Guillaume Coll

Maps of the adult human hypothalamus.

The human hypothalamus is a small deeply located region placed at the crossroad of neurovegetative, neuroendocrine, limbic, and optic systems. Although deep brain stimulation techniques have proven that it could be feasible to modulate these systems, targeting the hypothalamus and in particular specific nuclei and white bundles, is still challenging. Our goal was to make a synthesis of relevant topographical data of the human hypothalamus, under the form of magnetic resonance imaging maps useful for mastering its elaborated structure as well as its neighborhood. As from 1.5 Tesla, Inversion-Recovery sequence allows locating the hypothalamus and most of its components. Spotting hypothalamic compartments is possible according to specific landmarks: the anterior commissure, the mammillary bodies, the preoptic recess, the infundibular recess, the crest between the preoptic and the infundibular recesses, the optical tract, the fornix, and the mammillo-thalamic bundle. The identification of hypothalamus and most of its components could be useful to allow the quantification of local pathological processes and to target specific circuitry to alleviate severe symptoms, using physical or biological agents.

The growth of the foramen magnum in Crouzon syndrome.

BackgroundThough the craniovertebral junction is often abnormal in children with Crouzon’s syndrome, no study had measured accurately the size of their foramen magnum (FM).Patients and methodsWe compared the FM size (area, diameters) on computed tomography examination in 21 children with a genetically confirmed Crouzon’s syndrome prior to any surgery and in 23 control children without craniofacial abnormalities. We extrapolated the growth pattern in both groups.ResultsWe found a statistically significant smaller FM area (p = 0.0228), FM sagittal diameter (p = 0.0287), and FM sagittal posterior diameter (p = 0.0023) in children with Crouzon’s syndrome. No differences were detected with regard to the transversal diameter. Hydrocephalus in children with Crouzon’s syndrome was associated with a small FM area (p = 0.05), small sagittal diameter (p = 0.023), small sagittal posterior diameter (p = 0.0173), and reduced transversal diameter (p = 0.03985). No association of the aforementioned findings was found with the position of the cerebellar tonsils or the lambdoid suture functional state (open or fused). Comparable results were observed among the two genetic forms (exon 8 or 10 mutations). Concerning the growth pattern, a first phase of rapid increase and a second phase of slow increase could be recognized in all the measurements in both populations, though with some significant differences.Discussion and conclusionsThe growth of FM follows a biphasic pattern in both Crouzon’s and control children. The sagittal diameter and the global size of the FM are mostly affected in children with Crouzon’s syndrome. The small FM, especially its posterior part, is likely to play a key role in the physiopathology of hydrocephalus.

Anatomy of the Spinal Meninges

BACKGROUND: The spinal meninges have received less attention than the cranial meninges in the literature, although several points remain debatable and poorly understood, like their phylogenesis, their development, and their interactions with the spinal cord. Their constancy among the chordates shows their crucial importance in central nervous system homeostasis and suggests a role far beyond mechanical protection of the neuraxis. OBJECTIVE: This work provides an extensive study of the spinal meninges, from an overview of their phylogenesis and embryology to a descriptive and topographic anatomy with clinical implications. It examines their involvement in spinal cord development, functioning, and repair. METHODS: This work is a review of the literature using PubMed as a search engine on Medline. RESULTS: The stages followed by the meninges along the phylogenesis could not be easily compared with their development in vertebrates for methodological aspects and convergence processes throughout evolution. The distinction between arachnoid and pia mater appeared controversial. Several points of descriptive anatomy remain debatable: the functional organization of the arterial network, and the venous and lymphatic drainages, considered differently by classical anatomic and neuroradiological approaches. Spinal meninges are involved in neurodevelopment and neurorepair producing neural stem cells and morphogens, in cerebrospinal fluid dynamics and neuraxis functioning by the synthesis of active molecules, and the elimination of waste products of central nervous system metabolism. CONCLUSION: The spinal meninges should be considered as dynamic functional formations evolving over a lifetime, with ultrastructural features and functional interactions with the neuraxis remaining not fully understood. ABBREVIATIONS: CNS, central nervous system D, day LMD, limited dorsal myeloschisis

Skull base morphology in fibroblast growth factor receptor type 2-related faciocraniosynostosis: a descriptive analysis.

