Neurological and Neuropsychological Sequelae of COVID-19 Infection

COVID-19 Infection Clinical Trial

— NeNeSCo  

Official title:

Neurological and Neuropsychological Sequelae of COVID-19 Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04745611
• Other study ID #: NL75102.068.20
• Status: Completed
• Start date: December 12, 2020
• Est. completion date: February 21, 2022

Study information

• Verified date: April 2022
• Source: Maastricht University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

COVID-19 is known to affect the respiratory system but may also have an impact on other organ systems, including the brain. A number of severely ill patients also presents neurological symptoms that may be the result of COVID-19 associated brain damage. The aim of this study is to investigate the presence, type, and severity of brain damage as well as the neurological and neuropsychological sequelae of COVID-19 infection. Further, the impact of this infection on daily life functioning, quality of life, and the emotional well-being of family members will be assessed. In this multicenter study, 6-9 months after hospital discharge patients will undergo a 3-T MRI scan and a neuropsychological examination. Additionally, both patients and their family members will answer several questionnaires at 6- 9 and 12-15 months after hospital discharge. COVID-19 patients previously admitted to a general hospital ward will be compared with patients previously admitted to the intensive-care unit. The proposed study will create a more comprehensive picture of the prolonged COVID-19 effects on the brain, mental, and cognitive well-being. The findings will aid patient care and rehabilitation.

Description:

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). COVID-19 primarily affects the respiratory system. However, in severely ill patients damage is also reported to other organ systems including the heart, the kidneys, the circulatory, and gastrointestinal system. Further, research indicates an impact of the virus on the brain and, thereby, on cognition. Patients experience neurological symptoms, MR imaging implies the presence of brain abnormalities, specifically in severely ill patients and studies on cognition suggest problems with memory, attention, information processing and executive function. Preliminary clinical data also show that COVID-19 is associated with neurological and neuropsychiatric illness. Brain damage and therefrom resulting emotional and cognitive deficits in ICU-treated patients are not uncommon findings. Post-intensive care syndrome (PICS) summarizes physical, cognitive, and mental impairments associated with ICU admission. PICS is assumed to be induced by a combination of patient-specific (e.g., psychiatric history), disease-related (e.g., hypoxemia), and ICU factors (e.g., invasive procedures). These factors can cause a variety of pathophysiologic states including atrophy, encephalopathy, and neuropathy, eventually leading to impairment and reduced quality of life. Additionally, ICU-admission has been found to also affect the mental health of patients´ family members (PICS-F). Many of these PICS-inducing factors can be assumed to occur during severe COVID-19 illness and treatment. Therefore, it is likely that COVID-19 patients and their family members exhibit PICS symptoms. To date, it is not known to what extend COVID-19 related brain injury and therewith associated symptoms are present after the (sub)acute stages of illness and whether this will lead to long-term deficits in function. Further, it is to be determined whether COVID-19 patients develop PICS syndrome and if so, whether the therewith associated symptoms are limited to ICU-treated patients or may generally affect the broader group of hospitalized COVID-19 patients. The aim of this research is to fill these gaps in research through: (1) the identification of COVID-19 related brain abnormalities, cognitive impairments, and emotional deficits after the (sub)acute stages of illness (i.e., 6-9 months post-hospital discharge), 2) a comparison of COVID-19 related brain abnormalities, cognitive impairments, and emotional deficits to historical PICS cohorts 3) a comparison between COVID-19 ICU survivors and COVID-19 non-ICU patients in order to assess a potential PICS gradient and 3) a follow-up examination of the aforementioned groups 6 months after the first assessment to gain insight into the persistence of deficits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 329
• Est. completion date: February 21, 2022
• Est. primary completion date: February 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

Patients:

• Objectified COVID-19 infection for which ICU or non-ICU hospital admission was necessary at one of the participating hospitals
• Age > 18 years
• Sufficient command of the Dutch language to follow test instructions and understand questionnaires
• Informed consent. Family members (if present): Within the scope of this study, the term family member will be defined as a person who has good insight into the patient´s daily life functioning (before and after COVID-19 infection). This person can be the spouse, partner, adult child or, in some cases, another individual that plays the most significant role in the patient´s life. The patient will

decide who this family member is. We will check the following criteria:

• Family member of a participant with COVID-19 infection as described above;
• Requires participation of the aforementioned family member as COVID-19 patient
• Age > 18 years
• Sufficient command of the Dutch language to understand questionnaires
• Informed consent. Exclusion Criteria:

Patients:

• objectified cognitive impairments before the hospital admission for the COVID-19 infection
• an unexpected incident leading to severe neurological damage occurring after hospital discharge (such as stroke or traumatic brain injury)
• contra-indications for MRI scanning (e.g. metal implants, cardiac pacemaker, claustrophobia, pregnancy). Family member: no exclusion criteria.

