Test (SCT), Continuous Performance Test (CPT), and Digital Span Test (DST). No differences were seen on the TMT, SCT, or DST, but individuals who had recovered from COVID-19 scored lower on several aspects of the CPT, indicating sustained attention deficits.⁸

Although cognition is an important factor for assessing overall functioning and employment potential, other factors, such as medical and psychologic history, may also affect functioning. Fatigue, medication effects, possible dissimulation, and current psychologic functioning need to be considered. A detailed discussion of these factors is outside the scope of this article, and future research is needed to continue examining differences between those who had COVID-19 and were or were not hospitalized, as well as between people with mild vs severe symptoms during COVID-19.

Cognitive Screening Tests

Assessing cognitive complaints objectively during the short time of a typical office visit can be challenging, but screening tests can be done by a primary care physician or neurologist to determine whether more comprehensive cognitive testing is indicated. Several cognitive screening tests have been developed and used in a variety of populations. It is important to note, however, that literature directly comparing the 3 cognitive screening tests discussed in this article with each other is somewhat limited. There is also no literature yet regarding use of cognitive screening tests in a COVID-19 population.

Saint Louis University Mental Status (SLUMS) Examination

The SLUMS exam was created to detect mild cognitive impairment (MCI) in veterans,¹⁷ age 18 years and up; however, research regarding use in younger adults is limited. The SLUMS exam takes approximately 7 minutes to administer and is available in multiple languages. It is free to the public, with a brief training video available on the developers’ webpage.

MoCA

MoCA was developed as a rapid screening measure to detect mild cognitive dysfunction¹⁸ and has been validated for use in individuals ages 55 to 85. MoCA has been used as a screening tool in multiple populations, including people with a large range of neuropsychiatric conditions from Alzheimer disease (AD) to HIV-related dementia. Multiple versions are available to allow for serial testing in approximately 100 languages. The MoCA takes about 10 minutes to administer and is available digitally. The MoCA is available to the public, although the publishers require completion of brief (1 hour) training and certification, which costs $125, before administering the MoCA.

MMSE

The MMSE was developed to screen for cognitive impairment¹⁹ and is validated for use in ages 18 to 85 years. The MMSE takes approximately 10 minutes to administer and is available in about 70 languages. Before 2001, the MMSE was free, but in 2001, the test was licensed to a commercial company, PAR, through which MMSE must now be purchased.

Evidence for Use of Cognitive Screening Tests

Evidence for the MoCA

In a minireview of studies that used the MoCA to assess people with traumatic brain injury (TBI),²⁰ it was found to reliably detect cognitive impairment in people with mild TBI compared with normal controls. The MoCA is also said to differentiate cognitive disturbances between mild and severe TBI. Still, more research is needed to determine if the the MoCA can differentiate functional cognitive differences in mild vs moderate TBI. Use of the MMSE has been compared with use of the MoCA in TBI for prediction of outcome at discharge from an acute care setting, and both were found to have similar predictive abilities compared with the Disability Rating Scale.²¹ In a study of 130 individuals over age 55 without severe cognitive impairment who were administered 2 cognitive assessments between 2 and 4 months apart, the MoCA was more reliable than the MMSE, but all measures, including the MoCA, MMSE, and Color Trails Test (CTT) showed within-person variability.²²

Subtests of the MMSE and the MoCA have been compared, and the MoCA has more sensitivity for detecting executive dysfunction. In a study comparing Chinese-language versions of the MMSE and the MoCA in 1,222 individuals who had experienced a stroke, MoCA trail-making and abstraction subtests were more sensitive to executive dysfunction than the MMSE 3-step command test. The MoCA digit span forwards and backwards test, however, was less sensitive to executive dysfunction than the MMSE 3-step command subtest.²³

Evidence for the MMSE

In a meta-analysis of cognitive screening to assess MCI, Addenbrooke Cognitive Examination Revised (ACE-R), Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), MoCA, and the Quick Mild Cognitive Impairment (Qmci) screen were found to have similar diagnostic accuracy, whereas the MMSE had lower sensitivity.²⁴ The MMSE has high sensitivity for dementia and is the most frequently studied instrument used in assessing the US Hispanic population according a meta-analysis, but ethnicity and education were significant confounders.²⁵ This was also found for people over age 60.²⁶ In 93 individuals hospitalized for heart failure who had reported neurocognitive problems, scores on the MoCA and MMSE were compared. The MoCA classified 41% as cognitively impaired who were not detected with the MMSE.²⁷ In a study comparing the MoCA and the MMSE 1 week and 3 months after stroke in a group of 60 people (mean age 72), the MoCA scores were lower and the MMSE skewed more towards test ceiling (the point at which items become too difficult to answer). In this study, the MoCA was more sensitive than the MMSE, but the MoCA had poorer specificity. The MMSE was also found to be valid in this population.²⁸

