Intracranial complications of sinogenic and otogenic infections in children: an ESPN survey on their occurrence in the pre-COVID and post-COVID era.

BACKGROUND: COVID-19 pandemic is thought to have changed the epidemiology of some pediatric neurosurgical disease: among them are the intracranial complications of sinusitis and otitis (ICSO). According to some studies on a limited number of cases, both streptococci-related sinusitis and ICSO would have increased immediately after the pandemic, although the reason is not clear yet (seasonal changes versus pandemic-related effects). The goal of the present survey of the European Society for Pediatric Neurosurgery (ESPN) was to collect a large number of cases from different European countries encompassing the pre-COVID (2017-2019), COVID (2020-2021), and post-COVID period (2022-June 2023) looking for possible epidemiological and/or clinical changes. MATERIAL AND METHODS: An English language questionnaire was sent to ESPN members about year of the event, patient's age and gender, presence of immune-deficit or other favoring risk factors, COVID infection, signs and symptoms at onset, site of primary infection, type of intracranial complication, identified germ, type and number of surgical operations, type and duration of medical treatment, clinical and radiological outcome, duration of the follow-up. RESULTS: Two hundred fifty-four cases were collected by 30 centers coming from 14 different European countries. There was a statistically significant difference between the post-COVID period (129 children, 86 cases/year, 50.7% of the whole series) and the COVID (40 children, 20 cases/year, 15.7%) or the pre-COVID period (85 children, 28.3 cases/year, 33.5%). Other significant differences concerned the presence of predisposing factors/concurrent diseases (higher in the pre-COVID period) and previous COVID infection (higher in the post-COVID period). No relevant differences occurred as far as demographic, microbiological, clinical, radiological, outcome, morbidity, and mortality data were concerned. Paranasal sinuses and middle ear/mastoid were the most involved primary site of infection (71% and 27%, respectively), while extradural or subdural empyema and brain abscess were the most common ICSO (73% and 17%, respectively). Surgery was required in 95% of cases (neurosurgical and ENT procedure in 71% and 62% of cases, respectively) while antibiotics in 99% of cases. After a 12.4-month follow-up, a full clinical and radiological recovery was obtained in 85% and 84% of cases, respectively. The mortality rate was 2.7%. CONCLUSIONS: These results suggest that the occurrence of ICSO was significantly increased after the pandemic. Such an increase seems to be related to the indirect effects of the pandemic (e.g., immunity debt) rather than to a direct effect of COVID infection or to seasonal fluctuations. ICSO remain challenging diseases but the pandemic did not affect the management strategies nor their prognosis. The epidemiological change of sinusitis/otitis and ICSO should alert about the appropriate follow-up of children with sinusitis/otitis.

Posterior fossa ependymoma in children: A long-term single-center experience.

INTRODUCTION: Ependymomas in the posterior fossa have poor prognosis. This study reports a single-center pediatric series, focusing on the value of surgical resection. MATERIAL AND METHODS: A single-center retrospective study included all patients operated on by the senior author (CM) for posterior fossa ependymoma from 2002 to 2018. Medical and surgical data were extracted from the hospital's medical database. RESULTS: Thirty-four patients were included. Age ranged from 6 months to 18 years, with a median of 4.7 years. Fourteen patients underwent initial endoscopic third ventriculocisternostomy before the direct surgical resection. Surgical removal was complete in 27 patients. There were 32 surgeries for second-look, local recurrence or metastasis despite complementary chemotherapy and/or radiotherapy. Twenty patients were WHO grade 2 and 14 grade 3. Sixteen patients showed recurrence (47%). Overall survival was 61.8% at a mean 10.1 years' follow-up. Morbidities comprised facial nerve palsy, swallowing disorder, and transient cerebellar syndrome. Fifteen patients had normal schooling, 6 had special assistance; 4 patients reached university, 3 of whom experienced difficulties. Three patients had a job. CONCLUSION: Posterior fossa ependymomas are aggressive tumors. Complete surgical removal is the most important prognostic factor, despite risk of sequelae. Complementary treatment is mandatory, but no targeted therapy has so far proved effective. It is important to continue the search for molecular markers in order to improve outcomes.