BACKGROUND Children with faciocraniosynostosis present skull base abnormalities and may develop hydrocephalus or cerebellar tonsils ectopia (CTE). Several pathophysiological hypotheses were formulated in the past decades to explain these associations. However, no study has described in a genetically homogeneous population with confirmed fibroblast growth factor receptor type 2 (FGFR2) mutation eventual correlations between skull base abnormalities and hydrocephalus or CTE. OBJECTIVE To illustrate these features in children <2 years of age with a genetically confirmed FGFR2-related faciocraniosynostosis. METHODS We measured the foramen magnum area (FMA) and its sagittal and transversal components: the right, left, and mean area of the jugular foramen; the posterior fossa volume; and the cerebellar volume on preoperative millimetric computed tomography scan slices in 31 children with an FGFR2 mutation (14 with Crouzon syndrome, 11 with Apert syndrome, and 6 with Pfeiffer syndrome). They were compared with 17 children without synostosis. All children were <24 months of age. We correlated all these measures with the presence of hydrocephalus or CTE. RESULTS We observed a significantly small FMA in children with Crouzon (P = .03) and in children with Pfeiffer (P = .05) resulting from a reduced sagittal diameter (P = .02 for Crouzon and P = .002 for Pfeiffer). Hydrocephalus was associated with small FMA (P = .02). The jugular foramen area, posterior fossa volume, and cerebellar volume were not associated with hydrocephalus or CTE. Hydrocephalus and CTE were statistically associated (P = .002). CONCLUSION Hydrocephalus in FGFR2-related Crouzon and Pfeiffer syndromes is statistically associated with a small FMA. Hydrocephalus is statistically associated with CTE.

Human Foramen Magnum Area and Posterior Cranial Fossa Volume Growth in Relation to Cranial Base Synchondrosis Closure in the Course of Child Development

BACKGROUND To date, no study has compared the evolution of the foramen magnum area (FMA) and the posterior cranial fossa volume (PCFV) with the degree of cranial base synchondrosis ossification. OBJECTIVE To illustrate these features in healthy children. METHODS The FMA, the PCFV, and the ossification of 12 synchondroses according to the Madeline and Elster scale were retrospectively analyzed in 235 healthy children using millimeter slices on a computed tomography scan. RESULTS The mean FMA of 6.49 cm in girls was significantly inferior to the FMA of 7.67 cm in boys (P < .001). In both sexes, the growth evolved in a 2-phase process, with a phase of rapid growth from birth to 3.75 years old (yo) followed by a phase of stabilization. In girls, the first phase was shorter (ending at 2.6 yo) than in boys (ending at 4.33 yo) and proceeded at a higher rate. PCFV was smaller in girls (P < .001) and displayed a biphasic pattern in the whole population, with a phase of rapid growth from birth to 3.58 yo followed by a phase of slow growth until 16 yo. In girls, the first phase was more active and shorter (ending at 2.67 yo) than in boys (ending at 4.5 yo). The posterior interoccipital synchondroses close first, followed by the anterior interoccipital and occipitomastoidal synchondroses, the lambdoid sutures simultaneously, then the petro-occipital and spheno-occipital synchondroses simultaneously. CONCLUSION The data provide a chronology of synchondrosis closure. We showed that FMA and PCFV are constitutionally smaller in girls at birth (P ≤ .02) and suggest that a sex-related difference in the FMA is related to earlier closure of anterior interoccipital synchondroses in girls (P = .01). ABBREVIATIONS AIOS, anterior interoccipital synchondrosesFMA, foramen magnum areaLS, lambdoid suturesOMS, occipitomastoidal synchondrosesPCFV, posterior cranial fossa volumePIOS, posterior interoccipital synchondrosesPOS, petro-occipital synchondrosesSOS, spheno-occipital synchondrosisyo, years old.

