Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neurological and Neuropsychological Sequelae of COVID-19 Infection (NeNeSCo)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04745611
Recruitment Status : Recruiting
First Posted : February 9, 2021
Last Update Posted : February 9, 2021
Sponsor:
Collaborators:
Netherlands Brain Foundation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
UMC Utrecht
Information provided by (Responsible Party):
Maastricht University

Brief 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.

Condition or disease Intervention/treatment
COVID-19 Infection Diagnostic Test: MRI Diagnostic Test: Neuropsychological assessment Diagnostic Test: Questionnaires Patient Diagnostic Test: Questionnaires Family

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.

Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 400 participants
Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration: 12 Months
Official Title: Neurological and Neuropsychological Sequelae of COVID-19 Infection
Actual Study Start Date : December 12, 2020
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
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.
Diagnostic Test: MRI
3T cranial MRI with T1-, and T2 weighted imaging, a FLAIR sequence, diffusion-weighted imaging and susceptibility-weighted sequence

Diagnostic Test: 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)

Diagnostic Test: 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)

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.
Diagnostic Test: MRI
3T cranial MRI with T1-, and T2 weighted imaging, a FLAIR sequence, diffusion-weighted imaging and susceptibility-weighted sequence

Diagnostic Test: 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)

Diagnostic Test: 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)

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.
Diagnostic Test: 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)

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.
Diagnostic Test: 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)




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Deficits in cognition [ Time Frame: 6-9 months after hospital discharge ]
    Deficits in general cognition are measured with the Montreal Cognitive Assessment (MoCA).

  6. Deficits in memory [ Time Frame: 6-9 months after hospital discharge ]
    Measured with the Rey's auditory verbal learning test (RAVLT)

  7. Deficits in visual attention & task switching [ Time Frame: 6-9 months after hospital discharge ]
    Measured with Trail Making Test A/B (TMT)

  8. Deficits in selective attention, cognitive flexibility & processing speed [ Time Frame: 6-9 months after hospital discharge ]
    Measured with Stroop Test

  9. Deficits in working memory, attention & executive function [ Time Frame: 6-9 months after hospital discharge ]
    Measured with Digit Span Coding

  10. 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)

  11. 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

  12. 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

  13. 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)

  14. 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.


Secondary Outcome Measures :
  1. MRI abnormalities (specific) [ Time Frame: 6-9 months after hospital discharge ]
    MRI abnormalities such as cerebral micro-infarctions / bleedings, and white matter hyperintensities.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
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.
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04745611


Contacts
Layout table for location contacts
Contact: Simona Klinkhammer, MSc +31 43 3884117 s.Klinkhammer@maastrichtuniversity.nl
Contact: Caroline van Heugten, Prof. Dr. +31 43 388 4091 caroline.vanheugten@maastrichtuniversity.nl

Locations
Layout table for location information
Netherlands
Maastricht University Recruiting
Maastricht, Limburg, Netherlands, 6229 ER
Contact: Simona Klinkhammer, MSc       s.Klinkhammer@maastrichtuniversity.nl   
Amsterdam Universitair Medische Centra Recruiting
Amsterdam, Netherlands
Contact: Janneke Horn, Prof. Dr.       j.horn@amsterdamumc.nl   
Universitair Medische Centra Utrecht Not yet recruiting
Utrecht, Netherlands
Contact: Anne Visser-Meilij, Dr.       j.m.a.visser-meilij@umcutrecht.nl   
Sponsors and Collaborators
Maastricht University
Netherlands Brain Foundation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
UMC Utrecht
Investigators
Layout table for investigator information
Principal Investigator: Caroline van Heugten, Prof. Dr. Professor of clinical neuropsychology at Maastricht University,
Publications:
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.

Layout table for additonal information
Responsible Party: Maastricht University
ClinicalTrials.gov Identifier: NCT04745611    
Other Study ID Numbers: NL75102.068.20
First Posted: February 9, 2021    Key Record Dates
Last Update Posted: February 9, 2021
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Maastricht University:
Neurological
Neuropsychological
ARDS
Coronavirus
Severe acute respiratory syndrome coronavirus-2
SARS-CoV-2
Infection
Inflammation
Additional relevant MeSH terms:
Layout table for MeSH terms
Infection
Communicable Diseases