A new approach of crenellated fronto-orbital advancement for the management of trigonocephaly: Technical note.

Trigonocephaly is a craniosynostosis characterized by a premature fusion of the metopic suture associating a characteristic triangular head shape, with a frontal medial crest and hypotelorism. Various techniques have been described for its surgical treatment which is usually performed during the first year of life. However, there might be cases with a late referral, after the age of one year. One of the technical issues with a fronto-orbital advancement surgery in a child over one year of age is that there is a significant risk of persistent residual bone defects. This article describes a surgical technique of crenellated fronto-orbital advancement for correcting trigonocephaly in children over one year of age, allowing to reduce residual bone defects.

The ASIP gene in the llama (Lama glama): Alternative transcripts, expression and relation with color phenotypes.

The Agouti gene (ASIP) is one of the most important genes for coat color determination in mammals. It has a complex structure with several promoters and alternative non-coding first exons that are transcribed into mRNAs with different 5'UTR. These mRNA isoforms regulate the temporal and spatial expression of the gene, producing diverse pigmentation patterns. Here, we studied ASIP transcriptional variants and their expression in the skin of llamas with different coat color phenotypes. We also described the ASIP locus, including promoter usage and the splicing events that originate each transcript variant. Using 5'RACE-PCR we isolated seven ASIP transcripts with alternative 5'UTR, where exons 1A, 1A', 1C, 1D, and a novel non-coding exon 1A" were identified. Additionally, new alternative spliced forms were found. The diversity of ASIP 5'UTRs is originated by a complex pattern of alternative promoter usage, multiple transcription start sites and splicing events that include exon skipping and alternative 3' splicing site selection. We found that ASIP was highly expressed in llamas with white and brown phenotypes while black animals presented very low expression. The main responsible for this difference was a fusion transcript between ASIP and NCOA6 genes, which was present in the skin of white and brown llamas but not in the black ones. The rest of ASIP transcripts presented very low expression in the skin, indicating that the main regulation point for ASIP gene expression is at the transcriptional level. Nevertheless, the characteristics of the 5'UTRs sequences suggest that alternative transcripts could be regulated differently at the protein synthesis level.

Surgical management of posterior fossa medulloblastoma in children: The Lyon experience.

INTRODUCTION: Modern approach for the treatment of posterior fossa medulloblastomas remains a challenge for pediatric neurosurgeons and pediatric oncologists and requires a multidisciplinary approach to optimize survival and clinical results. MATERIAL AND METHODS: We report the surgical principles of the treatment of posterior fossa medulloblastomas in children and how to avoid technical mistakes especially in very young patients. We also report our experience in a series of 64 patients operated from a medulloblastoma between 2000 and 2018 in Lyon. RESULTS: All patients had a craniospinal MRI. Eighty-one percent of the patients (n=50) had strictly midline tumor while 19% (n=14) had lateralized one. Eleven percent (n=7) had metastasis at diagnosis on the initial MRI. Forty-one percent (n=29) had an emergency ETV to treat hydrocephaly and the intracranial hypertension. All patient underwent a direct approach and a complete removal was achieved in 78% (n=58) of the cases on the postoperative MRI realized within 48h postsurgery. Histological findings revealed classical medulloblastoma in 73% (n=46), desmoplastic medulloblastoma in 17% (n=11) and anaplastic/large cell medulloblastoma in 10% (n=7). Patients were classified as low risk in 7 cases, standard risk in 30 cases and high risk in 27 cases. Ninety-six percent (n=61) of the patient received radiotherapy. Seventy-six percent (n=48) received pre-irradiation or adjuvant chemotherapy. At last follow-up in December 2018, 65% (n=41) of the patient were in complete remission, 12% (n=8) were in relapse and 27% (n=15) had died from their disease. The overall survival at five , ten and fifteen years for all the series was of 76%, 73% and 65.7% respectively. CONCLUSIONS: Medulloblastomas remain a chimiosensible and radiosensible disease and the complete surgical removal represents a favorable prognostic factor. The extension of surgery has also to be weighted in consideration of the new biomolecular and genetic knowledge that have to be integrated by surgeons to improve quality of life of patients.

