Clinical trial NCT02389426: Transcranial Doppler in Multiple Sclerosis
Official title: Evaluation of Cerebrovascular Hemodynamics With Transcranial Doppler and Near-infrared Spectroscopy in Patients With Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis
Cerebral hemodynamics
Cerebral hypoperfusion
Cerebral circulation
Lead sponsor: Universitair Ziekenhuis Brussel
Sponsor class: OTHER
First posted: 2015-03-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL

Brief summary: The aim of this study is to investigate the potential of Transcranial doppler (TCD) and Near-Infrared Spectroscopy (NIRS), more simple and non-invasive bedside methods than magnetic resonance imaging (MRI), to evaluate changes in the cerebral circulation between patients with MS and control subjects.

Detailed description: MS is a poorly understood chronic disease of the central nervous system characterized by focal inflammatory demyelinating lesions and diffuse axonal degeneration. Recent magnetic resonance imaging (MRI) studies demonstrated a widespread decrease in cerebral perfusion - expressed as cerebral blood flow (CBF) - throughout the normal-appearing white matter of patients with MS, which seems not just to be secondary to axonal degeneration with reduced metabolic demands, but in contrast may actively contribute to MS pathology.

Reduced CBF in MS is mediated by elevated levels of the potent vasoconstrictive agent endothelin-1 (ET-1), likely released in the cerebral circulation by reactive astrocytes, and can reversed with administration of the ET-1 antagonist bosentan.

Phase-contrast MRI recently demonstrated reduced cervical arterial blood flow velocities to the brain in patients MS as compared to control subjects. The aim of this study is to investigate the potential of TCD and NIRS, more simple and non-invasive bedside method, to evaluate changes in the cerebral circulation between patients with MS and control subjects.

A baseline TCD examination will be performed in each subject (MS patients and controls) over the temporal bone window on both sides. Middle cerebral artery wave forms will be identified at a depth range of 40-60 mm and a stable forward waveform with good intensity will be selected. TCD probes (2 MHz) will be mounted by a head frame to ensure a constant angle of insonation throughout the procedure. Mean, peak-systolic and end-diastolic blood flow velocities can be directly recorded from the machine. Blood pressure (BP) and heart rate will be measured with a finger plethysmograph. The cuff will be applied to the middle finger of the left hand, first placed at the heart level to calibrate the system, afterwards the hand is placed next to the subject in rest. Near-infrared spectroscopy will be performed to measure cerebral frontal lobe oxygen saturation. NIRS is performed with two large sensors, attached on patient's forehead bilaterally. In bright environments, a light-blocker to cover the sensors will be used to reduce interference from ambient light. Continuously NIRS recording with a 2s interval refreshment. Measurements will be done in upright and supine positions. The expected duration of the entire TCD protocol is 30 minutes.

The TCD examination will be repeated only in the patients with MS (i.e. not in control subjects) 4 h after the oral intake of 62.5 mg bosentan (Tracleer®) (when peak plasma concentrations are expected). This is a purely academic study and Bosentan will be purchased through the hospital pharmacy. The most common side effect of daily treatment with bosentan is hepatotoxicity. Adverse reactions to one single dose are very unlikely. The primary aim is to investigate the potential of TCD to evaluate changes in the cerebral circulation between patients with MS and controls. Bosentan is not the object of investigation in this study but can be considered as a 'Non Investigational Medicinal Product' (N.I.M.P.). Patients with MS will receive the product to increase CBF, an effect which has already been demonstrated in an earlier perfusion-weighted MRI study.

Fifteen patients with relapsing-remitting or progressive MS and 15 healthy controls, matched for sex and age, will be included in this study. Sample size calculation is based on the number of inclusion in previous studies regarding cerebral hemodynamic parameters in MS (mostly between 10 and 30).

The statistical analyses will be conducted with Statistical Package for the Social Sciences (SPSS) software. Mann Whitney U or Wilcoxon signed rank tests will be used where appropriate.

Eligibility criteria: Inclusion Criteria:

* Patients with the diagnosis of relapsing-remitting, primary progressive of secondary progressive MS, according to the 2010 revised McDonald criteria.
* Written informed consent must be obtained.

Exclusion Criteria:

* MS patients with a known contra-indication for bosentan: liver dysfunction, use of cyclosporine A, allergy.
* Pregnancy
* No evidence of MS relapse within the 3 months prior to inclusion.

Primary outcomes:
measure: Detection of hemodynamic differences between MS patients and Healthy controls with TCD baseline.
timeFrame: a 10 minute recording with TCD baseline
Secondary outcomes:
measure: Hemodynamic changes in MS patients detected with TCD after administration of Bosentan
timeFrame: baseline and 4 hours after administration of bosentan a 10 minute recording with TCD
measure: Detection of frontal lobe oxygen saturation differences between patients with multiple sclerosis and healthy controls with near-infrared spectroscopy.
timeFrame: a 10 minute recording with NIRS baseline
measure: Frontal lobe oxygen saturation changes in MS patients detected with NIRS after administration of Bosentan
timeFrame: baseline and 4 hours after administration of bosentan a 10 minute recording with NIRS
Other outcomes:
Locations:
city: Jette
country: Belgium
facility: Department of Neurology, Universitair Ziekenhuis (UZ) Brussel. Center for Neurosciences, Vrije Universiteit Brussel
state: Vlaams-Brabant
Study officials:
affiliation: Department of Neurology, Universitair Ziekenhuis (UZ) Brussel, Brussels. Belgium Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
name: Ilse AS Peeters, Student
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Neurology, Universitair Ziekenhuis (UZ) Brussel, Brussels. Belgium Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
name: Miguel D'haeseleer, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Neurology, Universitair Ziekenhuis (UZ) Brussel, Brussels. Belgium Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium
name: Jacques De Keyser, MD, PhD
role: STUDY_DIRECTOR
References:
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citation: Adhya S, Johnson G, Herbert J, Jaggi H, Babb JS, Grossman RI, Inglese M. Pattern of hemodynamic impairment in multiple sclerosis: dynamic susceptibility contrast perfusion MR imaging at 3.0 T. Neuroimage. 2006 Dec;33(4):1029-35. doi: 10.1016/j.neuroimage.2006.08.008. Epub 2006 Sep 22.
citation: Varga AW, Johnson G, Babb JS, Herbert J, Grossman RI, Inglese M. White matter hemodynamic abnormalities precede sub-cortical gray matter changes in multiple sclerosis. J Neurol Sci. 2009 Jul 15;282(1-2):28-33. doi: 10.1016/j.jns.2008.12.036. Epub 2009 Jan 31.
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citation: D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J. Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.
citation: Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7.
citation: ElSankari S, Baledent O, van Pesch V, Sindic C, de Broqueville Q, Duprez T. Concomitant analysis of arterial, venous, and CSF flows using phase-contrast MRI: a quantitative comparison between MS patients and healthy controls. J Cereb Blood Flow Metab. 2013 Sep;33(9):1314-21. doi: 10.1038/jcbfm.2013.95. Epub 2013 Jun 19.