Better Understanding of Fatigue After STroke

Stroke is worldwide the second most common cause of death following heart attack and the leading cause of disability. Post-stroke fatigue (PSF) is a common complication after stroke and can be defined as 'an overwhelming exhaustion or tiredness, not related to exertion, which does not typically improve with rest'. Fatigue following stroke can be divided into early (< 3 months) and late (> 3 months) fatigue. PSF can have a considerable impact on a person's everyday activities and quality of life, participation in the rehabilitation process and levels of caregiver burden. Yet no efficient treatment exists to prevent or cure PSF because the pathophysiology remains unclear and seems to be multifaceted.

Autonomic dysfunction is a common complication after stroke, associated with higher morbidity and mortality. An easy tool to measure the function of the autonomic nervous system (ANS) is heart rate variability (HRV), which is defined as the beat-to-beat variation of the heart rate (= interbeat interval (IBI)). It is the result of alterations in the sympathetic and parasympathetic nervous system. In recent systematic reviews, authors stipulate that HRV can be regarded as a prognostic factor for short- and long-term stroke outcomes. HRV can be derived from 24 hours, 5 minutes (short-term) and < 5 minutes (ultra-short-term) measurements by applying time-domain and frequency-domain indices.

Autonomic dysfunction has been related to chronic fatigue syndrome, in addition to fatigue in multiple sclerosis, Parkinson's disease and myasthenia gravis. However, to the best of our knowledge, the relationship between autonomic dysfunction and PSF has not yet been fully investigated.

Fatigue is also common in cardiovascular diseases, especially in patients with heart failure (HF). HF can contribute to fatigue after stroke, independently of stroke.

Cardiac complications after acute ischemic stroke (AIS), such as arrhythmias, cardiac dysfunction and myocardial injury, are frequent. The so-called 'stroke-heart syndrome', a concept introduced in 2018, describes a broad spectrum of cardiac changes observed in 10-20% of patients with AIS within the first month after stroke onset, with a peak in the first 72 hours. A dysregulation in the neural-cardiac control after stroke is suspected to be the cause of the cascade leading to cardiac complications, in which autonomic dysfunction and inflammation seem to be part of the underlying mechanism.

Based on previous studies and by analogy with other neurological diseases, the investigators hypothesize that autonomic dysfunction following AIS contributes to PSF and that patients presenting heart failure as a complication following AIS have an increased risk of PSF.

To confirm this hypothesis, the investigators will conduct a prospective, interventional study where patients who are hospitalized at the Stroke Unit, within 72 hours after stroke symptom onset, will be included. Evaluation will take place of (a) the relationship between autonomic dysfunction (HRV) and early and late PSF, and of (b) the relationship between cardiac dysfunction and early PSF and late PSF.

There will also be an investigation into following elements:

• the association between early and late PSF and (a) certain inflammatory markers at admission (CRP, NLR), (b) stroke localization and (c) baseline imaging markers of brain frailty.
• the role of pre-existing fatigue + pre-existing or post-stroke newly diagnosed cognitive impairment, depression and sleep disturbances on the course of PSF.

Study Overview

• Status: Recruiting
• Conditions: Stroke
• Intervention / Treatment: Diagnostic test: ECG; Diagnostic test: Transthoracic echography (TTE); Diagnostic test: Blood sampling

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anissa Ourtani, MD; Phone Number: 3224754819; Email: Anissa.OURTANI@chu-brugmann.be

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Recruiting
    • CHU Brugmann
    • Contact: Anissa OURTANI, MD; Phone Number: 024754819; Email: Anissa.OURTANI@chu-brugmann.be
    • Principal Investigator: Anissa OURTANI
  • Brussels, Belgium, 1090
    • Recruiting
    • UZ Brussel
    • Contact: Sylvie De Raedt, MD; Email: Sylvie.DeRaedt@uzbrussel.be
    • Principal Investigator: Sylvie De Raedt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18
• First-ever (suspicion of) ischemic stroke based on clinical examination and/or brain imaging
• Onset < 72h at time of inclusion
• Admitted at the stroke unit of CHU Brugmann and UZ Brussel
• Ability to participate in assessment of fatigue, cognitive, mood and sleep disturbances
• Ability to undergo MRI of the brain

Exclusion Criteria:

• Unable to speak French or Dutch
• Pre-existing stroke or other structural brain lesion
• Life expectancy < 1 year
• Severe language impairment or dementia impeding assessment of fatigue, cognitive, mood and sleep disturbances
• Pregnancy or wish to become pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Stroke patients; Patients, hospitalized at the Stroke Unit of CHU Brugmann and UZ Brussel, after the clinical diagnosis of a first-ever ischemic stroke.

