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.

Neuropsychological improvement after posterior fossa arachnoid cyst drainage.

PURPOSE: Posterior fossa arachnoid cysts (PFAC) are mostly considered as benign lesions of the cerebellum. Although many studies have shown the major role of the cerebellum in modulating movement, language, cognition, and social interaction, there are few studies on the cognitive impact and surgical decompression of PFAC. METHODS: We present the cases of two brothers successively diagnosed with PFAC and neuropsychological delay. After multidisciplinary discussion with the boys' parents, it was decided to drain these lesions. Clinical signs, cerebral images, and neuropsychological status were assessed on admission and then 1 and 3 years after surgery. RESULTS: At presentation, both children had mild cerebellar signs, associated with cognitive and visual-motor impairments and academic regression. CT scans revealed retrovermian cysts, which were shunted. Post-operatively, both brothers demonstrated improved visual-motor skills and behavior. At follow-up, we observed disappearance of dysarthria and academic delay and significant improvement in cognition especially at the intelligence scale and in language. Fine motor skills had improved but remained slower than the average and writing skills appeared limited. CONCLUSION: Except for PFAC which impair cerebrospinal fluid circulation or which are responsible for a significant mass effect, most PFAC are usually considered as "asymptomatic" and do not require surgical treatment. The two cases reported herein suggest that these lesions might be responsible for some associated but potentially reversible neuropsychological impairment. In the future, clinical assessment should include neuropsychological evaluation to help inform decision for surgical decompression in these children with PFAC.

Assessment of executive functioning in children and young adults treated for frontal lobe tumours using ecologically valid tests.

There is a lack of studies assessing executive functions (EF) using ecologically valid tests in children with frontal lobe lesions. This study aimed to (1) evaluate EF in children, adolescents and young adults treated for childhood frontal lobe tumours, (2) identify factors influencing performance, such as age at diagnosis or type of treatment, and (3) examine correlations between intellectual ability and classical and ecological tests of EF. Twenty-one patients, aged 8-27 years, treated for a childhood benign or malignant frontal lobe tumour, and 42 healthy controls (matched for gender, age and socio-economic status) were assessed using classical tests of EF, and the BADS-C ecological battery. Patients also underwent assessment of intellectual ability and parent and teacher ratings of the BRIEF questionnaire. IQ scores ranged from 45 to 125 (mean FSIQ = 84) and were lower in case of epilepsy, hydrocephalus and lower parental education. Patients displayed deficits in most, but not all measures of EF. Most classical and ecological measures of EF were strongly correlated to IQ. This study confirms the frequency of EF deficits in this population; it also highlights the utility of ecological measures of EF and some limitations of classical tests of EF in children.

Choroid Plexus Neoplasms: Toward a Distinction between Carcinoma and Papilloma Using Arterial Spin-Labeling.

Pediatric choroid plexus papillomas and carcinomas are highly vascularized neoplasms, which are difficult to distinguish with conventional imaging. We aimed to analyze the diagnostic accuracy of PWI, by using both pseudocontinuous arterial spin-labeling and DSC-PWI. We reviewed the PWI of 13 children with choroid plexus neoplasms (7 papillomas and 6 carcinomas). We quantified CBF, relative CBF, and relative CBV in each lesion and compared papillomas and carcinomas. Relative CBF values by using arterial spin-labeling were significantly higher for carcinomas (P = .028). The median value of relative CBF was 1.7 (range, 1.4-1.9) for carcinomas and 0.4 (range, 0.3-0.6) for papillomas. The CBF median value was 115 mL/min/100 g (range, 90-140 mL/min/100 g) for carcinomas and 41 mL/min/100 g (range, 10-73 mL/min/100 g) for papillomas (P = .056). Measures with DSC-PWI were more variable and not significantly different (P = .393). Arterial spin-labeling is a promising technique to differentiate choroid plexus carcinomas and papillomas.

Clinical evidence of the role of the cerebellum in the suppression of overt articulatory movements during reading. A study of reading in children and adolescents treated for cerebellar pilocytic astrocytoma.