Evidence for the SLUMS

In a study comparing the SLUMS and the MMSE in 304 participants age 70 and older, the MMSE and the SLUMS correlated with each other and with 2 functional measures; however, the MMSE and the SLUMS categorized the same individual differently. The 1-year change in MMSE raw scores correlated with changes in 3 functional domains and age. In contrast, the SLUMS raw score change over a year did not correlate with any functional measures.²⁹ In a population of veterans (mean age 75) the SLUMS and the MMSE had similar sensitivity and specificity in detecting dementia.¹⁷ In a nonveteran group of 170 individuals age 60 or more who were administered the MMSE and the SLUMs as well as the more comprehensive neuropsychologic TMT, Rey Auditory Verbal Learning Test, and the Wisconsin Card Sorting Test, the SLUMS correlated more strongly with the TMT than the MMSE.³⁰ The SLUMS outperformed MMSE in predicting cognitive performance across all measures and demographic variables, with the exception of perseverative errors on the Wisconsin Card Sorting Test. Significant differences between the MMSE and the SLUMS were also been observed in people who resided in assisted- vs independent-living environments (n=118, age 41 to 96).³¹

A study of 136 veterans (median age 78) administered the SLUMS, the Short Test of Mental Status (STMS), and the MoCA in random order and the Clinical Dementia Rating (CDR) scale at a separate session showed all 3 screening tests correlated with the CDR. All had adequate specificity, sensitivity, and positive and negative predictive value. The authors also point out that compared with the MMSE, the SLUMS has better sensitivity and specificity for detecting both dementia and MCI when compared with DSM-IV criteria.³²

Working Model and Decision Tree

As described in a New York Times article, “. . .a veteran nurse practitioner at an urgent care clinic who fell ill with the virus in July, finds herself forgetting routine treatments and lab tests, and has to ask colleagues about terminology she used to know automatically.”³³ If a patient presents to a physician’s office with these cognitive symptoms, the physician could consider administering a cognitive screening measure (eg, MoCA, MMSE, or SLUMS) in order to obtain more information and facilitate decision making (Figure). Additionally, the physician may ask the patient how long they have been experiencing cognitive symptoms, and they may be interested in knowing if others have also noticed cognitive changes (Box). Ultimately, it is up to the physician to decide which cognitive screening tool to utilize in clinical practice. If no cognitive impairment is apparent on the cognitive screening test, no action may be necessary at that time. If symptoms re-emerge at a later date, the physician may choose to readminister a cognitive screen. We propose that if there is evidence of impairment during screening, the physician may choose to monitor the patient and reevaluate in 3 months. If impairment is still apparent on a cognitive screen at reassessment, and the patient continues to report cognitive symptoms, a referral for comprehensive neuropsychologic assessment may be necessary. A neuropsychologist can assess the validity and nature of the cognitive symptoms, along with severity of impairment and whether psychologic factors may be contributing to the presentation. Additionally, a neuropsychologist can provide treatment recommendations and facilitate return to work.

Limitations

Cognitive screening tools to assess individuals for cognitive symptoms after COVID-19 have limitations; there are none to date designed specifically for use in a COVID-19 population. Thus, cognitive screening tests developed for other patient populations must be implemented. Cognitive screening tools do not assess symptom validity or psychologic factors, for which comprehensive neuropsychologic evaluation is needed. Cognitive screening tests do not replace a comprehensive neuropsychologic assessment; however, a cognitive screening tool will facilitate physician decision-making and guide referrals to obtain appropriate assessment and treatment.

The cognitive screening tools discussed in this review are proposed as screening tests for cognitive impairment, not psychologic 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 impairment secondary to psychologic distress. A neuropsychologist can assist in making this differential diagnosis. A cognitive screening tool does not define a patient’s impairment, function, or disability. This determination requires a more comprehensive 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 cognitive 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 concentration,^8,10 executive functioning,^9-11 visuospatial functioning,¹⁰ and visual attention.¹¹ It is expected that physicians will encounter patients who are reporting some of these persistent cognitive symptoms weeks or months after COVID-19 diagnosis, including some individuals who never had a positive SARS-CoV-2 test. Physicians may choose to utilize cognitive screening tools in their practice as a quick and practical way to identify symptoms and guide decision making.