Méningiomes intracrâniens et utilisation prolongée d’acétate de cyprotérone à dose conventionnelle chez la femme : à propos de deux cas de régression tumorale après arrêt du traitement

The action of synthetic progestogens, prescribed at a conventional dose in women, for a meningioma, is still poorly understood, and could be related to progesterone receptors. We report two cases illustrating multiple meningiomas with stabilization or tumor reduction after withdrawal of cyproterone acetate originally prescribed for a long term period. We also review the influence of synthetic progestogens on meningiomas, particularly the impact of treatment withdrawal.

Incidence and survival of childhood central nervous system tumors: A report of the regional registry of childhood cancers in Auvergne-Limousin

INTRODUCTION Central nervous system tumors (CNST) are the most lethal of solid tumors in childhood cancer. PATIENTS AND METHODS We report incidence and survival data for all CNST (International Classification of Diseases for Oncology third edition, category III or Xa) recorded in children under 15 years of age by the Auvergne-Limousin cancer registry for the period 1986-2009. RESULTS Annual incidence of all CNST was 3.27 per 100,000 and the male to female ratio was 0.95. Over 45.0% of CNST were glial. Astrocytomas (36.2%) showed the highest incidence for each age group except between 1 and 4 years where embryonal tumors were more common. For all CNST, no significant variation in incidence over time was observed for the evaluated period of 23 years (annual percent change: -0.4%, 95% CI, [-2.8-2.1]). Globally, 5 years overall survival was 67% [59-73] and had increased by more than 16% between 1986-1999 and 2000-2009, mainly due to better survival for astrocytomas, other gliomas, ependymomas and choroid plexus tumors (P=0.01). CONCLUSION We report that the incidence of CNST in Auvergne-Limousin is similar to that in the literature and did not increase between 1986 and 2009. In addition, 5 years overall survival increased after 1999, especially for surgically treatable tumors.

Morphology of the foramen magnum in syndromic and non-syndromic brachycephaly: letter to the editor.

Dear Editor, It is with great interest that we read the paper entitled BMorphology of the foramen magnum in syndromic and non-syndromic brachycephaly^ by Assadsangabi et al.[1]. The authors studied the shape and size of the foramen magnum in syndromic craniosynostosis including Apert, Crouzon, and Pfeiffer syndromes. Using the same methodology we applied in a previous paper [2], that is (i) non-parametric comparison, (ii) transverse and anteroposterior diameter analysis, (iii) LOESS regression curve, the authors found that patients with Crouzon syndrome and Pfeiffer syndrome have a smaller area of the foramen magnum than control subjects. Conversely, patients with non-syndromic synostosis have a foramen magnum similar to controls. Unfortunately, it is not clear whether all the children included in their study were classified according to a genetic confirmation of the syndromes as the authors only mention that Bpatients with a clinical and/or genetic diagnosis of Crouzon, Pfeiffer, Apert and SaethreChotzen^ were studied. Including only patients with genetically confirmed syndromes is a strong argument for the homogeneity of the population and allows a comparison with published series [2–5]. This is of critical importance in the so-called non-syndromic cases in which a Pro250Arg mutation in FGFR3 or a TCF12 mutation could be missed clinically [6]. Indeed, in a previous study, we found that patients with bicoronal synostosis and FGFR3 mutation actually have a smaller foramen compared to controls [5]. Moreover, it is unfortunately not specified in the paper the percentage of hydrocephalic patients nor the number of patients who received a ventriculoperitoneal cerebrospinal fluid shunt or any other procedure for the management of CSF circulation disorders. It is well recognized in the medical literature that the placement of a ventriculoperitoneal shunt may induce a secondary craniosynostosis or aggravate a preexisting one [7–13]. Hydrocephalus is common in these children. In the literature, several studies have found hydrocephalus in 9 to 17 % of patients with Crouzon syndrome, 28 to 64 % of patients with Pfeiffer syndrome, and 4 to 7 % of patients with Apert syndrome [3, 14–21]. The presence of hydrocephalus is also important in regard to the size of the foramenmagnum [2, 3]. In a similar study in genetically confirmed FGFR2-related faciocraniosynostosis (31 children under 2 years of age before any surgical procedure, 14 with Crouzon syndrome, 11 with Apert syndrome, and 6 with Pfeiffer syndrome), we found in fact that hydrocephalus was statistically associated with a small foramen magnum area in Crouzon and Pfeiffer syndromes but not in Apert syndrome [3]. Finally, the disparity found in the ages of the children studied in the article also represents a limitation. The use of age groups would have overcome the bias related to the growth of the skull base found in the pediatric population [3]. It is nevertheless interesting that the results of this study corroborate those of the literature, thus adding some confirmation that the skull base growth is deeply altered in complex synostosis. * Guillaume Coll gcoll@chu-clermontferrand.fr