Diagnostic test: ECG; An electrocardiogram (ECG) is a simple, non-invasive test that records the electrical activity of the heart.; Diagnostic test: Transthoracic echography (TTE); A transthoracic echocardiogram (TTE) is a test that uses ultrasound (sound waves) to create images of the heart.; Diagnostic test: Blood sampling; Blood sampling will include: complete blood count, serum creatinine and electrolytes, liver enzymes, fast lipid profile, glucose, HbA1C, thyroid-stimulating hormone (TSH), CRP, iron status, cardiac troponin (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability (HRV)	Heart rate variability is assessed by ECG monitoring and analyzed by means of Kubios software.	Baseline (hospital admission)
Heart rate variability (HRV)	Heart rate variability is assessed by ECG monitoring and analyzed by means of Kubios software.	3 months after baseline
Heart rate variability (HRV)	Heart rate variability is assessed by ECG monitoring and analyzed by means of Kubios software.	12 months after baseline
Transthoracic echography (TTE)	Cardiac function will be evaluated by a cardiologist with transthoracic echography (TTE).	Baseline (hospital admission)
Transthoracic echography (TTE)	Cardiac function will be evaluated by a cardiologist with transthoracic echography (TTE).	3 months after baseline
Transthoracic echography (TTE)	Cardiac function will be evaluated by a cardiologist with transthoracic echography (TTE).	12 months after baseline
N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP blood levels	Baseline (hospital admission)
N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP blood levels	3 months after baseline
N-terminal pro-brain natriuretic peptide (NT-proBNP)	NT-proBNP blood levels	12 months after baseline
cardiac troponin (cTnT)	cardiac troponin blood levels	Baseline (hospital admission)
Fatigue Severity Scale (FSS-7)	The 7 items Fatigue Severity Scale (FSS-7) is a method of evaluating the impact of fatigue. The FSS-7 is a questionnaire with 7 statements rated from 1 (disagree) to 7 (agree). No official cut-off has been established, but most studies adopt the approach of using the average score: an average of ≥4 suggests clinically relevant fatigue, while an average <4 indicates low to moderate fatigue.	3 months after baseline
Fatigue Severity Scale (FSS-7)	The 7 items Fatigue Severity Scale (FSS-7) is a method of evaluating the impact of fatigue. The FSS-7 is a questionnaire with 7 statements rated from 1 (disagree) to 7 (agree). No official cut-off has been established, but most studies adopt the approach of using the average score: an average of ≥4 suggests clinically relevant fatigue, while an average <4 indicates low to moderate fatigue.	12 months after baseline
Non-Invasive Blood Pressure (NIBP)	Non-invasive blood pressure (NIBP) is measured continuously using a Finapres device. Outcomes are recorded as real-time systolic, diastolic, and mean arterial pressure values.	Baseline (hospital admission)
Non-Invasive Blood Pressure (NIBP)	Non-invasive blood pressure (NIBP) is measured continuously using a Finapres device. Outcomes are recorded as real-time systolic, diastolic, and mean arterial pressure values.	3 months after baseline
Non-Invasive Blood Pressure (NIBP)	Non-invasive blood pressure (NIBP) is measured continuously using a Finapres device. Outcomes are recorded as real-time systolic, diastolic, and mean arterial pressure values.	12 months after baseline
Baroreflex Sensitivity (BRS)	Baroreflex Sensitivity (BRS) quantifies the autonomic regulation of blood pressure by measuring the change in heart rate in response to spontaneous fluctuations in blood pressure. It is calculated from continuous blood pressure and ECG recordings (using Finapres). BRS is expressed in ms/mmHg, with higher values indicating stronger baroreflex function.	Baseline (hospital admission)
Baroreflex Sensitivity (BRS)	Baroreflex Sensitivity (BRS) quantifies the autonomic regulation of blood pressure by measuring the change in heart rate in response to spontaneous fluctuations in blood pressure. It is calculated from continuous blood pressure and ECG recordings (using Finapres). BRS is expressed in ms/mmHg, with higher values indicating stronger baroreflex function.	3 months after baseline
Baroreflex Sensitivity (BRS)	Baroreflex Sensitivity (BRS) quantifies the autonomic regulation of blood pressure by measuring the change in heart rate in response to spontaneous fluctuations in blood pressure. It is calculated from continuous blood pressure and ECG recordings (using Finapres). BRS is expressed in ms/mmHg, with higher values indicating stronger baroreflex function.	12 months after baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood CRP level	C-reactive protein (CRP) level in the blood (inflammatory marker)	Baseline (hospital admission)
Blood neutrophil-to-lymphocyte ratio (NLR)	The neutrophil-to-lymphocyte ratio (NLR), calculated by dividing the neutrophil count by the lymphocyte count, is an inflammatory marker.	Baseline (hospital admission)
Stroke localization in the brain	Manual segmentation of the acute ischemic lesion will be performed on the MRI of the brain	Baseline (hospital admission)
Fazekas scale	The Fazekas scale is a widely used method to visually rate hyperintense white matter signal abnormalities in magnetic resonance imaging (MRI) data. It ranges from 0 (no lesions) to 3.	Baseline (hospital admission)
Global cortical atrophy scale	Visual rating of cerebral atrophy on MRI images. Ranges from 0 (no lesions) to 39.	Baseline (hospital admission)
Presence for pre-existing fatigue (yes/no)	Questionnaire (did you experience fatigue before you had your stroke' (yes/no))	Baseline (hospital admission)
Duration of pre-existing fatigue	Questionnaire ('how long did you experience fatigue' (< 1 week, < 3 months, 3-6 months and > 6 months)	Baseline (hospital admission)
Montreal Cognitive Assessment (MoCA) questionnaire	Questionnaire. MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal.	3 months after baseline
