Pr. Yves BERTHEZENE
Diagnostic and Interventional Neurological Imaging department
The imaging department of the Eastern hospital group is organized into specialized departments (cardiology, gynecology, obstetrics, pediatrics, neurology) focused on diagnostic and interventional imaging, emergency, ongoing care and screening.
Axes de recherche
Appartenance Laboratoire CREATIS UMR CNRS 5220 INSERM U 1294
Publications
1. Blood-Brain Barrier Permeability and Kinetics of Inflammatory Markers in Acute Stroke
Patients Treated With Thrombectomy. Neurology. 2023 Aug 1;101(5):e502-e511.
Bani-Sadr A, Mechtouff L, De Bourguignon C, Mauffrey A, Boutelier T, Cho TH,Cappucci M, Ameli R, Hermier M, Derex L, Nighoghossian N, Berthezene Y.
Blood-Brain Barrier Permeability and Kinetics of Inflammatory Markers in Acute Stroke Patients Treated With Thrombectomy — Résumé
Background and objectives: The aim of this study was to investigate the relationship between baseline blood-brain barrier (BBB) permeability and the kinetics of circulating inflammatory markers in a cohort of acute ischemic stroke (AIS) patients treated with mechanical thrombectomy.
Methods: The CoHort of Patients to Identify Biological and Imaging markerS of CardiovascUlar Outcomes in Stroke includes AIS patients treated with mechanical thrombectomy after admission MRI and undergoing a sequential assessment of circulating inflammatory markers. Baseline dynamic susceptibility perfusion MRI was postprocessed with arrival time correction to provide K2 maps reflecting BBB permeability. After coregistration of apparent diffusion coefficient and K2 maps, the 90th percentile of K2 value was extracted within baseline ischemic core and expressed as a percentage change compared with contralateral normal-appearing white matter. Population was dichotomized according to the median K2 value. Univariable and multiple variable logistic regression analyses were performed to investigate factors associated with increased pretreatment BBB permeability in the whole population and in patients with symptom onset <6 hours.
Results: In the whole population (n = 105 patients, median K2 = 1.59), patients with an increased BBB permeability had higher serum levels of matrix metalloproteinase (MMP)-9 at H48 (p = 0.02), a higher C-reactive protein (CRP) serum level at H48 (p = 0.01), poorer collateral status (p = 0.01), and a larger baseline ischemic core (p < 0.001). They were more likely to have hemorrhagic transformation (p = 0.008), larger final lesion volume (p = 0.02), and worst neurologic outcome at 3 months (p = 0.04). The multiple variable logistic regression indicated that an increased BBB permeability was associated only with ischemic core volume (odds ratio [OR] 1.04, 95% CI 1.01-1.06, p < 0.0001). Restricting analysis to patients with symptom onset <6 hours (n = 72, median K2 = 1.27), participants with an increased BBB permeability had higher serum levels of MMP-9 at H0 (p = 0.005), H6 (p = 0.004), H24 (p = 0.02), and H48 (p = 0.01), higher CRP levels at H48 (p = 0.02), and a larger baseline ischemic core (p < 0.0001). The multiple variable logistic analysis showed that increased BBB permeability was independently associated with higher H0 MMP-9 levels (OR 1.33, 95% CI 1.12-1.65, p = 0.01) and a larger ischemic core (OR 1.27, 95% CI 1.08-1.59, p = 0.04).
Discussion: In AIS patients, increased BBB permeability is associated with a larger ischemic core. In the subgroup of patients with symptom onset <6 hours, increased BBB permeability is independently associated with higher H0 MMP-9 levels and a larger ischemic core.
2. Is the optimal Tmax threshold identifying perfusion deficit volumes variable across MR
perfusion software packages? A pilot study. MAGMA.
Bani-Sadr A, Trintignac M, Mechtouff L, Hermier M, Cappucci M, Ameli R, de
Bourguignon C, Derex L, Cho TH, Nighoghossian N, Eker OF, Berthezene Y.
Is the optimal Tmax threshold identifying perfusion deficit volumes variable across MR perfusion software packages? A pilot study — Résumé
Purpose: Accurate quantification of ischemic core and ischemic penumbra is mandatory for late-presenting acute ischemic stroke. Substantial differences between MR perfusion software packages have been reported, suggesting that the optimal Time-to-Maximum (Tmax) threshold may be variable. We performed a pilot study to assess the optimal Tmax threshold of two MR perfusion software packages (A: RAPID®; B: OleaSphere®) by comparing perfusion deficit volumes to final infarct volumes as ground truth.
