Bart, P.A.

Beaud, V.

Bernard-Valnet, R.

Clarke, S.

Crottaz-Herbette, S.

Du Pasquier, R.

Dunet, V.

Vaucher, J.

Journal of Neurology Neurosurgery & Psychiatry

English

Serveur académique lausannois

1J Neurol Neurosurg Psychiatry Month 2020 Vol 0 No 0Pattern of cognitive deficits in severe COVID-19The severe form of COVID-19 tends to be associated with neurological defi-cits.1 2 Among patients with acute respi-ratory distress syndrome (ARDS), who benefited from mechanical ventilation and were examined after discontinuation of sedation and neuromuscular blockade, 69% presented agitation, 65% confusion, 67% corticospinal tract signs and 33% dysexecutive syndrome.2We describe here the pattern of cogni-tive deficits in a series of 13 consecutive inpatients hospitalised in the Lausanne University Hospital, whom we exam-ined during the post- critical acute stage of severe COVID-19 (table 1). Inclusion criteria were COVID-19 diagnosed by PCR and ARDS that required intubation and mechanical ventilation in intensive care unit (ICU). Exclusion criteria were prior psychiatric or neurological diseases, including neurocognitive impairment or dementia. At the time of testing, patients were no longer sedated and ICU delirium symptoms, which were present in seven patients, resolved in six of them (P5–P7, P10, P11, P13) or subsided to a great extent (P12).The neuropsychological evaluation comprised two standardised test batteries. The Montreal Cognitive Assessment (MoCA; https://www. mocatest. org), which covers main cognitive functions, revealed normal cognitive performances in four patients (table 1; P1–P4), mild deficits in four (P5–P8) and moderate to severe deficits in five (P9–P13). MoCA subtests revealed selective cognitive pattern with lower performances in exec-utive functions for patients with normal MoCA scores and more extensive cogni-tive impairment in executive, memory, attentional and visuospatial functions, with relatively preserved orientation and language, for patients with mild to severe MoCA deficits.The Frontal Assessment Battery (FAB; www. psychdb. com/ cognitive- testing/ fab) revealed executive dysfunction in eight patients (table 1; P6–P13). Among the FAB subtests, the most affected was lexical fluency, impaired in all patients except in one (with normal MoCA: P3).Pearson (r) and Spearman (rho) correlation analyses were conducted. MoCA and FAB scores were correlated (r=0.88; p<0.001). Mental fatigue and cognitive slowness, assessed with obser-vational scales, correlated with MoCA (respectively: rho=−0.67; p=0.012; rho=−0.74; p=0.004) and FAB scores (respectively: rho=−0.85; p<0.001; rho=−0.72; p=0.006). Age correlated with FAB (r=−0.591; p=0.033) but not with MoCA scores. There was no signif-icant correlation between MoCA or FAB scores and the following measures: gender, length of ICU stay, duration of mechanical ventilation, delay between ICU discharge and cognitive assessment, mood and anxiety disturbances. Mood disturbance, assessed in self- report, was considerable (table 1; ≥5/10) in 38% of patients and 23% reported anxiety about breathing difficulties, fear of dying or reminiscences of intensive care. Seven patients presented ICU delirium (table 1); its occurrence was correlated with MoCA score (rho=−0.619; p=0.024) and cogni-tive slowness (rho=0.585; p=0.036), but not with FAB, length of ICU stay, duration of mechanical ventilation, delay between ICU discharge and cognitive assessment, age, gender, mental fatigue, mood and anxiety disturbances.Eleven patients had brain imaging. None of them sustained acute stroke or isch-aemic damage; among the eight patients who had MRI- based morphometry, focal brain atrophy was, however, present in patients with normal (table 1; P1) or defi-cient performance at MoCA (P10–P13) as it was absent in patients with normal (P3, P4) or deficient performance at MoCA (P7). Four patients had lumbar puncture, revealing enhanced proteinorachia (P3, P11, P13) and barrier index (P11, P13) or normal values (P12).Two cognitive profiles characterise the post- critical acute phase of severe COVID-19: (1) normal score at MoCA, but tendency for lower performances in LetterTable 1 Patient (P1–P13) characteristics and performance in cognitive testsPatientsAge (years) SexICU stay (days)Mechanical ventilation (days)ICU discharge to cognitive assessment (days) Brain atrophyICU deliriumMoCA scores(0–30)FAB scores(0–18)MoCA mean subtest scores(0–6)FAB mean subtest scores(0–3)Cognitive slowness(0–3)Mental fatigue(0–3)Mood(0–10) and anxiety* disturbancesP1 60s m 46 38 4 rFgm; fv N 29 16.8 Ex: 3.63Me: 5.10VS: 5.63La: 5.70At: 5.75Or: 6.00Fl:1.75Co: 2.50Pr: 2.75Inh: 3.00Int: 3.001 2 8*P2 60s f 12 11 6 – N 28 15.6 2 2 2P3 70s m 31 21 6 None N 26.9 15.6 0 2 3P4 60s m 67 50 10 None N 26 14.4 1 2 1P5 60s m 16 10 9 None Y 23 16.8 Ex: 2.25Me: 3.00At: 3.75VS: 4.13Or: 5.25La: 5.40Fl: 1.25Pr: 2.00Co: 2.50Inh: 2.75Int: 