[The ethics of fetal myelomeningocele surgery]. / Réflexions éthiques concernant la chirurgie fœtale de réparation des myéloméningocèles.

Fetal myelomeningocele surgery was introduced in France in 2014. Developments in prenatal diagnosis of neural tube defects have accompanied the development of prenatal diagnosis. This fetal surgery represents one of the three possible care paths for pregnant women faced with this prenatal diagnosis. The ethical issues of this fetal surgery are discussed and in particular regarding prenatal counselling and patient autonomy of choice.

Cell therapy for prenatal repair of myelomeningocele: A systematic review.

Myelomeningocele (MMC) is a spinal cord congenital defect that leads to paraplegia, bladder incontinence and bowel dysfunction. A randomized human trial demonstrated that in utero surgical repair of the MMC defect improves lower limb motor function. However, functional recovery remains incomplete. Stem cell therapy has recently generated great interest in the field of prenatal repair of MMC. In this systematic review we attempt to provide an overview of the current application of stem cells in different animal models of MMC. Publications were retrieved from PubMed and Cochrane Library databases. This process yielded twenty-two studies for inclusion in this review, experimenting five different types of stem cells: human embryonic stem cells, neural stem cells, induced pluripotent stem cells, human amniotic fluid stem cells, and mesenchymal stem cells (MSCs). Rodents and ovine were the two major species used for animal model studies. The source, the aims, and the main results were analyzed. Stem cell therapy appears to be a promising candidate for prenatal repair of MMC, especially MSCs. Further explorations in ovine and rodent models, reporting clinical and functional results, are necessary before an application in humans.

Fatal intoxication with ivabradine: First case report.

Ivabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45bpm) and a low blood pressure (116/21mmHg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200×2.1mm, 1.9µm) and an acetonitrile/formiate 2mM, 0.1% formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210ng/mL. Ivabradine was also quantified in different viscera like lung (2910ng/g), kidney (1510ng/g), liver (1050ng/g), heart (900ng/g), and brain (110ng/g). The vitreous humor concentration was 760ng/mL. Pregabalin and zopiclone were also found in blood at 50µg/mL and 206ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs.

[Secondary surgeries in craniosynostosis and faciocraniosynostosis]. / Chirurgie secondaire des craniosténoses et faciocraniosténoses.

Secondary surgeries for single craniosynostosis surgeries are mainly esthetic refinements rather than functional indications. However, cranioplasties for bone defects correction or insufficient corrections may be undertaken. Management of syndromic craniosynostoses usually requires multiple surgical interventions, the sequence of which might vary per the genetic mutation. It is commonplace to start with posterior vault expansion before age 6 months, then treat cerebellar tonsillar herniation by the age of twelve months, and delay fronto-facial monobloc advancement until at least 18-24 months of age. Ventricular shunting is preferably avoided or delayed. Failure to respect these guidelines can significantly complicate the subsequent management. Primary fronto-orbital advancement or early facial osteotomy type Le Fort3, may compromise the subsequent fronto-facial monobloc advancement. However, this salvage secondary monobloc may be undertaken in some instances despite previous anterior osteotomies with a higher morbidity.

Correction to: Diffusion tensor imaging (DTI) and Tractography of the spinal cord in pediatric population with spinal lipomas: preliminary study.

The article which was recently published contained error. The figures and figure captions were interchanged during the publication process of the paper.

Diffusion tensor imaging (DTI) and Tractography of the spinal cord in pediatric population with spinal lipomas: preliminary study.