It has been suggested that the cerebellum is involved in reading acquisition and in particular in the progression from automatic grapheme-phoneme conversion to the internalization of speech required for silent reading. This idea is in line with clinical and neuroimaging data showing a cerebellar role in subvocal rehearsal for printed verbalizable material and with computational "internal models" of the cerebellum suggesting its role in inner speech (i.e. covert speech without mouthing the words). However, studies examining a possible cerebellar role in the suppression of articulatory movements during silent reading acquisition in children are lacking. Here, we report clinical evidence that the cerebellum plays a part in this transition. Reading performances were compared between a group of 17 paediatric patients treated for benign cerebellar tumours and a group of controls matched for age, gender, and parental socio-educational level. The patients scored significantly lower on all reading, but the most striking difference concerned silent reading, perfectly acquired by almost all controls, contrasting with 41 % of the patients who were unable to read any item silently. Silent reading was correlated with the Working Memory Index. The present findings converge with previous reports on an implication of the cerebellum in inner speech and in the automatization of reading. This cerebellar implication is probably not specific to reading, as it also seems to affect non-reading tasks such as counting.

Long-term functional outcome of patients with cerebellar pilocytic astrocytoma surgically treated in childhood.

UNLABELLED: Abstract Purpose: A number of studies report neurological and cognitive deficits and behavioural disorders in children after surgical treatment for a benign cerebellar tumour. The present study explores functional outcome in adolescents and adults treated for a low-grade cerebellar astrocytoma in childhood. MATERIALS AND METHODS: Participants were 18 adolescents and 46 adults treated for low-grade astrocytoma in childhood. Academic achievement, professional status and neurological, cognitive and behavioural disturbances were collected using self-completed and parental questionnaires for adolescents and phone interview for adults. For the adolescent group, a control group filled in the same questionnaires. RESULTS: Mean time lapse from surgery was 7.8 years for adolescents and 12.9 years for adults. Five adults (11%) had major sequelae related to post-operative complications, post-operative mutism and/or brain stem involvement. All the other participants presented close-to-normal academic achievement and normal autonomy, despite a high rate of reported cognitive difficulties and difficulties related to mild neurological sequelae (fine motor skills, balance). CONCLUSION: The long-term functional outcome of low-grade cerebellar astrocytoma is generally favourable, in the absence of post-operative complications and brain stem involvement. No major impact of neurological deficits, cognitive problems and emotional disorders on academic achievement and independent functioning was observed.

[Chordoma]. / Les chordomes.