2.752 1 5P6 50s m 21 16 7 – Y 22 13.2 2 2 0P7 50s m 21 17 5 None Y 21 14.4 2 2 3P8 70s f 14 13 4 None N 19 9.6 1 2 2*P9 60s m 21 17 4 None N 17 7.2 Me: 0.48VS: 1.13Ex: 1.30At: 2.00Or: 3.40La: 4.08Fl: 0.00Inh: 0.80Pr: 0.80Int: 1.00Co: 1.603 3 8*P10 60s m 27 19 2 rlFgm; lTgm; rlFwm; rlv; tv; fvY 16.8 2.4 3 3 3P11 50s m 40 23 2 rlFgm; rlCgm Y 13 9.6 2 2 2P12 70s m 25 25 7 rFgm; rlFwm; lPwm; rlOwmY 10 4.8 3 3 8P13 70s f 24 19 6 rlFgm; rPgm; rlTgm; rlv; tvY 4 1.2 3 3 6MEAN: 64.8 28.1 21.5 5.5   19.7 10.9   1.9 2.2 3.9SD: 7.6 15.2 11.2 2.4   7.5 5.5   1.0 0.6 2.8Patients were ranked from highest to lowest performing at MoCA test. Three patients had a CT scan, which was within normal range (P5, P8, P9); eight patients had an MRI- based morphometry, which was within normal range in three patients (P3, P4, P7) and showed signs of atrophy, in bold, in five other patients (P1, P10–P13). ICU delirium was rated N (no delirium) or Y (with delirium). Scores at MoCA and FAB: performance within normal limits is in italics, deficient in bold. For the MoCA, the maximum score is 30 and deficient score below 26 (see https://www.mocatest.org for details): four patients (P1–P4) had normal performances (score ≥26), four patients (P5–P8) had mild deficits (score between 25 and 18) and five patients (P9–P13) had moderate to severe deficits (score below 18). For the FAB, the maximum score is 18. The cut- off score of normal performance is determined by age and educational level (see www.psychdb.com/cognitive-testing/fab for details). The subtest environmental autonomy not having been evaluated because of sanitary requirements, we have extrapolated for the missing subtest by multiplying the FAB score by 1.2. For each MoCA subtest (At: attention, Ex: executive functions, La: language, Me: memory, Or: orientation, VS: visuospatial abilities) and FAB subtest (Co: conceptualisation, Fl: mental flexibility, Inh: inhibitory control, Int: sensitivity to interference, Pr: programming) means were calculated within three groups of patients: normal performance at MoCA score (mean P1–P4), mild deficits at MoCA score (mean P5–P8), moderate to severe deficits at MoCA score (mean P9–P13). Cognitive slowness and mental fatigue were rated on an observational scale of 3 (3 corresponding to a severe manifestation). Mood disturbance was rated on a self- assessment scale of 10 (10 corresponding to most affected) and anxiety with a yes/no question (yes=present*). Last two rows: mean and SD.C, cingulate gyrus; f, female; F, frontal gyrus; FAB, Frontal Assessment Battery; fv, fourth ventricle; gm, grey matter; ICU, intensive care unit; l, left; lv, left ventricle; m, male; MoCA, Montreal Cognitive Assessment; O, occipital gyrus; P, parietal gyrus; r, right; rv, right ventricle; T, temporal gyrus; tv, third ventricle; wm, white matter.Psychiatrique Universitaire de Lausanne. Protected by copyright. on February 26, 2021 at Bibliothequehttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325173 on 20 November 2020. Downloaded from 2 J Neurol Neurosurg Psychiatry Month 2020 Vol 0 No 0Letterexecutive than in other cognitive functions; (2) mild to severe deficits at MoCA with extensive cognitive impairment in execu-tive, memory, attentional and visuospatial functions, but relatively preserved orienta-tion and language, executive dysfunction being confirmed by the FAB score. These cognitive profiles together with mood and anxiety disturbances, which we observed in the acute stage, in the absence of stroke, are reminiscent of those reported in the aftermath of ARDS of other aetiologies, where up to 70% of ARDS survivors had presented at hospital discharge cognitive deficits, affecting predominantly atten-tion, mental processing speed, memory and executive functions,3–5 with a high prevalence of depression and anxiety.5Furthermore, cognitive impairment in severe COVID-19, as in ARDS of other aetiologies,5 does not correlate with length of mechanical ventilation or length of ICU stay and thus severity of the acute illness. However, the occurrence of ICU delirium tends to be associated with poorer cogni-tive performance.1Structural damage, such as ischaemic or hypoxemic lesions of the hippocampus, basal ganglia or cerebellum lesions as well as brain atrophy (in particular hippocampal) or disruption of functional connectivity, which occur frequently in ARDS survivors,3 4 may contribute to cognitive dysfunction. In the context of COVID-19, stroke and perfusion abnor-malities have been reported,1 2 but were excluded here in all 11 patients, who had brain imaging during the acute stage.Prior brain atrophy may confer worse outcome as shown for the risk to develop delirium and cognitive disorders in ARDS of other aetiologies.3 4 Patchy grey and/or white matter atrophy was present in five patients (of the eight who had MRI), most likely reflecting a prior condition; it was associated with cognitive