Detection and Management of Cerebral Vasculopathy

Cerebral vasculopathy in children with sickle cell anemia is responsible for strokes and silent cerebral infarcts and is the most debilitating complication providing motor sequelae and cognitive deficiency. However, the most important advance in pediatric management is the detection of children at a risk of stroke using transcranial Doppler with chronic transfusion applied in children detected at risk, which reduces the stroke risk from 11% to less than 2%. In this chapter, we will describe the place of Doppler, magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) with neck assessment and the place of different treatments, i.e., chronic transfusion, hydroxyurea, new drugs, and stem cell transplantation

Acute cervical lymphadenitis and infections of the retropharyngeal and parapharyngeal spaces in children

International audienceBackground: Acute cervical adenitis can evolve into suppurative cervical lymphadenitis and may sometimes be associated with infection of the retropharyngeal and parapharyngeal spaces (i.e., retropharyngeal and poststyloid parapharyngeal abscesses). This study aimed to describe the clinical presentation of acute cervical lymphadenitis and infections of the retropharyngeal and parapharyngeal spaces in children and examine the management of these conditions. Methods: This was a retrospective study including children from 3 months to 18 years old who were hospitalized in the Pediatric Department of the Centre-Intercommunal-de-Créteil between January 2003 and May 2010. Selected cases were based on the diagnosis of acute cervical lymphadenitis, suppurative cervical lymphadenitis, or infections of the retropharyngeal or parapharyngeal spaces. Case history, clinical signs, laboratory tests, imaging, treatment and clinical course were collected from patient charts. Results: We included 75 children (54 males [72%]); 62 (83%) were 3 years old (48%) underwent a rapid antigen detection test (RADT) for group A beta-hemolytic Streptococcus pyogenes; results for 10 were positive (48%). Contrast-enhanced CT scan of the neck in children with torticollis (n = 31) demonstrated an abscess in 21 (68%). Fine-needle aspiration was performed in 8 patients (11%) and 8 (11%) required surgical drainage. Bacteriology was positive in 8 patients (11%), with a predominance of Staphylococcus aureus and S. pyogenes. All patients received intravenous antibiotics and the outcome was favorable regardless of surgery. Recurrence was observed in only 1 case among the 34 patients with a follow-up visit after discharge. Conclusion: Our data suggest that presentation with cervical lymphadenitis associated with fever and torticollis requires evaluation by contrast-enhanced CT scan. Furthermore, abscess drainage should be restricted to the most severely affected patients who do not respond to antibiotic therapy

One-Fifth of Children with Sickle Cell Anemia Show Exercise-Induced Hemoglobin Desaturation: Rate of Perceived Exertion and Role of Blood Rheology