PURPOSES: To review in the literature, all the epidemiological, clinical, radiological, histological and therapeutic data regarding chordomas as well as various notochordal entities: ecchordosis physaliphora, intradural and intraparenchymatous chordomas, benign notochordal cell tumors, parachordomas and extra-axial chordomas. To identify different types of chordomas, including familial forms, associations with tuberous sclerosis, Ollier's disease and Maffucci's syndrome, forms with metastasis and seeding. To assess the recent data regarding molecular biology and progress in targeted therapy. To compare the different types of radiotherapy, especially protontherapy and their therapeutic effects. To review the largest series of chordomas in their different localizations (skull base, sacrum and mobile spine) from the literature. MATERIALS: The series of 136 chordomas treated and followed up over 20 years (1972-2012) in the department of neurosurgery at Lariboisière hospital is reviewed. It includes: 58 chordomas of the skull base, 47 of the craniocervical junction, 23 of the cervical spine and 8 from the lombosacral region. Similarly, 31 chordomas in children (less than 18 years of age), observed in the departments of neurosurgery of les Enfants-Malades and Lariboisière hospitals, are presented. They were observed between 1976 and 2010 and were located intracranially (n=22 including 13 with cervical extension), 4 at the craniocervical junction level and 5 in the cervical spine. METHODS: In the entire Lariboisière series and in the different groups of localization, different parameters were analyzed: the delay of diagnosis, of follow-up, of occurrence of metastasis, recurrence and death, the number of primary patients and patients referred to us after progression or recurrence and the number of deaths, recurrences and metastases. The influence of the quality of resection (total, subtotal and partial) on the prognosis is also presented. Kaplan-Meier actuarial curves of overall survival and disease free survival were performed in the entire series, including the different groups of localization based on the following 4 parameters: age, primary and secondary patients, quality of resection and protontherapy. In the pediatric series, a similar analysis was carried-out but was limited by the small number of patients in the subgroups. RESULTS: In the Lariboisière series, the mean delay of diagnosis is 10 months and the mean follow-up is 80 months in each group. The delay before recurrence, metastasis and death is always better for the skull base chordomas and worse for those of the craniocervical junction, which have similar results to those of the cervical spine. Similar figures were observed as regards the number of deaths, metastases and recurrences. Quality of resection is the major factor of prognosis with 20.5 % of deaths and 28 % of recurrences after total resection as compared to 52.5 % and 47.5 % after subtotal resection. This is still more obvious in the group of skull base chordomas. Adding protontherapy to a total resection can still improve the results but there is no change after subtotal resection. The actuarial curve of overall survival shows a clear cut in the slope with some chordomas having a fast evolution towards recurrence and death in less than 4 years and others having a long survival of sometimes more than 20 years. Also, age has no influence on the prognosis. In primary patients, disease free survival is better than in secondary patients but not in overall survival. Protontherapy only improves the overall survival in the entire series and in the skull base group. Total resection improves both the overall and disease free survival in each group. Finally, the adjunct of protontherapy after total resection is clearly demonstrated. In the pediatric series, the median follow-up is 5.7 years. Overall survival and disease free survival are respectively 63 % and 54.3 %. Factors of prognosis are the histological type (atypical forms), localization (worse for the cervical spine and better for the clivus) and again it will depend on the quality of resection. CONCLUSIONS: Many different pathologies derived from the notochord can be observed: some are remnants, some may be precursors of chordomas and some have similar features but are probably not genuine chordomas. To-day, immuno-histological studies should permit to differentiate them from real chordomas. Improving knowledge of molecular biology raises hopes for complementary treatments but to date the quality of surgical resection is still the main factor of prognosis. Complementary protontherapy seems useful, especially in skull base chordomas, which have better overall results than those of the craniocervical junction and of the cervical spine. However, we are still lacking an intrinsic marker of evolution to differentiate the slow growing chordomas with an indolent evolution from aggressive types leading rapidly to recurrence and death on which more aggressive treatments should be applied.

Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity.

CONTEXT: Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE: We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN: Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING: The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS: Thirty-seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES: Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS: Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS: Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate.

Natural history of cerebral dot-like cavernomas.

AIM: To elucidate the natural history of dot-like or "black spot" cavernomas. MATERIALS AND METHODS: Data of 18 children with black spot cavernomas were analysed retrospectively. RESULTS: Eleven boys and seven girls presented 187 black spot cavernomas during a mean observation period of 5.5 years. Mean and median age at diagnosis of the 187 cavernomas was 9.6 years. There were 70 de novo black spot cavernomas. Boys presented significantly more cavernomas than girls. There were three KRIT1 mutation carriers and four PDCD 10 mutation carriers. Children with a PDCD 10 mutation presented significantly more lesions than those children with a KRIT1 mutation (mean number of lesions per patient: 23.3 versus 3.3, respectively). There were 10 radiological haemorrhagic events caused by 10 black spot lesions. Two of these events were symptomatic. The haemorrhage rate of black spot cavernomas was 0.7% per lesion-year. CONCLUSIONS: A mean bleeding rate of 0.7% per lesion-year is lower than the overall haemorrhage rates provided in the literature. Nonetheless, black spot cavernomas are not purely benign lesions. Furthermore, genetic mutations may play a role in the natural history of black spot cavernomas.

[The mystery of prehistoric trepanations: Is neurosurgery the world eldest profession?]. / Le mystère des trépanations préhistoriques : la neurochirurgie serait-elle le plus vieux métier du monde ?

Trepanation is known to be the first surgical procedure ever performed. Its origins date from the Neolithic Age in Europe and the operation was particularly performed in South America at the Pre-Colombian era, a few thousand years later. Based on many archeological studies on trepanned skulls, we compare the differences and similarities of these two periods through epidemiological, topographical, and technical approaches. Signs of bony regeneration are assessed in an attempt to understand the postoperative survival of trepanned patients. The literature in surgery and archeology does not mention the possible relation between trepanations and growing skull fractures. However, it is reasonable to think that these cranial holes, occurring after a pediatric skull fracture, could mimic real trepanation orifices. The possible connections between these two entities are discussed. The etiological hypotheses on prehistoric trepanation are reviewed.