impairment in four patients. However, brain atrophy did not always induce cognitive impairment and conversely, cognitive impairment was also present without imaging abnor-malities, as in previous non- COVID-19 studies.4Our sparse data on cerebrospinal fluid suggest that increased blood–brain barrier permeability may contribute to neurolog-ical symptoms, as previously described for mild central nervous system inflammation in ICU patients.1In conclusion, pattern of cognitive deficits, present during the acute stage in our 13 patients without history of cogni-tive, psychiatric or neurological disor-ders, is probably linked to critical illness as part of ARDS due to COVID-19, since it is very similar to those reported in ARDS of other aetiologies. Further investigations are needed to determine predictive factors and underlying neural mechanisms, and clarify with a long- term follow- up whether patients will completely recover.Valérie Beaud   ,1 Sonia Crottaz- Herbette   ,1 Vincent Dunet   ,2 Julien Vaucher   ,3 Raphaël Bernard- Valnet   ,4 Renaud Du Pasquier   ,4 Pierre- Alexandre Bart   ,3 Stephanie Clarke   11Service of Neuropsychology and Neurorehabilitation, CHUV, Lausanne, Switzerland2Service of Diagnostic and Interventional Radiology, CHUV, Lausanne, Switzerland3Service of Internal Medicine, CHUV, Lausanne, Switzerland4Service of Neurology, CHUV, Lausanne, SwitzerlandCorrespondence to Valérie Beaud, Service of Neuropsychology and Neurorehabilitation, CHUV, Lausanne 1011, VD, Switzerland;  valerie. beaud@ chuv. chContributors SC participated in study conception and design, interpretation and draft of the manuscript. VB participated in study conception and design, performed neuropsychological data acquisition and interpretation, and draft of the manuscript. SC- H performed statistical analysis, interpretation and draft of the manuscript. VD performed radiological data acquisition and interpretation, and draft of the manuscript, RB- V performed neurological data acquisition and interpretation, and draft of the manuscript, JV, RDP and P- AB participated in elaborating the large scale of this study and performed critical revision of the manuscript.Funding This work was supported by the Biaggi de Blasys Foundation for SC- H.Competing interests None declared.Patient consent for publication Not required.Ethics approval The procedure was approved by the Cantonal Ethics Committee of Vaud and informed consent was obtained in agreement with the requirements of the Ethics Committee.Provenance and peer review Not commissioned; externally peer reviewed.Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non- commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non- commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.© Author(s) (or their employer(s)) 2020. Re- use permitted under CC BY- NC. No commercial re- use. See rights and permissions. Published by BMJ.To cite Beaud V, Crottaz- Herbette S, Dunet V, et al. J Neurol Neurosurg Psychiatry Epub ahead of print: [please include Day Month Year]. doi:10.1136/jnnp-2020-325173Received 24 September 2020Revised 3 November 2020Accepted 4 November 2020J Neurol Neurosurg Psychiatry 2020;0:1–2.doi:10.1136/jnnp-2020-325173ORCID iDsValérie Beaud http:// orcid. org/ 0000- 0001- 5808- 2166Sonia Crottaz- Herbette http:// orcid. org/ 0000- 0003- 3944- 3952Vincent Dunet http:// orcid. org/ 0000- 0002- 9897- 4561Julien Vaucher http:// orcid. org/ 0000- 0002- 9462- 8282Raphaël Bernard- Valnet http:// orcid. org/ 0000- 0001- 7447- 344XRenaud Du Pasquier http:// orcid. org/ 0000- 0002- 2786- 3434Pierre- Alexandre Bart http:// orcid. org/ 0000- 0001- 7685- 8968Stephanie Clarke http:// orcid. org/ 0000- 0001- 9393- 5718REFERENCES 1 Helms J, Kremer S, Merdji H, et al. Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. Crit Care 2020;24:491. 2 Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS- CoV-2 infection. N Engl J Med 2020;382:2268–70. 3 Wilcox ME, Brummel NE, Archer K, et al. Cognitive dysfunction in ICU patients: risk factors, predictors, and rehabilitation interventions. Crit Care Med 2013;41:S81–98. 4 Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj 2006;20:263–71. 5 Hopkins RO, Weaver LK, Collingridge D, et al. Two- Year cognitive, emotional, and quality- of- life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005;171:340–7.Psychiatrique Universitaire de Lausanne. Protected by copyright. on February 26, 2021 at Bibliothequehttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325173 on 20 November 2020. Downloaded from 

Pattern of cognitive deficits in severe COVID-19.

UNIL IRIS | Institutional Research Information System

https://serval.unil.ch/resource/serval:BIB_F33888332B52.P001/REF.pdf

Pattern of cognitive deficits in severe COVID-19.

Abstract

Similar works

Full text

Available Versions

Serveur académique lausannois

UNIL IRIS | Institutional Research Information System