Emissary veins and pericerebral cerebrospinal fluid in trigonocephaly: do they define a specific subtype?

INTRODUCTION: The premature fusion of the metopic suture may be associated with the presence of emissary veins (EV) and abnormally large pericerebral cerebrospinal fluid (CSF) spaces which suggest an associated focal disturbance in CSF dynamics. The incidence of such findings and their potential significance in terms of management of the disease have not been fully elucidated. The aim of this study is to investigate whether these phenomena identify specific subtypes of trigonocephaly. In such a direction, we evaluated the volume of the pericerebral CSF spaces and their relationship to the morphology ("Ω," "V," or flat type) of the prematurely fused metopic suture and to the value of the interfrontal angle value on the grounds of computed tomographic (CT) scan examinations. METHOD: The preoperative brain CT scans of 74 children (52 boys, 22 girls) with trigonocephaly who had undergone fronto-orbital remodeling were evaluated. The volume of the pericerebral CSF spaces and the value of the interfrontal angle were calculated. The type of intracranial notch was studied and classified according to its shape on the preoperative CT scan: a groove "Ω," a ridge/"V" ridge or absent when flat and evidence of emissary veins related to the abnormally fused suture. RESULTS: Preoperatively, an endocranial metopic groove or ridge was seen in 70% of the children. Emissary veins were identified in 34 of 74 patients (45%), at a mean distance of 2.04 cm (1.18-2.94 cm) from the nasion. The presence of large pericerebral CSF spaces significantly correlated with the presence of EV (p < 0.05), with the "Ω" type (p < 0.05) and with interfrontal angles under 134° (p < 0.005). CONCLUSIONS: Metopic suture early fusion shows an association between EV, pericerebral CSF spaces, and the "Ω" groove appearance of the suture. This association identifies a specific subgroup in which the presence of emissary veins and large pericerebral CSF spaces is an indicator of local venous hypertension due to the sagittal sinus constriction within an osseous groove created by the abnormal suture fusion process. The implications for the surgical management and long-term results as compared to trigonocephalic children with small or absent normal peripheral spaces and EV are still to be determined.

Cranioplasty for bone defects after craniosynostosis surgery. Case series with literature review.

INTRODUCTION: Surgical treatment of craniosynostosis in children may generate secondary cranial vault defects by incomplete ossification process. The incidence of cranial defects after craniosynostosis surgery is poorly reported in the literature with a variable incidence of 0.5% to 18.2%. To better understand the impact and management of the cranial defects after craniosynostosis surgery, we selected and reviewed al cranioplasties that met this criterion between 2002 and 2019. PATIENTS AND METHOD: We found 41 patients (28 M and 13 F) operated between January 2002 to January 2019 who underwent cranioplasty for cranial defects secondary to craniosynostosis surgery in the infancy. All patient were at least 5 years old (range 5 to 17 years, median 11). The indication was aesthetic in 28 patients and for headaches, learning difficulties or changes in the cerebral blood flow in 13 patients. The material used in cranioplasty was the poly-methyl-methacrylate (PMMA) in 40 patients and customized porous hydroxyapatite (CPHA) in 1 patient. RESULTS: The mean follow-up period after cranioplasty was of 37 months (range 2 to 125 months, median of 27 months). In the postoperative period there were no mortality nor neurological complications. There were 3 cases (7%) of superficial local postoperative wound infection but with no evidence of long-term infection. The long-term CT scan follow-up showed no material migration, dislocation or fractures. CONCLUSION: Considering the characteristics of the cranial vault after craniosynostosis surgery the treatment by cranioplasty with heterologous materials appears to be feasible thus avoiding donor site morbidity. For selected cases with small defects, our experience shows that the use of PMMA may be a safe alternative for the cranial vault repair in children older than 5 years.