International audienc

Development of a Personalized 3D Carotid Model for Cerebral Vasculopathy Monitoring in Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most prevalent and severe monogenic disorder due to a mutation in the b-globin gene, responsible for the production of an abnormal hemoglobin (HbS) which polymerizes under hypoxia. Cerebral vasculopathy (CV) generally appearing during childhood, is responsible for ischemic stroke, making SCD the first etiology of stroke in children and young adults. To date, several biological and hemodynamical determinants have been identified in CV development such as severe anemia and/or high intracranial vascular flow velocities (> 200 cm/s). Chronic blood exchange transfusion decreases the risk of stroke in children having a pathological Doppler. However some patients still have a progressive impairment despite conventional treatment highlighting the need for new therapeutic strategies and a better understanding of the physiopathology. Therefore, by developing a 3D carotid model reproducing exactly vascular parameters of a SCD patient, we aim to: (i) determine the mechanisms of CV development in SCD, (ii) find new therapeutic approaches and (iii) predict the risk of progression of CV. Materials and methods Three-dimensional reconstructions of the internal carotid, middle cerebral and anterior cerebral artery from SCD patients were generated from magnetic resonance angiograms (MIMICS & 3Matics software, Materialise). We performed 3D simulations of the Navier-Stokes equations in patient specific geometries, including the state-of-the-art techniques of Computational Hemodynamics (multiscale coupling, backflow stabilization - FeLiSCe software) and other factors - such as the increase of the ejection fraction or the drop of peripheral resistances). Blood viscosity was based on a SCD cohort. Hemodynamic properties such as flow velocities (TMMV) and wall shear stress (WSS) in different areas of modelled carotid were then computed according to flow variations. Modelled carotid was obtained by 3D printing according to computer design (CATIA software). The next steps will consist in 1/importing doppler parameters from patients in a programmable pump for flow assays with blood mimicking fluid to measure TMMV and WSS at different areas in carotid, 2/incorporating resting or activated platelets in BMF to evaluate impact of high WSS on platelets degranulation, 3/developing a flow co-culture of smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) on carotid wall. HUVECs and SMCs at different zones of the carotid undergoing high/low WSS and oscillatory flow will be analysed Preliminary results Our preliminary results suggest that the carotid inlet flow but not blood viscosity is responsible for the pathological intra cranial velocities (Figure 1A). At high carotid inlet flow, areas of high and low WSS appeared in children (Figure 1B), suggesting the existence of turbulent flow that could lead to arterial wall damages. Figure 2A shows a 3D printed carotid reproducing the exact SCD child's one. The material of artificial carotid is compatible with HUVECs culture (Figure 2B) and fluidic experiment at high inlet flow (Figure 2C). On Doppler ultrasonography, the velocities measured in different sections of carotid were comparable to patient's data and these velocities were modified according to variations of inlet flow values. Conclusions and perspectives By modification of input conditions, our 3D personalized model can predict high or low vascular velocities areas and will allow a better understanding of the pathophysiological processes involved at the interface between abnormal flow and cells on carotid wall. This innovative model could be a pertinent tool to evaluate individually effectiveness of new therapeutic strategies in SCD patients. Furthermore, this work may constitute a proof of concept that can be transposed to other diseases. Disclosures Verlhac: Addmedica, Paris: Other: Financial Support; Bluebird Bio: Consultancy. Bartolucci:AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees

Effect of transfusion therapy on cerebral vasculopathy in children with sickle-cell anemia

This study emphasizes the wide heterogeneity of the course of cerebral vasculopathy in children with sickle-cell anemia on regular transfusion protocol

Brain injury pathophysiology study by a multimodal approach in children with sickle cell anemia with no intra or extra cranial arteriopathy

International audienceDespite its high prevalence in children with sickle cell anemia (SCA), the pathophysiology of silent cerebral infarcts (SCIs) remains elusive. The main objective of this study was to explore the respective roles of major determinants of brain perfusion in SCA children with no past or current history of intracranial or extracranial vasculopathy. We used a multimodal approach based notably on perfusion imaging Arterial spin labelling (ASL) MRI and Near Infra-Red Spectroscopy (NIRS), as well as biomarkers reflecting blood rheology and endothelial activation. Out of 59 SCA patients (mean age 11.4} 3.9 yrs), 8 (13%) had a total of 12 SCIs. Children with SCIs had a distinctive profile characterized by decreased blood pressure, impaired blood rheology, increased P-selectin levels, and marked anemia. Although ASL perfusion and oximetry values did not differ between groups, comparison of biological and clinical parameters according to the level of perfusion categorized in terciles showed an independent association between high perfusion and increased sP-selectin, decreased RBC deformability, low HbF level, increased blood viscosity and no alpha-thalassemia deletion. NIRS measurements did not yield additional novel results. Altogether, these findings argue for early MRI detection of SCIs in children with no identified vasculopathy and suggest a potential role for ASL as an additional screening tool. Early treatment targeting hemolysis, anemia and endothelial dysfunction should reduce the risk of this under diagnosed and serious complication

Association of Matched-Sibling Donor Hematopoietic Stem Cell Transplantation with Transcranial-Doppler Velocities in Children with Sickle Cell Anemia

International audienceImportance: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown.Objective: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA.Design, Setting, and Participants: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor.Exposures: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching.Main Outcomes and Measures: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years.Results: Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001).Conclusions and Relevance: Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up