Pattern of Closure of Skull Base Synchondroses in Crouzon Syndrome

BACKGROUND The age of closure of skull base synchondroses has never been analyzed in a homogenous population of children with Crouzon syndrome. METHODS A retrospective case-control study was performed on 30 Crouzon children (17 male, 13 female) aged 1 month to 12.48 years with Fibroblast Growth Factor Receptor type 2 mutation. Eleven synchondroses were analyzed on millimetric computed tomodensitometric slices before surgery. Syndromic patients were compared with a series of 235 healthy children previously published. RESULTS Synchondrosis closure follows a global pattern that occurs earlier in Crouzon syndrome than in controls (P ≤ 0.002). Synchondrosis fusion starts at 10 months of age with posterior intraoccipital synchondroses and lambdoid sutures, followed by occipitomastoid synchondroses between 1.85 (right) and 2.27 years (left) and anterior intraoccipital synchondroses at approximately 2.80 years. Time to complete fusion varies considerably according to the synchondroses. Spheno-occipital and petro-occipital synchondroses fuse last, at approximately 3 years old. CONCLUSIONS In children with Crouzon syndrome, synchondrosis closure occurs prematurely, with a time course specific to each synchondrosis.

Assessment of citalopram and escitalopram on neuroblastoma cell lines: Cell toxicity and gene modulation

Selective serotonin reuptake inhibitors (SSRI) are common antidepressants which cytotoxicity has been assessed in cancers notably colorectal carcinomas and glioma cell lines. We assessed and compared the cytotoxicity of 2 SSRI, citalopram and escitalopram, on neuroblastoma cell lines. The study was performed on 2 non-MYCN amplified cell lines (rat B104 and human SH-SY5Y) and 2 human MYCN amplified cell lines (IMR32 and Kelly). Citalopram and escitalopram showed concentration-dependent cytotoxicity on all cell lines. Citalopram was more cytotoxic than escitalopram. IMR32 was the most sensitive cell line. The absence of toxicity on human primary Schwann cells demonstrated the safety of both molecules for myelin. The mechanisms of cytotoxicity were explored using gene-expression profiles and quantitative real-time PCR (qPCR). Citalopram modulated 1 502 genes and escitalopram 1 164 genes with a fold change ≥ 2. 1 021 genes were modulated by both citalopram and escitalopram; 481 genes were regulated only by citalopram while 143 genes were regulated only by escitalopram. Citalopram modulated 69 pathways (KEGG) and escitalopram 42. Ten pathways were differently modulated by citalopram and escitalopram. Citalopram drastically decreased the expression of MYBL2, BIRC5 and BARD1 poor prognosis factors of neuroblastoma with fold-changes of -107 (p<2.26 10−7), -24.1 (p<5.6 10−9) and -17.7 (p<1.2 10−7). CCNE1, AURKA, IGF2, MYCN and ERBB2 were more moderately down-regulated by both molecules. Glioma markers E2F1, DAPK1 and CCND1 were down-regulated. Citalopram displayed more powerful action with broader and distinct spectrum of action than escitalopram.