Positional cranial deformation in children: A plea for the efficacy of the cranial helmet in children.

BACKGROUND: Cranial deformations have historically aroused the interest of people worldwide. One of the more debated points about positional plagiocephaly is the choice of the treatment. In this article, the senior author (CM) shares his experience on almost 30 years of use of the helmet molding therapy in children with deformation plagiocephaly. METHODS AND POPULATION: We retrospectively and systematically reviewed the cases of 2188 patients (75% males and 25% females) presenting positional head deformity and treated between 1991 and 2013 with a cranial helmet. To assess the effectiveness of the helmet, we compared the cranial index in bilateral plagiocephaly and the Cranial Diagonals Difference (CDD) in unilateral plagiocephaly at the beginning and at the end of the treatment. RESULTS: The cranial indexes ranged between 94.4% and 124.2% before the treatment and decreased significantly between 86.8% and 121.4% after the treatment (P<0.01). The CDD ranged between 0.3 cm and 4.5 cm with an average of 1.50±0.54 cm before the treatment and decreased significantly between 0.1 cm and 2.5 cm with an average of 0.72±0.37 cm after the treatment (P<0.01). For unilateral plagiocephaly, at the beginning of the treatment, 2.5% children presented a mild plagiocephaly, 19.6% a moderate plagiocephaly and 77.9% a severe plagiocephaly. At the end of the treatment, the deformation was classified as mild in 40.2% children, moderate in 44.3% children and severe in 15.5% children with significantly less children in the most severe subgroups (P<0.01) Facial symmetry pre-existed before the treatment in 13.7% of children. This rate was significantly increased at the end of the treatment to 66.7% (P<0.01). In only 8 cases (0.2%), the helmet therapy did not allow to obtain correct clinical results and a surgical posterior cranial remodeling was performed. CONCLUSIONS: The results observed in this series confirms that cranial helmet is a simple and well tolerated alternative which bring satisfying results. Its success implies a good collaboration with parents and a management both by orthoptist, physiotherapist and doctor. Nevertheless, it remains many controversies in the literature concerning in particular long-term cosmetic and functional outcomes. A long-term multicentric prospective study could enable to remove doubts.

Genetic bases of craniosynostoses: An update.

Craniosynostosis (CS) is defined as the premature fusion of cranial sutures, leading to an abnormal skull shape. The overall incidence is between 1: 2,000 and 1: 3,000 live births. Genetic causes are found in 20% of cases. CS can be isolated (non-syndromic CS/NSCS) or they can be part of multiple congenital abnormalities syndromes (syndromic CS/SCS). A few SCS, such as Crouzon, Pfeiffer, Apert and Saethre-Chotzen syndromes, are very well known and their molecular bases have been clarified in the 90s and early 2000s, thus showing the major role of the FGF receptors and TWIST signaling pathways in the etiology of these conditions. The recent availability of powerful molecular tools for genetic diagnosis, such as whole exome or whole genome sequencing, has led to the characterization of the molecular bases of an increasing number of CS, thus emphasizing the significant genetic heterogeneity of these conditions, and blurring the limit between SCS and NSCS. The genetic characterization of patients affected by CS leads to appropriate genetic counseling and provides relevant information concerning comorbidity and prognosis. Nevertheless, this can also lead to the detection of susceptibility factors with low penetrance whose interpretation in genetic counseling is difficult and it raises the question of its cost-effectiveness for health systems. These aspects suggest the need of a patient-tailored clear rationale for performing genetic tests. In this study, we reviewed the main molecular etiologies reported in the last 15 years of either SCS or NSCS, and we propose a systematic multidisciplinary approach as well as a diagnostic flowchart for the genetic evaluation of these patients.