Neonatal ruptured intracranial aneurysms: case report and literature review.

INTRODUCTION: Intracranial aneurysms are exceptional in neonatal patients: There are only 16 cases previously reported. We describe the first case of neonatal posterior inferior cerebellar artery (PICA) aneurysm and review the literature. CASE REPORT: A 7-day-old girl presented with irritability, anorexia, fever and abnormally enlarging head circumference. Computed tomography (CT) and magnetic resonance (MR) imaging demonstrated intraventricular haemorrhage, secondary hydrocephalus and a pontine cistern haematoma. A PICA aneurysm was suspected on the CT angiogram (CTA) and the diagnosis was confirmed by conventional cerebral angiography. She was successfully treated by surgical clipping of the parent vessel and excision of the aneurysm. Postoperatively, she experienced transient swallowing difficulties and required a ventriculo-peritoneal shunt for hydrocephalus. Histopathological evaluation demonstrated a calcified arterial wall with thrombosis, signs of prior haemorrhage and the absence of the internal elastic lamina. CONCLUSION: Neonatal intracranial aneurysms are rare. Clinical presentation of subarachnoid haemorrhage in this age group is often non-specific. First-line investigation should start with transfontanelle cranial ultrasound, followed by MR angiography then CTA if necessary. Posterior circulation aneurysms and large or giant aneurysms are more frequent in neonates and children than in adults. Early diagnosis and treatment are important for improved outcome. Surgery is better tolerated than in adults.

[Childhood cerebral tumors: morbidity and follow-up into adulthood]. / Tumeurs cérébrales de l'enfant: morbidité et suivi à l'âge adulte.

This chapter presents guidelines for the follow-up of children with brain tumors, whether benign or malignant, in their transition to adulthood. The consequences of their disease and its treatment overlap greatly. The complications and long-term follow-up are detailed based on the specialists involved.

[Epilepsy and focal lesions in children. Surgical management]. / Epilepsie et lésions focales chez l'enfant. Traitement chirurgical.

Epilepsy surgery has gained a large role in the treatment of intractable seizures in the last few decades because of the development of operative techniques and better identification of the cerebral anomalies using electrophysiological recordings and neuroimaging. A series of 419 children, aged from five months to 15 years, with epilepsy (medically refractory in 85.5% of them) associated with focal cortical lesions, who underwent surgery between 1986 and 2006 was analyzed to identify the factors that correlated with outcome. Mean follow-up was 5.2 years. According to Engel's classification; 75.8% of the children were seizure-free. When the lesion was well defined, correlations between clinical data, radiological features and electrophysiological features, suggesting a zone of seizure onset around (or even in) the lesion, was the best guarantee of achieving good seizure control by lesionectomy. Nevertheless, seizure outcome was also determined by other factors: the duration of the epilepsy and the surgery. Persistence of seizures was found to be significantly associated with the preoperative duration of epilepsy, the completeness of the lesional resection and de novo brain damage induced by the surgical procedure itself. Early surgery must be considered in children because of the benefits of seizure control on the developing brain and the risk of secondary epileptogenesis.

[Epilepsy surgery in children: from a multidisciplinary network to the creation of an expertise and care centre]. / Chirurgie des épilepsies de l'enfant: du fonctionnement en réseau à la création d'un centre d'expertise et de soins.