Montreal Cognitive Assessment (MoCA) score	Questionnaire.MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal.	12 months after baseline
Insomnia Severity Index (ISI)	Insomnia will be assessed by using the Insomnia Severity Index (ISI). The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	Baseline (hospital admission)
Insomnia Severity Index (ISI)	Insomnia will be assessed by using the Insomnia Severity Index (ISI). The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	3 months after baseline
Insomnia Severity Index (ISI)	Insomnia will be assessed by using the Insomnia Severity Index (ISI). The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28).	12 months after baseline
Complete blood count abnormalities: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Renal insufficiency: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Electrolyte imbalance: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Abnormal liver enzymes: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Dyslipidemia: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Diabetes: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Thyroid disorder: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Iron deficiency: yes/no	Clinical decision based on the analysis of the blood sample results	Baseline (hospital admission)
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)	The 26-item IQCODE questionnaire is completed by an informant to assess changes in cognitive function over the past 10 years in elderly individuals. Each item is rated on a 5-point scale from 1 (much improved) to 5 (much worse). The total score is calculated as the mean of all items, giving a range of 1-5. A mean score of ≥3.44 indicates significant cognitive decline.	Baseline (hospital admission)
Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-item questionnaire assessing the frequency of depressive symptoms over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day), giving a total score range of 0-27. Total scores can be interpreted as follows: 0-4: minimal or no depression 5-9: mild depression 10-14: moderate depression 15-19: moderately severe depression 20-27: severe depression	Baseline (hospital admission)
Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-item questionnaire assessing the frequency of depressive symptoms over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day), giving a total score range of 0-27. Total scores can be interpreted as follows: 0-4: minimal or no depression 5-9: mild depression 10-14: moderate depression 15-19: moderately severe depression 20-27: severe depression	3 months after baseline
Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-item questionnaire assessing the frequency of depressive symptoms over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day), giving a total score range of 0-27. Total scores can be interpreted as follows: 0-4: minimal or no depression 5-9: mild depression 10-14: moderate depression 15-19: moderately severe depression 20-27: severe depression	12 months after baseline
Epworth Sleepiness Scale (ESS)	Description and scoring: the ESS is a questionnaire consisting of 8 daily-life situations in which the patient rates their likelihood of falling asleep on a scale from 0 (would never doze) to 3 (high chance of dozing). Total score = sum of the 8 items → possible range 0 to 24. Common interpretation: 0-10: normal daytime sleepiness 11-24: excessive daytime sleepiness (higher score = greater sleepiness)	Baseline (hospital admission)
Epworth Sleepiness Scale (ESS)	Description and scoring: the ESS is a questionnaire consisting of 8 daily-life situations in which the patient rates their likelihood of falling asleep on a scale from 0 (would never doze) to 3 (high chance of dozing). Total score = sum of the 8 items → possible range 0 to 24. Common interpretation: 0-10: normal daytime sleepiness 11-24: excessive daytime sleepiness (higher score = greater sleepiness)	3 months after baseline
Epworth Sleepiness Scale (ESS)	Description and scoring: the ESS is a questionnaire consisting of 8 daily-life situations in which the patient rates their likelihood of falling asleep on a scale from 0 (would never doze) to 3 (high chance of dozing). Total score = sum of the 8 items → possible range 0 to 24. Common interpretation: 0-10: normal daytime sleepiness 11-24: excessive daytime sleepiness (higher score = greater sleepiness)	12 months after baseline
Generalized Anxiety Disorder scale (GAD-7)	Description and scoring: the GAD-7 is a 7-item questionnaire assessing symptoms of generalized anxiety over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day). Total score: sum of all 7 items → possible range 0-21. Common interpretation: 0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety	Baseline (hospital admission)
Generalized Anxiety Disorder scale (GAD-7)	Description and scoring: the GAD-7 is a 7-item questionnaire assessing symptoms of generalized anxiety over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day). Total score: sum of all 7 items → possible range 0-21. Common interpretation: 0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety	3 months after baseline
Generalized Anxiety Disorder scale (GAD-7)	Description and scoring: the GAD-7 is a 7-item questionnaire assessing symptoms of generalized anxiety over the past two weeks. Each item is scored from 0 (not at all) to 3 (nearly every day). Total score: sum of all 7 items → possible range 0-21. Common interpretation: 0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety	12 months after baseline

Collaborators and Investigators

• Sponsor: Brugmann University Hospital
• Investigators: Principal Investigator: Anissa Ourtani, MD, CHU Brugmann

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 27, 2024
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Electrodiagnosis; Electrocardiography; Blood Specimen Collection
• Other Study ID Numbers: BRUFAST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No