[Neuropsychological consequences of craniosynostosis: Non-syndromic scaphocephaly]. / Le retentissement neuropsychologique de la craniosténose : cas de la scaphocéphalie non syndromique.

BACKGROUND: Scaphocephaly increases the rate of some modifications of cognitive and mood profile in a manner that remains to be elucidated. OBJECTIVE: We aimed to describe the impact of scaphocephaly on neuropsychological profile and more particularly on the executive functions. PATIENTS AND METHODS: An experimental group of 19 children older than 5 years, operated on for scaphocephaly, was compared with a control group of 10 children operated on for trigonocephaly, using IQ tasks, attention tasks and mood scales. A group of 6 children from 2 to 4 years old, operated on for scaphocephaly, and a group of 6 children with non-operated scaphocephaly are also described. RESULTS: Both the experimental group and the control group showed unchanged IQ, whereas attention deficit and anxiety disorder were more frequent in the experimental group. Cognitive profiles differed between groups, with a higher rate of impaired inhibitory control of visual processing in the scaphocephaly group, contrasting with a higher rate of impaired auditory verbal working memory in the trigonocephaly group. Comparable profiles were also found in groups of younger or non-operated children with scaphocephaly. CONCLUSIONS: Many children with scaphocephaly must cope with a specific neuropsychological profile throughout development. This study suggests the interest for these children and their families of specific follow-up in reference centers.

Hydrocephalus and Chiari malformation pathophysiology in FGFR2-related faciocraniosynostosis: A review.

BACKGROUND: Patients with syndromic faciocraniosynostosis due to the mutation of the fibroblast growth factor receptor (FGFR) 2 gene present premature fusion of the coronal sutures and of the cranial base synchondrosis. Cerebrospinal fluid (CSF) circulation disorders and cerebellar tonsil prolapse are frequent findings in faciocraniosynostosis. OBJECTIVE: We reviewed the medical literature on the pathophysiological mechanisms of CSF disorders such as hydrocephalus and of cerebellar tonsil prolapse in FGFR2-related faciocraniosynostosis. DISCUSSION: Different pathophysiological theories have been proposed, but none elucidated all the symptoms present in Apert, Crouzon and Pfeiffer syndromes. The first theory that addressed CSF circulation disruption was the constrictive theory (cephalocranial disproportion): cerebellum and brain stem are constricted by the small volume of the posterior fossa. The second theory proposed venous hyperpressure due to jugular foramens stenosis. The most recent theory proposed a pressure differential between CSF in the posterior fossa and in the vertebral canal, due to foramen magnum stenosis.

Craniosynostosis and metabolic bone disorder. A review.

INTRODUCTION: Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder. MATERIAL AND METHODS: A review of the literature on metabolic forms of craniosynostosis was performed. RESULTS: The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe. CONCLUSION: The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.

Sagittal suture craniosynostosis or craniosynostoses? The heterogeneity of the most common premature fusion of the cranial sutures.

BACKGROUND: Scaphocephaly is usually defined as the deformation of the skull resulting from the premature fusion of the sagittal suture. It is the most common type of craniosynostosis, and can be easily recognized on simple clinical examination. Its pathophysiology is easy to understand and to confirm on neuroradiological examination. In contrast, surgical indications are still somewhat controversial, the dispute mainly concerning therapeutic versus esthetic objectives. In recent years, however, several studies have challenged these basic and relatively simplistic interpretations of the pathophysiology of the condition. MATERIALS AND METHODS: To assess the heterogeneity of scaphocephaly, we reviewed cases of scaphocephaly operated on at the Hôpital Femme-Mère-Enfant, Lyon University Hospital, France during a 10-year period (2008-2017) and performed a review of the literature on scaphocephaly and sagittal suture closure. RESULTS: During the 10-year period, 401 children were operated on for a scaphocephaly at the Hôpital Femme Mère Enfant, Lyon University Hospital. Mean age at surgery was 1.14 years, for a median 0.7 years (range, 4 months to 8. 5 years). Several subtypes could be distinguished according to morphology, intracranial findings on imaging, patient age, and etiology associated to the sagittal synostosis. Two main surgical techniques were used to correct the malformation, depending on patient age, type of deformation and the surgeon's preference: cranial vault remodeling with occipital pole widening, with the patient in a prone position, and parietal enlargement with or without forehead remodeling, in dorsal decubitus. CONCLUSIONS: The complexity and heterogeneous nature of sagittal synostoses depend on different pathogenic mechanisms leading to and interfering with the skull abnormalities: abnormalities of CSF dynamics, possibly associated with systemic alterations, accounting for the varied postoperative morphological and functional course, in terms of cognitive impairment and late complications (notably intra-cranial pressure elevation). However, the real impact of such heterogeneous clinical presentations on surgical indications and surgical results remains to be elucidated.