PURPOSE: Diffusion tensor imaging (DTI) allows studying the micro and macro architecture. One of the major challenges in dysraphism is to know the morphologic organization of the spinal cord. In a preliminary work, spinal lipoma was chosen for analyzing the micro-architecture parameters and fiber morphology of the spinal cord by DTI with tractography. METHODS: Twelve patients (0-8 years) related to spinal lipomas treated between May 2017 and March 2018 were included. Tractography reconstruction of the conus medullaris of 12 patients were obtained using the MedINRIA software. The diffusion parameters have been calculated by Osirix DTImap plugin. RESULTS: We found a significant difference in the FA (p = 0.024) between two age groups (< 24 months old and > 24 months old). However, no significant differences in the mean values of FA, RD, and MD between the level of the lipoma and the level above were noted. The tractography obtained in each case was coherent with morphologic sequences and reproducible. The conus medullaris was deformed and shifted. Destruction or disorganization of fibers and any passing inside the lipomas was not observed. CONCLUSIONS: Tractography of the conus medullaris in a very young pediatric population (0-8 years old) with a spinal lipoma is possible, reproductive, and allows visualization of the spinal cord within the dysraphism. Analysis of the FA shows that the presence of a lipoma seems to have an effect on the myelination of the conus medullaris. It is during the probable myelination phase that the majority of symptoms appear. Is the myelination per se the cause?

Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?

Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

[Diagnosis, evolution and prognosis of prenatally diagnosed suprasellar cysts]. / Diagnostic, évolution et pronostic des kystes supra-sellaires de découverte anténatale.

Suprasellar arachnoid cysts (SAC) in children are considered rare, but the incidence is increasing due to the improvement of prenatal diagnosis. We present 15 cases of SAC diagnosed during the antenatal period between 2005 and 2015. The records were reviewed retrospectively by specifying the radiological characteristics, treatment modalities, outcomes, and long-term monitoring. Mean follow-up was 71 months. The forms (SAC-1) accounted for 2 cases (13%) with hydrocephalus. We observed 8 (53%) lower forms (SAC-2) with interpeduncular cistern expansion without hydrocephalus. The 5 (33.5%) remaining patients showed asymmetrical forms (SAC-3). Six patients (40%) were treated by ventriculo-cysto-cisternostomy, 1 by fetoscopy, 1 (6.5%) by ventriculo-peritoneal shunt, 2 (13.5%) by pterional craniotomy, and 6 (40%) were simply followed. The surgical outcomes were initially favorable in 9 cases (100%), 1 patient (13%) had to be re-treated later. Non-operated patients were all type 2 and showed no radiological changes. In the long-term, 1 patient (6.5%) had endocrine disruption, 1 had delayed development, 2 (13.5%) had minor neuropsychological impairments, and 1 had epilepsy. Combined monitoring with prenatal MRI and ultrasound can be used to distinguish three subtypes of SAC. SAC-1 and SAC-3 have an excellent prognosis after treatment in the perinatal period. SAC-2 can benefit from simple monitoring and remain asymptomatic in their majority. This classification allows a better prognosis estimation and better treatment decision.

[Craniofacial strategy for syndromic craniosynostosis]. / Stratégie craniofaciale pour les faciocraniosténoses.

The complexity of treatment of faciocraniosynostosis justifies the treatment in a reference center for rare diseases. The growth disturbances in the skull and face being variable according to the type of mutation in the FGFr (Crouzon, Pfeiffer, Apert), the strategy is adapted to the phenotype according to the following principles: posterior expansion with or without distraction around 6 months to limit the descent of the cerebellum tonsils and to prevent the turricephalic development; fronto-facial monobloc advancement with internal distraction around the age of 18 months in case of severe exorbitism or breathing impairment. The dissociated strategy (fronto-orbital advancement first, followed by facial osteotomy of Le Fort 3 type). The growing evolution dictates the sequence of subsequent surgeries according to the monitoring of intracranial pressure by fundus examination and of the respiration by polysomnography. Le Fort 3 and transversal maxillary distraction may be repeated if necessary. Orthognathic surgery is almost always compulsory after the age of 14, before the aesthetic refinements which can be undertaken ultimately (rhinoplasty, genioplasty, canthopexies, fat grafting…).

Cerebral Blood Flow Improvement after Indirect Revascularization for Pediatric Moyamoya Disease: A Statistical Analysis of Arterial Spin-Labeling MRI.