We report on the experience of a network created in 1994 to evaluate children with drug-resistant epilepsies who are candidates for surgical treatment. The network includes epilepsy units from several university hospitals in France that decided to share not only their clinical expertise to better respond to the need for a multidisciplinary approach of epilepsy surgery in children, but also all the technical and human resources available in the various teams. This mode of operation has certainly provided concrete proof of its efficacy since it undoubtedly facilitated, and even accelerated, access to optimal presurgical evaluation and epilepsy surgery for hundreds of children. However, after 10 years of this very enriching practice it became evident that our approach was certainly necessary but not sufficient. It is estimated that every year in France nearly 500 children are candidates for surgical treatment, and following a presurgical evaluation, 50% of them could be operated on. Today, only 150-200 children have access to a presurgical evaluation every year. This is a highly paradoxical situation since, even if the human suffering component that such a situation generates is set aside, the direct and indirect life-time costs for every 100 nonoperated patients is estimated at 40 million euros. As a result of our cumulated experience, in 2004 we proposed a different operating model with the creation of an expertise center that will combine not only medical care services provided by a fully equipped multidisciplinary team, but also a pole of applied clinical and fundamental research, a medicosocial center managed by a lay association and an industrial development pole. The project has been recently validated by the Ministry of Health and is supported by a number of national and regional institutions. The Institute for Children and Adolescents with Epilepsy--IDEE--is designed to accelerate diagnostic procedures and, when indicated, access to optimal presurgical evaluation, while also serving as a model for a medical and economic evaluation of epilepsy care in children.

hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities.

Rhabdoid tumours (RTs) are rare but highly aggressive tumours of childhood. Their rarity and their miscellaneous locations make the diagnosis particularly challenging for pathologists. Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene. Immunohistochemistry (IHC) with a monoclonal anti-hSNF5/INI1 antibody has recently been proposed as an efficient diagnostic tool for RTs. We have conducted a retrospective study of 55 tumours referred to our institution with a suspicion of RT. This analysis included pathological review, IHC with anti-hSNF5/INI1 antibody, and molecular investigation using quantitative DNA fluorescent analysis and sequencing of the nine exons of hSNF5/INI1. The molecular lesion could be detected in 37 of the 39 cases exhibiting negative staining for hSNF5/INI1. In the two discrepant cases, the lack of detection of genetic abnormality was probably owing to the presence of a high number of non-tumour cells in the samples. This indicates that hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function. Among the 38 cases with typical RT histological features, six failed to exhibit hSNF5/INI1 mutation and stained positive for hSNF5/INI1. This strongly supports the evidence of a second genetic locus, distinct from hSNF5/INI1, associated with RT. Conversely, seven tumours with histological features poorly compatible with RT stained negative for hSNF5/INI1; they nevertheless exhibited an age of onset and a clinical behaviour similar to RT. This suggests that hSNF5/INI1 inactivation is not strictly limited to typical RT but characterizes a wider family of hSNF5/INI1-deficient tumours. Consequently, we believe that anti-hSNF5/INI1 IHC should be performed widely, even when the pathological characteristics are not typical. The molecular investigation should be performed in infants when a rhabdoid predisposition syndrome is suspected.

Social and psycho-intellectual outcome following radical removal of craniopharyngiomas in childhood. A prospective series.

BACKGROUND: A prospective study on childhood craniopharyngiomas (CPs) was conducted from 1994 to 1998 to appreciate the pre- and postoperative clinical, endocrine, mental, and intellectual status of the patients and to determine the incidence and severity of the postoperative hypothalamic syndrome. METHODS: The series included 14 consecutive CPs. Twelve were retrochiasmatic and intraventricular, and two were partly prechiasmatic and extraventricular. All were treated with the aim of "total" removal. The removal was "total" in nine cases but incomplete in the other five. Immediate postoperative follow-up was uncomplicated in all cases. CONCLUSION: At 2-year follow-up, the two children with an extraventricular CP and a "total" tumor removal were intellectually normal, had no hypothalamic syndrome, and attended normal school with good results. The 12 others, although still intellectually normal, were more or less severely affected by a hypothalamic syndrome which altered their social insertion and caused academic failure. The authors conclude from this study that radical surgery should be reserved to extraventricular CPs only.

[Central nervous system tumor: an unusual etiology for limb pain]. / Tumeur cérébrale: une cause inhabituelle de douleurs des membres inférieurs.

Limb pain in children is one of the most frequent reasons to refer to the emergency unit. Most often it suggests an orthopaedic, a muscular, a peripheral neurologic or a spinal affection. We report two cases of recurrent limb pains revealing a central nervous system tumor.