COVID-19 InfectionNeNeSCoNCT04745611
Neurological and Neuropsychological Sequelae of COVID-19 Infection
An observational study of COVID-19 Infection, run by Maastricht University at 3 sites in Netherlands.
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- COVID-19 Infection
- What is being tested?
- MRI, Neuropsychological assessment and Questionnaires Patient
- Type of treatment
- Pill or oral medicine
- How many people
- 329 participants
- Where
- 3 sitesNetherlands
- Study dates
- 12 Dec 2020to 21 Feb 2022
- How long will I take part?
- 6 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Former COVID-19 patients who were either admitted to the general hospital ward or the intensive care unit and their respective family members.
Who may be able to join
- 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):
Show all 12Show fewer
- 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.
Who cannot join
- 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.
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
Amsterdam Universitair Medische Centra
Amsterdam
Maastricht University
Maastricht, Limburg, 6229 ER
Universitair Medische Centra Utrecht
Utrecht
About this study
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.
Read the detailed 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.
- Conditions
- COVID-19 Infection
- Being tested
- MRI, Neuropsychological assessment, Questionnaires Patient, Questionnaires Family
- Keywords
- Neurological, Neuropsychological, ARDS, Coronavirus, Severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, Infection, Inflammation
- Medical subject headings
- COVID-19, Neurologic Manifestations, Coronavirus Infections, Infections, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MRIDiagnostic test
3T cranial MRI with T1-, and T2 weighted imaging, a FLAIR sequence, diffusion-weighted imaging and susceptibility-weighted sequence
Neuropsychological assessmentDiagnostic test
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 PatientDiagnostic test
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 FamilyDiagnostic test
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)
| Study group | Role | What they receive |
|---|---|---|
| COVID-19 non-ICU patients | Patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were not admitted to an intensive care unit. Receives: Diagnostic Test: MRI; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Questionnaires Patient | |
| COVID-19 ICU patients | Patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were admitted to an intensive care unit. Receives: Diagnostic Test: MRI; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Questionnaires Patient | |
| COVID-19 non-ICU family members | Close family members of patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were not admitted to an intensive care unit. Receives: Diagnostic Test: Questionnaires Family | |
| COVID-19 ICU family members | Close family members of patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were admitted to an intensive care unit. Receives: Diagnostic Test: Questionnaires Family |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
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.
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
Presence of MRI abnormalities
Presence or absence of MRI abnormalities assessed with a 3T cranial MRI scan
Measured: 6-9 months after hospital discharge
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.
Measured: 6-9 months after hospital discharge
Deficits in cognition
Deficits in general cognition are measured with the Montreal Cognitive Assessment (MoCA).
Measured: 6-9 months after hospital discharge
Deficits in memory
Measured with the Rey's auditory verbal learning test (RAVLT)
Measured: 6-9 months after hospital discharge
Deficits in visual attention & task switching
Measured with Trail Making Test A/B (TMT)
Measured: 6-9 months after hospital discharge
Deficits in selective attention, cognitive flexibility & processing speed
Measured with Stroop Test
Measured: 6-9 months after hospital discharge
Deficits in working memory, attention & executive function
Measured with Digit Span Coding
Measured: 6-9 months after hospital discharge
Change in subjective cognitive complaints
Assessed with the Checklist for post-IC cognitive complaints (CLC-IC)
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
Change in depression/anxiety
Measured with the Hospital anxiety and depression scale
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
Change in post-traumatic stress symptoms
Measured with the Primary Care Post-Traumatic Stress Disorder (PC-PTSD-5) questionnaire
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
Change in family burden
Measured with the Caregiver Strain Index (CSI)
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
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.
Measured: 1) 6-9 months and 2) 12-15 months after hospital discharge
Secondary outcomes (1)
MRI abnormalities (specific)
MRI abnormalities such as cerebral micro-infarctions / bleedings, and white matter hyperintensities.
Measured: 6-9 months after hospital discharge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Feb 2021
- Study start12 Dec 2020
- Primary completion21 Feb 2022
- Study completion21 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for COVID-19 InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 329 participants (actual)
- Target duration
- 6 Months
Sponsor and investigators
- Lead sponsor
- Maastricht University
- Sponsor type
- University, hospital or other
- Collaborators
- Netherlands Brain Foundation, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), UMC Utrecht
- Responsible party
- Sponsor
- Investigators
- Caroline van Heugten, Prof. Dr., Principal investigator, Professor of clinical neuropsychology at Maastricht University,
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04745611
- Sponsor's protocol ID
- NL75102.068.20
- Acronym
- NeNeSCo
- Status last verified
- Apr 2022
- First submitted
- 26 Jan 2021
- Last updated
- 2 May 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
PubMed 32109013Carod-Artal FJ. Neurological complications of coronavirus and COVID-19. Rev Neurol. 2020 May 1;70(9):311-322. doi: 10.33588/rn.7009.2020179. English, Spanish.