BACKGROUND AND PURPOSE: The severity of Moyamoya disease is generally scaled with conventional angiography and nuclear medicine. Arterial spin-labeling MR imaging is now acknowledged for the noninvasive quantification of cerebral blood flow. This study aimed to analyze CBF modifications with statistical parametric mapping of arterial spin-labeling MR imaging in children undergoing an operation for Moyamoya disease. MATERIALS AND METHODS: We included 15 children treated by indirect cerebral revascularization with multiple burr-holes between 2011 and 2013. Arterial spin-labeling MR imaging and T1 sequences were then analyzed under SPM8, according to the general linear model, before and after the operation (3 and 12 months). Voxel-based analysis was performed at the group level, comparing all diseased hemispheres with all normal hemispheres and, at the individual level, comparing each patient with a control group. RESULTS: Group analysis showed statistically significant preoperative hypoperfusion in the MCA territory in the Moyamoya hemispheres and a significant increase of cerebral perfusion in the same territory after revascularization (P < .05 family-wise error-corrected). Before the operation, individual analysis showed significant hypoperfusion for each patient co-localized with the angiographic defect on DSA. All except 1 patient had improvement of CBF after revascularization, correlated with their clinical status. CONCLUSIONS: SPM analysis of arterial spin-labeling MR imaging offers a noninvasive evaluation of preoperative cerebral hemodynamic impairment and an objective assessment of postoperative improvement in children with Moyamoya disease.

[Preliminary results from the French study on prenatal repair for fetal myelomeningoceles (the PRIUM study)]. / Résultats préliminaires de l'étude PRIUM : programme de réparation in utero des myéloméningocèles.

OBJECTIVES: To present the preliminary results of the PRIUM study, a French pilot study of prenatal repair for myelomeningoceles (MMC). MATERIAL AND METHODS: The fetal surgery for MMC is offered in cases of patients that did not opt for termination of pregnancy. RESULTS: Thirty-six patients were referred in an 18-month period. Eight patients were not eligible for prenatal repair. Another type of dysraphism was made in 6 cases (one spina-lipoma, 5 cases of limited dorsal myeloschisis). Twenty-two patients were eligible to fetal surgery. A prenatal repair was performed in three cases (14%). Four patients opted for a conventional postnatal treatment. Fifteen patients opted for termination of the pregnancy. CONCLUSION: The establishment of a prenatal repair of MMC protocol in France was justified. The experience of the first 18months of this study however suggests that only a limited number of couples will choose this procedure after specialized counseling in a reference center.

[Sacral dimple: What form of management is best?]. / Quelle conduite devant une fossette sacrée ?

A sacral dimple measuring less than 5mm, within 25mm of the anus on the median line, with no other cutaneous anomaly, does not require any complementary examination. Parents can be reassured. However, any cutaneous depression in the sacrolumbar region not respecting these criteria must be considered as an occult dysraphism until proved otherwise. A medullary ultrasound examination and a consultation with a specialist (pediatric neurosurgeon) are necessary. The dermic sinus is the main differential diagnosis, with favorable outcome in case of early treatment before any infectious complication arises. Conversely, the risk of permanent sequelae is high if neglected or in case of late diagnosis.

Prospective Hemorrhage Rates of Cerebral Cavernous Malformations in Children and Adolescents Based on MRI Appearance.

BACKGROUND AND PURPOSE: Current classifications of cerebral cavernous malformations focus solely on morphologic aspects. Our aim was to provide a morphologic classification that reflects hemorrhage rates. MATERIALS AND METHODS: We retrospectively categorized 355 cavernous malformations of 70 children and adolescents according to their morphologic appearance on MR imaging and calculated prospective hemorrhage rates on the basis of survival functions for 255 lesions in 25 patients with a radiologic observation period of >180 days. RESULTS: Overall, there were 199 MR imaging examinations with 1558 distinct cavernous malformation observations during a cumulative observation period of 1094.2 lesion-years. The mean hemorrhage rate of all 355 cavernous malformations was 4.5% per lesion-year. According to Kaplan-Meier survival models, Zabramski type I and II cavernous malformations had a significantly higher hemorrhage rate than type III and IV lesions. The presence of acute or subacute blood-degradation products was the strongest indicator for an increased hemorrhage risk (P = .036, Cox regression): The mean annual hemorrhage rate and mean hemorrhage-free interval for cavernous malformations with and without signs of acute or subacute blood degradation products were 23.4% and 22.6 months and 3.4% and 27.9 months, respectively. Dot-sized cavernous malformations, visible in T2* and not or barely visible in T1WI and T2WI sequences, had a mean annual hemorrhage rate of 1.3% and a mean hemorrhage-free interval of 37.8 months. CONCLUSIONS: It is possible to predict hemorrhage rates based on the Zabramski classification. Our findings imply a tripartite classification distinguishing lesions with and without acute or subacute blood degradation products and dot-sized cavernous malformations.