Methods: The HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated by mechanical thrombectomy after MRI triage. Mechanical thrombectomy failure was defined as a modified thrombolysis in cerebral infarction score of 0. Admission MR perfusion were post-processed using two packages with increasing Tmax thresholds (≥ 6 s, ≥ 8 s and ≥ 10 s) and compared to final infarct volume evaluated with day-6 MRI.
Results: Eighteen patients were included. Lengthening the threshold from ≥ 6 s to ≥ 10 s led to significantly smaller perfusion deficit volumes for both packages. For package A, Tmax ≥ 6 s and ≥ 8 s moderately overestimated final infarct volume (median absolute difference: – 9.5 mL, interquartile range (IQR) [- 17.5; 0.9] and 0.2 mL, IQR [- 8.1; 4.8], respectively). Bland-Altman analysis indicated that they were closer to final infarct volume and had narrower ranges of agreement compared with Tmax ≥ 10 s. For package B, Tmax ≥ 10 s was closer to final infarct volume (median absolute difference: – 10.1 mL, IQR: [- 17.7; – 2.9]) versus – 21.8 mL (IQR: [- 36.7; – 9.5]) for Tmax ≥ 6 s. Bland-Altman plots confirmed these findings (mean absolute difference: 2.2 mL versus 31.5 mL, respectively).
Conclusions: The optimal Tmax threshold for defining the ischemic penumbra appeared to be most accurate at ≥ 6 s for package A and ≥ 10 s for package B. This implies that the widely recommended Tmax threshold ≥ 6 s may not be optimal for all available MRP software package. Future validation studies are required to define the optimal Tmax threshold to use for each package.
Keywords: Image processing; Perfusion MR; Stroke; Thrombectomy.
3. Vascular hyperintensities on baseline FLAIR images are associated with functional outcome in stroke patients with successful recanalization after mechanical thrombectomy. Diagn Interv Imaging. 2023 Jul-Aug;104(7-8):337-342.
Bani-Sadr A, Escande R, Mechtouff L, Pavie D, Hermier M, Derex L, Choc TH,
Eker OF, Nighoghossian N, Berthezène Y.
4. Brush sign and collateral supply as potential markers of large infarct growth after successful
thrombectomy. Eur Radiol. 2023 Jun;33(6):4502-4509.
Bani-Sadr A, Pavie D, Mechtouff L, Cappucci M, Hermier M, Ameli R, Derex L,
De Bourguignon C, Cho TH, Eker O, Nighoghossian N, Berthezene Y.
Brush sign and collateral supply as potential markers of large infarct growth after successful thrombectomy.— Résumé
Objectives
To investigate the relationships between brush sign and cerebral collateral status on infarct growth after successful thrombectomy.
Methods
HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated with thrombectomy after MRI triage and undergoing a day-6 MRI including FLAIR images to quantify final infarct volume (FIV). Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score ≥ 2B. Infarct growth was calculated by subtracting FIV from baseline ischemic core after co-registration and considered large (LIG) when > 11.6 mL. Brush sign was assessed on T2*-weighted-imaging and collaterals were assessed using the hypoperfusion intensity ratio, which is the volume of Time-To-Tmax (Tmax) ≥ 10 s divided by the volume of Tmax ≥ 6 s. Good collaterals were defined by a hypoperfusion intensity ratio < 0.4.
Results
One hundred and twenty-nine patients were included, of whom 45 (34.9%) had a brush sign and 63 (48.8%) good collaterals. Brush sign was associated with greater infarct growth (p = 0.01) and larger FIV (p = 0.02). Good collaterals were associated with a smaller baseline ischemic core (p < 0.001), larger penumbra (p = 0.04), and smaller FIV (p < 0.001). Collateral status was not significantly associated with brush sign (p = 0.20) or with infarct growth (p = 0.67). Twenty-eight (22.5%) patients experienced LIG. Univariate regressions indicated that brush sign (odds ratio (OR) = 4.8; 95% confidence interval (CI): [1.9;13.3]; p = 0.004) and hemorrhagic transformation (OR = 1.7; 95%CI: [1.2;2.6]; p = 0.04) were predictive of LIG. In multivariate regression, only the brush sign remained predictive of LIG (OR = 5.2; 95%CI: [1.8-16.6], p = 0.006).
Conclusions
Brush sign is a predictor of LIG after successful thrombectomy and cerebral collateral status is not.
Key points
• Few predictors of ischemic growth are known in ischemic stroke patients achieving successful mechanical thrombectomy. • Our results suggest that the brush sign-a surrogate marker of severe hypoperfusion-is independently associated with large ischemic growth (> 11.6 mL) after successful thrombectomy whereas cerebral collateral status does not.
5. Assessment of three MR perfusion software packages in predicting final infarct volume after mechanical thrombectomy. J Neurointerv Surg. 2023 Apr;15(4):393-398.