Animal models of craniosynostosis.

BACKGROUND: Various animal models mimicking craniosynostosis have been developed, using mutant zebrafish and mouse. The aim of this paper is to review the different animal models for syndromic craniosynostosis and analyze what insights they have provided in our understanding of the pathophysiology of these conditions. MATERIAL AND METHODS: The relevant literature for animal models of craniosynostosis was reviewed. RESULTS: Although few studies on craniosynostosis using zebrafish were published, this model appears useful in studying the suture formation mechanisms conserved across vertebrates. Conversely, several mouse models have been generated for the most common syndromic craniosynostoses, associated with mutations in FGFR1, FGFR2, FGFR3 and TWIST genes and also in MSX2, EFFNA, GLI3, FREM1, FGF3/4 genes. The mouse models have also been used to test pharmacological treatments to restore craniofacial growth. CONCLUSIONS: Several zebrafish and mouse models have been developed in recent decades. These animal models have been helpful for our understanding of normal and pathological craniofacial growth. Mouse models mimicking craniosynostoses can be easily used for the screening of drugs as therapeutic candidates.

The growth of the posterior cranial fossa in FGFR2-induced faciocraniosynostosis: A review.

BACKGROUND: The growth of the posterior fossa in syndromic craniostenosis was studied in many papers. However, few studies described the pathophysiological growth mechanisms in non-operated infants with fibroblast growth factor receptor (FGFR) type 2 mutation (Crouzon, Apert or Pfeiffer syndrome), although these are essential to understanding cranial vault expansion and hydrocephalus treatment in these syndromes. OBJECTIVE: A review of the medical literature was performed, to understand the physiological and pathological growth mechanisms of the posterior fossa in normal infants and infants with craniostenosis related to FGFR2 mutation. DISCUSSION: Of the various techniques for measuring posterior fossa volume, direct slice-by-slice contouring is the most precise and sensitive. Posterior fossa growth follows a bi-phasic pattern due to opening of the petro-occipital, occipitomastoidal and spheno-occipital sutures. Some studies reported smaller posterior fossae in syndromic craniostenosis, whereas direct contouring studies reported no difference between normal and craniostenotic patients. In Crouzon syndrome, synchondrosis fusion occurs earlier than in normal subjects, and follows a precise pattern. This premature fusion in Crouzon syndrome leads to a stenotic foramen magnum and facial retrusion.

[Psychological support for children operated on for craniosynostosis and their family. Some thoughts for the craniofacial surgeon]. / Suivi psychologique des enfants opérés de craniosténoses et de leurs proches. Quelques éléments de réflexions pour le chirurgien craniofacial.

What is the impact on child and family when they receive a diagnosis of craniostenosis? And what is the impact of surgery? What is the role of the clinical psychologist in accompanying the child and family, especially during hospital stay and surgery time? We present a few thoughts that help understand the psychological processes at work in case of craniostenosis, giving a little hint of the impact on the life of the child and family - which surgeons, preoccupied by more technical questions, sometimes tend to overlook.