Frequent Neurocognitive Deficits After Covid 19
Frequent Neurocognitive Deficits After Covid 19
Frequent Neurocognitive Deficits After Covid 19
BRAIN
AIN COMMUNICATIONS
Neuropsychiatric complications associated with coronavirus disease 2019 caused by the Coronavirus SARS-CoV-2 (COVID-19)
are increasingly appreciated. While most studies have focussed on severely affected individuals during acute infection, it remains
unclear whether mild COVID-19 results in neurocognitive deficits in young patients. Here, we established a screening approach to
detect cognitive deficiencies in post-COVID-19 patients. In this cross-sectional study, we recruited 18 mostly young patients 20–
105 days (median, 85 days) after recovery from mild to moderate disease who visited our outpatient clinic for post-COVID-19
care. Notably, 14 (78%) patients reported sustained mild cognitive deficits and performed worse in the Modified Telephone
Interview for Cognitive Status screening test for mild cognitive impairment compared to 10 age-matched healthy controls. While
short-term memory, attention and concentration were particularly affected by COVID-19, screening results did not correlate with
hospitalization, treatment, viremia or acute inflammation. Additionally, Modified Telephone Interview for Cognitive Status scores
did not correlate with depressed mood or fatigue. In two severely affected patients, we excluded structural or other inflammatory
causes by magnetic resonance imaging, serum and cerebrospinal fluid analyses. Together, our results demonstrate that sustained
sub-clinical cognitive impairments might be a common complication after recovery from COVID-19 in young adults, regardless of
clinical course that were unmasked by our diagnostic approach.
1 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
2 Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
3 Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
4 Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
5 German Center for Infection Disease (DZIF), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Correspondence to: Prof Manuel A. Friese, MD, Institute of Neuroimmunology and Multiple
Sclerosis (INIMS), Center for Molecular Neurobiology Hamburg (ZMNH), University Medical
Centre Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
E-mail: [email protected]
Received August 3, 2020. Revised October 31, 2020. Accepted November 6, 2020. Advance Access publication November 23, 2020
C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
V
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2 | BRAIN COMMUNICATIONS 2020: Page 2 of 9 M. S. Woo et al.
Graphical Abstract
Here, we established a facile screening approach for and (iv) semantic memory, comprehension and repetition
cognitive deficits in 18 young patients without diagnosed (language/concentration) (De Jager et al., 2003). The
cognitive pre-conditions after recovery from COVID-19 TICS-M included the following items: (i) name, (ii) age,
and discovered widespread sub-clinical deficits. (iii) date, (iv) weekday, (v) season, (vi) phone number
(each 1 point), (vii) counting backward (2 points), (viii)
first, a 10-word list learning exercise and then a delayed
Materials and methods (21) recall of that word list (10 points each), (ix) subtrac-
tions (5 points); (x–xiii) responsive naming (4 points),
Patient cohorts (xiv–xv) repetition (2 points), (xvi) current chancellor and
For this cross-sectional study, we randomly interviewed (xvii) president of Germany (each 2 points), (xviii) finger
patients from the outpatient clinic of the University tapping (2 points) and (xix, xx) word opposites (2
Medical Centre Hamburg-Eppendorf (UKE) and included points). The total score was 50 points. The TICS-M score
corrected for multiple comparisons. Exact P-values are considered important when conducting larger studies that
reported in respective sections of the article and figure include affected individuals who might not seek profes-
legends. We analysed the scores of Fatigue Assessment sional health care and stay in home quarantine.
Scale and Patient Health Questionnaire-9 Depression Strikingly, post-COVID-19 patients scored significantly
Scale as well as age, length of hospitalization, sickness lower results in the TICS-M (mean, 38.83; range, 31–46)
duration, time from recovery to neurocognitive assess- compared to healthy controls (mean, 45.8; range, 43–50)
ment, maximal PCR cycle threshold values, maximal anti- (Fig. 1A), especially regarding short-term memory, atten-
body titres, maximal CRP, IL-6, ferritin and D-dimers as tion and concentration/language tasks (Fig. 1B). Notably,
predictors. The outcome variable was the TICS-M score. results from screening for depression (Personal Health
For effect size of non-parametric comparisons, we calcu- Questionnaire 9) and for fatigue (Fatigue Assessment
lated Rosenthals r. Significant results are indicated by *P Scale) did not show significant correlation with TICS-M
< 0.05, **P < 0.01 and ***P < 0.001. scores (Fig. 1C and D). In terms of patients’ self-reported
Table 1 Summary of characteristics and manifestations of post-COVID-19 patients and healthy control subjects
acute inflammation. Detailed neuropsychologic evaluation Cerebrovascular events and altered mental status have
confirmed deficits of attention, executive functions and been described to be common neuropsychiatric manifesta-
memory (detailed case vignettes are reported in the sup- tions in acute COVID-19 in a nationwide surveillance
plementary material). study in the UK (Varatharaj et al., 2020). In total, 59%
of patients with altered mental status could be assigned
to a neuropsychiatric disorder, underlining the diversity
Discussion of COVID-19-associated manifestations. We screened
patients after recovery from COVID-19 and found sub-
SARS-CoV-2 affects multiple organ systems by infiltrating stantial neurocognitive deficits that sustained after acute
endothelial cells of blood vessels throughout the whole infection. Moreover, we detected subtle cognitive deficits
body (Varga et al., 2020). Thus, a multitude of symp- that did not restrain most patients in daily life and were
toms and clinical disease courses have been described only unmasked by our specific screening, including defi-
(Gupta et al., 2020). Here, we focussed on the evaluation cits in short-term memory, attention and concentration.