Bani-Sadr A, Cho TH, Cappucci M, Hermier M, Ameli R, Filip A, Riva R, Derex
L, De Bourguignon C, Mechtouff L, Eker OF, Nighoghossian N, Berthezene Y.
Assessment of three MR perfusion software packages in predicting final infarct volume after mechanical thrombectomy — Résumé
Aims: To evaluate the performance of three MR perfusion software packages (A: RAPID; B: OleaSphere; and C: Philips) in predicting final infarct volume (FIV).
Methods: This cohort study included patients treated with mechanical thrombectomy following an admission MRI and undergoing a follow-up MRI. Admission MRIs were post-processed by three packages to quantify ischemic core and perfusion deficit volume (PDV). Automatic package outputs (uncorrected volumes) were collected and corrected by an expert. Successful revascularization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2B. Uncorrected and corrected volumes were compared between each package and with FIV according to mTICI score.
Results: Ninety-four patients were included, of whom 67 (71.28%) had a mTICI score ≥2B. In patients with successful revascularization, ischemic core volumes did not differ significantly from FIV regardless of the package used for uncorrected and corrected volumes (p>0.15). Conversely, assessment of PDV showed significant differences for uncorrected volumes. In patients with unsuccessful revascularization, the uncorrected PDV of packages A (median absolute difference -40.9 mL) and B (median absolute difference -67.0 mL) overestimated FIV to a lesser degree than package C (median absolute difference -118.7 mL; p=0.03 and p=0.12, respectively). After correction, PDV did not differ significantly from FIV for all three packages (p≥0.99).
Conclusions: Automated MRI perfusion software packages estimate FIV with high variability in measurement despite using the same dataset. This highlights the need for routine expert evaluation and correction of automated package output data for appropriate patient management.
Keywords: MR perfusion; Stroke; Thrombectomy.
6. In vivo targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF 3 nanoparticles. Nanomedicine (Lond). 2022 Dec;17(29):2173-2187.
Lerouge F, Ong E, Rositi H, Mpambani F, Berner LP, Bolbos R, Olivier C,
Peyrin F, Apputukan VK, Monnereau C, Andraud C, Chaput F, Berthezène Y, Braun B,
Jucker M, Åslund AK, Nyström S, Hammarström P, R Nilsson KP, Lindgren M, Wiart
M, Chauveau F, Parola S.
In vivo targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF3 nanoparticles | Nanomedicine — Résumé
Aim: To propose a new multimodal imaging agent targeting amyloid-β (Aβ) plaques in Alzheimer’s disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer’s disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood–brain barrier status. Nevertheless, multimodal imaging showed successful Aβ targeting in both transgenic mice and Aβ fibril-injected rats.
Plain language summary
The design and study of a new contrast agent targeting amyloid-β (Aβ) plaques in Alzheimer’s disease (AD) is proposed. Aβ plaques are the earliest pathological sign of AD, silently appearing in the brain decades before the symptoms of the disease are manifested. While current detection of Aβ plaques is based on nuclear medicine (a technique using a radioactive agent), a different kind of contrast agent is here evaluated in animal models of AD. The contrast agent consists of a nanoparticle made of gadolinium and fluorine ions (core), and decorated with a molecule previously shown to bind to Aβ plaques (grafting). The core is detectable with MRI and x-ray imaging, while the grafting molecule is detectable with fluorescence imaging, thus allowing different imaging methods to be combined to study the pathology. In this work, the structure, stability and properties of the contrast agent have been verified in vitro (in tubes and on brain sections). Then the ability of the contrast agent to bind to Aβ plaques and provide a detectable signal in MRI, x-ray or fluorescence imaging has been demonstrated in vivo (in rodent models of AD). This interdisciplinary research establishes the proof of concept that this new class of versatile agent contrast can be used to target pathological processes in the brain.
7. Comparison of magnetic resonance angiography techniques to brain digital subtraction arteriography in the setting of mechanical thrombectomy: A non-inferiority study. Rev Neurol (Paris). 2022 Jun;178(6):539-545.
Bani-Sadr A, Aguilera M, Cappucci M, Hermier M, Ameli R, Filip A, Riva R,
Tuttle C, Cho TH, Mechtouff L, Nighoghossian N, Eker O, Berthezene Y.
Comparison of magnetic resonance angiography techniques to brain digital subtraction arteriography in the setting of mechanical thrombectomy: — Résumé
Introduction: We performed a non-inferiority study comparing magnetic resonance angiography (MRA) techniques including contrast-enhanced (CE) and time-of-flight (TOF) with brain digital subtraction arteriography (DSA) in localizing occlusion sites in acute ischemic stroke (AIS) with a prespecified inferiority margin taking into account thrombus migration.