Related Conditions & MeSH terms

• Communicable Diseases
• COVID-19
• COVID-19 Infection
• Infections

Intervention

Diagnostic Test:
• MRI
3T cranial MRI with T1-, and T2 weighted imaging, a FLAIR sequence, diffusion-weighted imaging and susceptibility-weighted sequence
• Neuropsychological assessment
Montreal Cognitive Assessment (MoCA), Rey-Auditory Verbal Learning Test (RAVLT), Trail making A/B, Stroop, Digit Span Coding, Judgement of line orientation (JOLO), Boston Naming Task (BNT), Controlled Oral Word Associations Task (COWAT), Category Fuency, Test of Memory Malingering (TOMM)
• Questionnaires Patient
EuroQol-5D-5L (EQ-5D-5L), Utrecht Scale for Evaluation of Rehabilitation-Participation - Restrictions (USER-P-R), NeNeSCo-Q (questionnaire created for this study, including common neurological symptoms), Checklist for post-IC cognitive complaints (CLC-IC self-report), Hospital Anxiety and Depression Scale (HADS), Primary Care Post-Traumatic Stress Disorder (PC-PTSD-5), Utrecht Coping List (UCL) (subscale passive coping), PROMIS physical functioning short form, Items of Insomnia Severity Index (ISI) & Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Social Support List (SSL-12-I)
• Questionnaires Family
EuroQol-5D-5L (EQ-5D-5L), Utrecht Scale for Evaluation of Rehabilitation-Participation - Restrictions (USER-P-R), Checklist for post-IC cognitive complaints (CLC-IC proxy-report), Hospital Anxiety and Depression Scale (HADS), Primary Care Post-Traumatic Stress Disorder (PC-PTSD-5), Utrecht Coping List (UCL) (subscale passive coping), Social Support List (SSL-12-I), Caregiver Strain Index (CSI)

Locations

Country	Name	City	State
Netherlands	Amsterdam Universitair Medische Centra	Amsterdam
Netherlands	Maastricht University	Maastricht	Limburg
Netherlands	Universitair Medische Centra Utrecht	Utrecht

Sponsors (4)

Lead Sponsor	Collaborator
Maastricht University	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Netherlands Brain Foundation, UMC Utrecht

Country where clinical trial is conducted

Netherlands, 

References & Publications (17)

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Gulko E, Oleksk ML, Gomes W, Ali S, Mehta H, Overby P, Al-Mufti F, Rozenshtein A. MRI Brain Findings in 126 Patients with COVID-19: Initial Observations from a Descriptive Literature Review. AJNR Am J Neuroradiol. 2020 Dec;41(12):2199-2203. doi: 10.3174/ajnr.A6805. Epub 2020 Sep 3. Review. — View Citation

Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, Anheim M, Meziani F. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020 Jun 4;382(23):2268-2270. doi: 10.1056/NEJMc2008597. Epub 2020 Apr 15. — View Citation

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Kremer S, Lersy F, de Sèze J, Ferré JC, Maamar A, Carsin-Nicol B, Collange O, Bonneville F, Adam G, Martin-Blondel G, Rafiq M, Geeraerts T, Delamarre L, Grand S, Krainik A, Caillard S, Constans JM, Metanbou S, Heintz A, Helms J, Schenck M, Lefèbvre N, Boutet C, Fabre X, Forestier G, de Beaurepaire I, Bornet G, Lacalm A, Oesterlé H, Bolognini F, Messié J, Hmeydia G, Benzakoun J, Oppenheim C, Bapst B, Megdiche I, Henry Feugeas MC, Khalil A, Gaudemer A, Jager L, Nesser P, Talla Mba Y, Hemmert C, Feuerstein P, Sebag N, Carré S, Alleg M, Lecocq C, Schmitt E, Anxionnat R, Zhu F, Comby PO, Ricolfi F, Thouant P, Desal H, Boulouis G, Berge J, Kazémi A, Pyatigorskaya N, Lecler A, Saleme S, Edjlali-Goujon M, Kerleroux B, Zorn PE, Matthieu M, Baloglu S, Ardellier FD, Willaume T, Brisset JC, Boulay C, Mutschler V, Hansmann Y, Mertes PM, Schneider F, Fafi-Kremer S, Ohana M, Meziani F, David JS, Meyer N, Anheim M, Cotton F. Brain MRI Findings in Severe COVID-19: A Retrospective Observational Study. Radiology. 2020 Nov;297(2):E242-E251. doi: 10.1148/radiol.2020202222. Epub 2020 Jun 16. — View Citation

Lane-Fall MB, Kuza CM, Fakhry S, Kaplan LJ. The Lifetime Effects of Injury: Postintensive Care Syndrome and Posttraumatic Stress Disorder. Anesthesiol Clin. 2019 Mar;37(1):135-150. doi: 10.1016/j.anclin.2018.09.012. Epub 2018 Dec 19. Review. — View Citation