of neurocognitive post-COVID-19 manifestations in most- Retrospective meta-analysis of SARS and MERS out-
ly young adults who recovered from acute uncomplicated breaks has revealed acute and long-term neuropsycho-
COVID-19. This study demonstrates substantial neuro- logical deficits. Similar to our findings, most-common
cognitive deficits that sustain after recovery and advocate post-illness manifestations included impaired concentra-
screening routines for cognitive deficits during medical tion and attention in 19.9% and impaired memory in
care of post-COVID-19 patients. 18.9% of patients after recovery (Rogers et al., 2020).
6 | BRAIN COMMUNICATIONS 2020: Page 6 of 9 M. S. Woo et al.
Figure 2 Cognitive deficits are independent from hospitalization and sickness duration. (A) Comparison of TICS-M total scores
(P ¼ 0.9644) between female (n ¼ 10) and male (n ¼ 8) post-COVID-19 patients. Two-tailed Wilcoxon-test was used. (B–E) Linear regression
analysis of TICS-M scores and age in years (B; t ¼ 1.0241, FDR-adjusted P ¼ 0.6420, Estimate ¼ 0.057), time to recovery from acute COVID-19
in days (C; t ¼ 0.0576, FDR-adjusted P ¼ 0.9548, Estimate ¼ 0.003), duration of sickness in days (D; t ¼ 0.0576, FDR-adjusted P ¼ 0.9548,
Estimate ¼ 0.023) and duration of inpatient treatment in days (E; t ¼ 0.8254, FDR-adjusted P ¼ 0.7021, Estimate ¼ 0.112) of post-COVID-
patients. (F) Self-reported somatic symptoms that appeared at least once after recovery from COVID-19 and were reported from at least two
patients. (G,H) Linear regression analysis of number of somatic and neurocognitive symptoms (G; t ¼ 1.282, FDR-adjusted P ¼ 0.2181, Estimate
¼ 0.177) and number of somatic symptoms and TICS-M scores (H; t ¼ 0.161, FDR-adjusted P ¼ 0.874, Estimate ¼ 0.068).
Post-COVID-19 neurocognitive deficits BRAIN COMMUNICATIONS 2020: Page 7 of 9 | 7
Therefore, our study represents first indications that war- reports assessing fatigue in COVID-19 (Menni et al.,
rant broad screenings in post-COVID-19 patients to clar- 2020) and histopathological findings of viral infiltrates
ify the diversity of neuropsychological deficits and and diffuse immune cell activation in brains from
prevent potential further harm. deceased COVID-19 patients (Polak et al., 2020) may in-
Screening methods for mild cognitive deficits are mostly dicate similar clinical presentations. However, systematic
used in the diagnostics of dementia that were validated in analysis with large patient cohorts in different cultural
elderly adults (Castanho et al., 2014). Here, we chose settings and different countries is needed for clarification.
TICS-M as it has been validated as a telephone screening To exclude potential biases and classical post-viral-syn-
method which is important for prospective studies that dromes, we additionally screened for fatigue and depres-
include patients who did not seek professional medical sion. Our data indicate that neurocognitive deficits after
care during or after COVID-19. However, TICS-M has recovery from COVID-19 are independent from fatigue
been validated for the diagnosis of mild amnestic demen- and mood alterations and therefore might be different
tia in a patient cohort with an average age of 74.9 years from the classical post-viral syndrome (Perrin et al.,
(Cook et al., 2009). Since the average age of our patient 2020) but a specific post-COVID-19 manifestation.
cohort (42.1 years) was considerably lower, we addition- SARS-CoV-2 might infiltrate the CNS through the nose
ally tested a healthy control group with similar age as (Riel et al., 2015) and trigger a reactive immune response
control. Thus, further optimization of a standardized in the brain that could alter neuronal signalling. In add-
screening tool is needed. Our findings suggest to especial- ition, exposure of human brain organoids to SARS-CoV-
ly focus the screening on short-term memory, attention 2 revealed direct infection of neurons with subsequent
and concentration. In contrast to currently available alterations of intracellular signalling and cell death
screening tools, validation should include all age groups (Ackermann et al., 2020) that could disturb neuronal
since we and others (Dinakaran et al., 2020; Nalleballe connectivity. Notably, TICS-M scores of post-COVID-19
et al., 2020) observed neurocognitive deficits in young patients did not significantly correlate with the maximal
adults. inflammatory response during the acute infection. Studies
Post-viral-syndromes have been described for multiple that investigated chronic fatigue syndrome in rheumatic
viral infections, such as Epstein–Barr–Virus or influenza disorders (Korte and Straub, 2019) and multiple sclerosis
(Hotchin et al., 1989) and are characterized by severe fa- (Giovannoni, 2006) found that chronic but not acute dys-
tigue (Thomas, 1987). Smartphone-App-based patients’ regulation of the immune metabolism and especially
8 | BRAIN COMMUNICATIONS 2020: Page 8 of 9 M. S. Woo et al.
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