Materials and methods: HIBISCUS-STROKE (CoHort of Patients to Identify Biological and Imaging markerS of CardiovascUlar Outcomes in Stroke) includes large-vessel-occlusion (LVO) AIS treated with mechanical thrombectomy (MT) following brain magnetic resonance imaging (MRI) including both CE-MRA and TOF-MRA. Locations of arterial occlusions were assessed independently for both MRA techniques and compared to brain DSA findings. Number of patients needed was 48 patients to exclude a difference of more than 20%. Discrepancy factors were assessed using univariate general linear models analysis.
Results: The study included 151 patients with a mean age of 67.6±15.9years. In all included patients, TOF-MRA and CE-MRA detected arterial occlusions, which were confirmed by brain DSA. For CE-MRA, 38 (25.17%) patients had discordant findings compared with brain DSA and 50 patients (33.11%) with TOF-MRA. The discordance factors were identical for both MRA techniques namely, tandem occlusions (OR=1.29, P=0.004 for CE-MRA and OR=1.61, P<0.001 for TOF-MRA), proximal internal carotid artery occlusions (OR=1.30, P=0.002 for CE-MRA and OR=1.47, P<0.001 for TOF-MRA) and time from MRI to MT (OR=1.01, P=0.01 for CE-MRA and OR=1.01, P=0.02 for TOF-MRA).
Conclusion: Both MRA techniques are inferior to brain DSA in localizing arterial occlusions in LVO-AIS patients despite addressing the migratory nature of the thrombus.
Keywords: Magnetic resonance angiography; Stroke; Thrombectomy.
8. Early Detection of Underlying Cavernomas in Patients with Spontaneous Acute Intracerebral Hematomas. AJNR Am J Neuroradiol. 2023 Jul;44(7):807-813.
Bani-Sadr A, Eker OF, Cho TH, Ameli R, Berhouma M, Cappucci M, Derex L,
Mechtouff L, Meyronet D, Nighoghossian N, Berthezène Y, Hermier M.
Early Detection of Underlying Cavernomas in Patients with Spontaneous Acute Intracerebral Hematomas— Résumé
Background and purpose: Early identification of the etiology of spontaneous acute intracerebral hemorrhage is essential for appropriate management. This study aimed to develop an imaging model to identify cavernoma-related hematomas.
Materials and methods: Patients 1-55 years of age with acute (≤7 days) spontaneous intracerebral hemorrhage were included. Two neuroradiologists reviewed CT and MR imaging data and assessed the characteristics of hematomas, including their shape (spherical/ovoid or not), their regular or irregular margins, and associated abnormalities including extralesional hemorrhage and peripheral rim enhancement. Imaging findings were correlated with etiology. The study population was randomly split to provide a training sample (50%) and a validation sample (50%). From the training sample, univariate and multivariate logistic regression was performed to identify factors predictive of cavernomas, and a decision tree was built. Its performance was assessed using the validation sample.
Results: Four hundred seventy-eight patients were included, of whom 85 had hemorrhagic cavernomas. In multivariate analysis, cavernoma-related hematomas were associated with spherical/ovoid shape (P < .001), regular margins (P = .009), absence of extralesional hemorrhage (P = .01), and absence of peripheral rim enhancement (P = .002). These criteria were included in the decision tree model. The validation sample (n = 239) had the following performance: diagnostic accuracy of 96.1% (95% CI, 92.2%-98.4%), sensitivity of 97.95% (95% CI, 95.8%-98.9%), specificity of 89.5% (95% CI, 75.2%-97.0%), positive predictive value of 97.7% (95% CI, 94.3%-99.1%), and negative predictive value of 94.4% (95% CI, 81.0%-98.5%).
Conclusions: An imaging model including ovoid/spherical shape, regular margins, absence of extralesional hemorrhage, and absence of peripheral rim enhancement accurately identifies cavernoma-related acute spontaneous cerebral hematomas in young patients.
9. Simultaneous assessment of microcalcifications and morphological criteria of vulnerability in carotid artery plaque using hybrid 18 F-NaF PET/MRI. J Nucl Cardiol. 2022 Jun;29(3):1064-1074.
Mechtouff L, Sigovan M, Douek P, Costes N, Le Bars D, Mansuy A, Haesebaert J, Bani-Sadr A, Tordo J, Feugier P, Millon A, Luong S, Si-Mohamed S, Collet- Benzaquen D, Canet-Soulas E, Bochaton T, Crola Da Silva C, Paccalet A, Magne D, Berthezene Y, Nighoghossian N.
Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH) — Résumé
Background: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage.
Methods: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding.
Findings: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group.
Interpretation: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage.
Funding: French Ministry of Health.