PubMed 32329044Egbert AR, Cankurtaran S, Karpiak S. Brain abnormalities in COVID-19 acute/subacute phase: A rapid systematic review. Brain Behav Immun. 2020 Oct;89:543-554. doi: 10.1016/j.bbi.2020.07.014. Epub 2020 Jul 17.
PubMed 32682993Gulko 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.
PubMed 32883670Helms 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. No abstract available.
PubMed 32294339Kandemirli SG, Dogan L, Sarikaya ZT, Kara S, Akinci C, Kaya D, Kaya Y, Yildirim D, Tuzuner F, Yildirim MS, Ozluk E, Gucyetmez B, Karaarslan E, Koyluoglu I, Demirel Kaya HS, Mammadov O, Kisa Ozdemir I, Afsar N, Citci Yalcinkaya B, Rasimoglu S, Guduk DE, Kedir Jima A, Ilksoz A, Ersoz V, Yonca Eren M, Celtik N, Arslan S, Korkmazer B, Dincer SS, Gulek E, Dikmen I, Yazici M, Unsal S, Ljama T, Demirel I, Ayyildiz A, Kesimci I, Bolsoy Deveci S, Tutuncu M, Kizilkilic O, Telci L, Zengin R, Dincer A, Akinci IO, Kocer N. Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection. Radiology. 2020 Oct;297(1):E232-E235. doi: 10.1148/radiol.2020201697. Epub 2020 May 8.
PubMed 32384020Kremer S, Lersy F, de Seze J, Ferre 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, Lefebvre N, Boutet C, Fabre X, Forestier G, de Beaurepaire I, Bornet G, Lacalm A, Oesterle H, Bolognini F, Messie 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, Carre S, Alleg M, Lecocq C, Schmitt E, Anxionnat R, Zhu F, Comby PO, Ricolfi F, Thouant P, Desal H, Boulouis G, Berge J, Kazemi 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.
PubMed 32544034Lane-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.
PubMed 30711227Langerud AK, Rustoen T, Smastuen 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.
PubMed 29940026Langerud AK, Rustoen T, Smastuen MC, Kongsgaard U, Stubhaug A. Intensive care survivor-reported symptoms: a longitudinal study of survivors' symptoms. Nurs Crit Care. 2018 Jan;23(1):48-54. doi: 10.1111/nicc.12330. Epub 2017 Dec 15.
PubMed 29243344Leonardi M, Padovani A, McArthur JC. Neurological manifestations associated with COVID-19: a review and a call for action. J Neurol. 2020 Jun;267(6):1573-1576. doi: 10.1007/s00415-020-09896-z. Epub 2020 May 20.
PubMed 32436101Needham 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.
PubMed 21946660Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):1306-16. doi: 10.1056/NEJMoa1301372.
PubMed 24088092Rabinovitz 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.
PubMed 32901580Soliman 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.
PubMed 25305070
Study at a glance
From the registry record, last updated by the sponsor on 2 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neurological and Neuropsychological Sequelae of COVID-19 Infection
- ClinicalTrials.gov ID
- NCT04745611
- Acronym / sponsor ID
- NeNeSCo / NL75102.068.20
- Conditions
- COVID-19 Infection
- Keywords
- Neurological, Neuropsychological, ARDS, Coronavirus, Severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, Infection, Inflammation
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 329 participants (actual)
- Lead sponsor
- Maastricht UniversityUniversity, hospital or other
- Collaborators
- Netherlands Brain Foundation, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), UMC Utrecht
- Study start
- 12 Dec 2020 (actual)
- Primary completion
- 21 Feb 2022 (actual)
- Study completion
- 21 Feb 2022 (actual)
- First posted
- 9 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 6 Months
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| COVID-19 non-ICU patients | – | Diagnostic Test: MRI, Diagnostic Test: Neuropsychological assessment, Diagnostic Test: Questionnaires PatientPatients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were not admitted to an intensive care unit. |
| COVID-19 ICU patients | – | Diagnostic Test: MRI, Diagnostic Test: Neuropsychological assessment, Diagnostic Test: Questionnaires PatientPatients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were admitted to an intensive care unit. |
| COVID-19 non-ICU family members | – | Diagnostic Test: Questionnaires FamilyClose family members of patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were not admitted to an intensive care unit. |
| COVID-19 ICU family members | – | Diagnostic Test: Questionnaires FamilyClose family members of patients who were admitted to one of six recruiting hospitals in the Netherlands due to COVID-19 during the first patient wave (march-june 2020) and who were admitted to an intensive care unit. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Former COVID-19 patients who were either admitted to the general hospital ward or the intensive care unit and their respective family members.
Key inclusion criteria (12 listed)
- 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.