Langerud AK, Rustøen T, Småstuen MC, Kongsgaard U, Stubhaug A. Health-related quality of life in intensive care survivors: Associations with social support, comorbidity, and pain interference. PLoS One. 2018 Jun 25;13(6):e0199656. doi: 10.1371/journal.pone.0199656. eCollection 2018. — View Citation

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Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, Brady SL, Brodsky MB, Denehy L, Elliott D, Flatley C, Harabin AL, Jones C, Louis D, Meltzer W, Muldoon SR, Palmer JB, Perme C, Robinson M, Schmidt DM, Scruth E, Spill GR, Storey CP, Render M, Votto J, Harvey MA. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference. Crit Care Med. 2012 Feb;40(2):502-9. doi: 10.1097/CCM.0b013e318232da75. Review. — View Citation

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Rabinovitz B, Jaywant A, Fridman CB. Neuropsychological functioning in severe acute respiratory disorders caused by the coronavirus: Implications for the current COVID-19 pandemic. Clin Neuropsychol. 2020 Oct - Nov;34(7-8):1453-1479. doi: 10.1080/13854046.2020.1803408. Epub 2020 Sep 9. Review. — View Citation

Soliman IW, de Lange DW, Peelen LM, Cremer OL, Slooter AJ, Pasma W, Kesecioglu J, van Dijk D. Single-center large-cohort study into quality of life in Dutch intensive care unit subgroups, 1 year after admission, using EuroQoL EQ-6D-3L. J Crit Care. 2015 Feb;30(1):181-6. doi: 10.1016/j.jcrc.2014.09.009. Epub 2014 Sep 22. — View Citation

Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL, Sultan M, Easton A, Breen G, Zandi M, Coles JP, Manji H, Al-Shahi Salman R, Menon DK, Nicholson TR, Benjamin LA, Carson A, Smith C, Turner MR, Solomon T, Kneen R, Pett SL, Galea I, Thomas RH, Michael BD; CoroNerve Study Group. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020 Oct;7(10):875-882. doi: 10.1016/S2215-0366(20)30287-X. Epub 2020 Jun 25. Erratum in: Lancet Psychiatry. 2020 Jul 14;:. — View Citation

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* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in participation	Life participation (social, occupational, mobility) measured by the Utrecht Scale for Evaluation of Rehabilitation-Participation - Restrictions subscale (USER-P-R). The subscale consists of 11 items. Each item score ranges from 0 (not possible at all) to 3 (no difficulty at all), resulting in a total minimum score of 0 and a total maximum score of 33 points, with a higher score indicating less participation restrictions.	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Change in patient quality of life	Quality of life measured by the EuroQol-5D-5L (EQ-5D-5L). The EQ-5D-5L consists of 5 items with 5 levels. The minimum total score is 5 and the maximum total score is 25, with higher scores indicating more problems.	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Presence of MRI abnormalities	Presence or absence of MRI abnormalities assessed with a 3T cranial MRI scan	6-9 months after hospital discharge
Primary	Neurological symptoms	Measures with the neurological and neuropsychological sequelae of COVID-19 questionnaire (NeNeSCo-Q), a questionnaire that has been created for the purpose of this study to assess the most common neurological symptoms (e.g., reduced sense of taste and/or smell, headaches, neuropathic pain) experienced by patients infected with COVID-19. The questionnaire consists of 9 items being rated with present (yes = 1) and not present (no = 0), resulting in a minimum total score of 0 and a maximum total score of 9.	6-9 months after hospital discharge
Primary	Deficits in cognition	Deficits in general cognition are measured with the Montreal Cognitive Assessment (MoCA).	6-9 months after hospital discharge
Primary	Deficits in memory	Measured with the Rey's auditory verbal learning test (RAVLT)	6-9 months after hospital discharge
Primary	Deficits in visual attention & task switching	Measured with Trail Making Test A/B (TMT)	6-9 months after hospital discharge
Primary	Deficits in selective attention, cognitive flexibility & processing speed	Measured with Stroop Test	6-9 months after hospital discharge
Primary	Deficits in working memory, attention & executive function	Measured with Digit Span Coding	6-9 months after hospital discharge
Primary	Change in subjective cognitive complaints	Assessed with the Checklist for post-IC cognitive complaints (CLC-IC)	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Change in depression/anxiety	Measured with the Hospital anxiety and depression scale	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Change in post-traumatic stress symptoms	Measured with the Primary Care Post-Traumatic Stress Disorder (PC-PTSD-5) questionnaire	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Change in family burden	Measured with the Caregiver Strain Index (CSI)	1) 6-9 months and 2) 12-15 months after hospital discharge
Primary	Change in family quality of life	Measured by the EQ-5D-5L. The EQ-5D-5L consists of 5 items with 5 levels. The minimum total score is 5 and the maximum total score is 25, with higher scores indicating more problems.	1) 6-9 months and 2) 12-15 months after hospital discharge
Secondary	MRI abnormalities (specific)	MRI abnormalities such as cerebral micro-infarctions / bleedings, and white matter hyperintensities.	6-9 months after hospital discharge