Solid aneurysmal bone cyst on the cervical spine of a young child.

INTRODUCTION: Solid aneurysmal bone cyst (S-ABC) is a variant of aneurysmal bone cyst (ABC), an uncommon benign bone tumor. There are few cases described in the cervical spine in kids up today. We treated a recurrent case with neurological involvement that needed multiple surgical procedures and radiotherapy. CASE PRESENTATION: We report a case of C4 located S-ABC concerning a 2-year-old boy treated surgically by anterior and posterior approach. Three months after the initial procedure appearance of a tetraparesis led to diagnose a local recurrence treated by sclerotherapy and a second surgery. The patient had a full neurological recovery. Three months later, a follow-up CT scan showed a second recurrence requiring a new surgical revision by anterior approach and radiotherapy. OUTCOME: At 6-year follow-up after four surgical procedures, sclerotherapy and radiotherapy, the aneurysmal bone cyst has been healed. Patient had neurological impairment after a local recurrence but had full recovered after final revision surgery.

[Imaging Moya-Moya disease]. / Imagerie du Moya-Moya.

Moya-Moya disease is a rare arterial occlusive disease affecting the internal carotid artery and its branches. It is found in both pediatric and adult populations, and it may lead to severe clinical presentations such as stroke and intracranial hemorrhage. Several surgical procedures have been developed to improve its clinical outcome. Imaging techniques have a key role in management of Moya-Moya disease, as they are necessary for diagnosis, choice of treatment and follow-up. Although catheter angiography remains the diagnostic gold standard, and nuclear-medicine techniques best perform hemodynamic studies, less invasive imaging techniques have become efficient in serving these purposes. Conventional MRI and MR angiography, as well as MR functional and metabolic studies, are now widely used in each stage of disease management, from diagnosis to follow-up. CT scan and Doppler sonography may also help assess severity of disease and effects of treatment. The aim of this review is to clarify the utility, efficiency and latest developments of each imaging modality in management of Moya-Moya disease.

Limits of the surgically induced model of myelomeningocele in the fetal sheep.

PURPOSE: The prevention of Chiari type II malformation (CM) is commonly used as a primary outcome for the evaluation of techniques of fetal myelomeningocele (MMC) surgery in the fetal lamb. The aim of our study was to investigate the frequency of the associated CM in the MMC fetal sheep model and to investigate the contribution of prenatal ultrasound evaluation of CM at the time of prenatal repair. METHODS: A MMC-like lesion was surgically created at 75 days of gestation in 21 fetuses performing a L1-L5 laminectomy followed by an excision of the exposed dura and a midline myelotomy. At a 90-day gestation, among the 19 alived fetuses, a conventional repair of the MMC-like lesion was performed in seven, four of whom underwent cerebral ultrasound (US) examination before the repair. Twelve fetuses remained untreated (control group). All fetuses underwent post-mortem examination (PM) at 138 days. RESULTS: At a 90-day gestation, CM was demonstrated by US examination in all four evaluated fetuses. At birth, CM was found in 3/6 control whether CM was absent in all alived fetuses in the prenatal repair group (n = 4). CONCLUSIONS: Creation of a MMC-like lesion with an additional myelotomy does not always lead to hindbrain herniation. Our study suggests that CM should be assessed by ultrasound examination at the time of the prenatal repair to demonstrate the effectiveness of new techniques for the prenatal repair of MMC.