- 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:
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MRI3T cranial MRI with T1-, and T2 weighted imaging, a FLAIR sequence, diffusion-weighted imaging and susceptibility-weighted sequence | Diagnostic test | COVID-19 ICU patients, COVID-19 non-ICU patients |
| Neuropsychological assessmentMontreal 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) | Diagnostic test | COVID-19 ICU patients, COVID-19 non-ICU patients |
| Questionnaires PatientEuroQol-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) | Diagnostic test | COVID-19 ICU patients, COVID-19 non-ICU patients |
| Questionnaires FamilyEuroQol-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) | Diagnostic test | COVID-19 ICU family members, COVID-19 non-ICU family members |
Primary outcome
Change in participation
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
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.
Change in patient quality of life
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
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.
Presence of MRI abnormalities
Time frame: 6-9 months after hospital discharge
Presence or absence of MRI abnormalities assessed with a 3T cranial MRI scan
Neurological symptoms
Time frame: 6-9 months after hospital discharge
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.
Deficits in cognition
Time frame: 6-9 months after hospital discharge
Deficits in general cognition are measured with the Montreal Cognitive Assessment (MoCA).
Deficits in memory
Time frame: 6-9 months after hospital discharge
Measured with the Rey's auditory verbal learning test (RAVLT)
Deficits in visual attention & task switching
Time frame: 6-9 months after hospital discharge
Measured with Trail Making Test A/B (TMT)
Deficits in selective attention, cognitive flexibility & processing speed
Time frame: 6-9 months after hospital discharge
Measured with Stroop Test
Deficits in working memory, attention & executive function
Time frame: 6-9 months after hospital discharge
Measured with Digit Span Coding
Change in subjective cognitive complaints
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
Assessed with the Checklist for post-IC cognitive complaints (CLC-IC)
Change in depression/anxiety
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
Measured with the Hospital anxiety and depression scale
Change in post-traumatic stress symptoms
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
Measured with the Primary Care Post-Traumatic Stress Disorder (PC-PTSD-5) questionnaire
Change in family burden
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
Measured with the Caregiver Strain Index (CSI)
Change in family quality of life
Time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge
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 secondary outcome
MRI abnormalities (specific)
Time frame: 6-9 months after hospital discharge
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 May 2022.
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- Background: PubMed 32329044Carod-Artal FJ. Neurological complications of coronavirus and COVID-19. Rev Neurol. 2020 May 1;70(9):311-322. doi: 10.33588/rn.7009.2020179. English, Spanish.
- Background: PubMed 32682993Egbert AR, Cankurtaran S, Karpiak S. Brain abnormalities in COVID-19 acute/subacute phase: A rapid systematic review. Brain Behav Immun. 2020 Oct;89:543-554. doi: 10.1016/j.bbi.2020.07.014. Epub 2020 Jul 17.
- Background: PubMed 32883670Gulko 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.
- Background: PubMed 32294339Helms 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. No abstract available.
- Background: PubMed 32384020Kandemirli SG, Dogan L, Sarikaya ZT, Kara S, Akinci C, Kaya D, Kaya Y, Yildirim D, Tuzuner F, Yildirim MS, Ozluk E, Gucyetmez B, Karaarslan E, Koyluoglu I, Demirel Kaya HS, Mammadov O, Kisa Ozdemir I, Afsar N, Citci Yalcinkaya B, Rasimoglu S, Guduk DE, Kedir Jima A, Ilksoz A, Ersoz V, Yonca Eren M, Celtik N, Arslan S, Korkmazer B, Dincer SS, Gulek E, Dikmen I, Yazici M, Unsal S, Ljama T, Demirel I, Ayyildiz A, Kesimci I, Bolsoy Deveci S, Tutuncu M, Kizilkilic O, Telci L, Zengin R, Dincer A, Akinci IO, Kocer N. Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection. Radiology. 2020 Oct;297(1):E232-E235. doi: 10.1148/radiol.2020201697. Epub 2020 May 8.
- Background: PubMed 32544034Kremer S, Lersy F, de Seze J, Ferre 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, Lefebvre N, Boutet C, Fabre X, Forestier G, de Beaurepaire I, Bornet G, Lacalm A, Oesterle H, Bolognini F, Messie 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, Carre S, Alleg M, Lecocq C, Schmitt E, Anxionnat R, Zhu F, Comby PO, Ricolfi F, Thouant P, Desal H, Boulouis G, Berge J, Kazemi 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.
- Background: PubMed 30711227Lane-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.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Caroline van Heugten, Prof. Dr. principal investigator
Professor of clinical neuropsychology at Maastricht University,
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of COVID-19 Infection, run by Maastricht University at 3 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in participation (time frame: 1) 6-9 months and 2) 12-15 months after hospital discharge). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04745611, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2022.