Cormac O. Maher
Kévin Beccaria, Michael Canney, Guillaume Bouchoux, Stéphanie Puget, Jacques Grill and Alexandre Carpentier
Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.
Ulrich-Wilhelm Thomale and Matthias Schulz
Aymeric Amelot, Kevin Beccaria, Thomas Blauwblomme, Marie Bourgeois, Giovanna Paternoster, Marie-Laure Cuny, Michel Zerah, Christian Sainte-Rose and Stephanie Puget
Arachnoid cysts (ACs) are most frequently located in the middle cranial fossa. Some patients are asymptomatic whereas others exhibit signs of increased intracranial pressure, seizures, or cognitive and behavioral symptoms. When ACs do require treatment, the optimal surgical technique remains controversial. This study was conducted to assess the most effective surgical treatment for these cysts.
The authors retrospectively reviewed 240 temporal intracranial ACs managed over a 25-year period in their pediatric neurosurgical unit. Pre- and posttreatment results were clinically and radiologically assessed.
A majority of male patients (74.6%) with an overall median age of 6.9 years were included. The mean cyst size was 107 cm3; the Galassi classification showed 99 (41.3%) type I, 77 (32.1%) type II, and 64 (26.7%) type III cysts. Forty-four ACs (18.3%) were diagnosed after rupture. Surgical management was performed by microsurgery (28.3%), endoscopic cyst fenestration (14.6%), cystoperitoneal shunting (CPS; 16.2%), or subdural shunting (10%). Furthermore, 74 children (30.8%) did not undergo operations. After a mean follow-up of 4.1 years, the mean percentage decrease in cyst volume and the overall rate of clinical improvement did not significantly differ. The endoscopy group had earlier complications and a shorter event-free survival (EFS) time (EFS at 3 years = 67.7%, vs 71.5% and 90.5% for CPS and microsurgery, respectively; p < 0.007) and presented with more subdural hematomas compared to the microsurgery group (p < 0.005). The microsurgery group also showed a tendency for longer cystocisternostomy permeability than the endoscopy group.
Concerning the management of unruptured symptomatic temporal ACs, microsurgery appears to be the most effective treatment, with longer EFS and fewer complications compared to shunting or endoscopy.
Pierre-Aurelien Beuriat, Stephanie Puget, Giuseppe Cinalli, Thomas Blauwblomme, Kevin Beccaria, Michel Zerah and Christian Sainte-Rose
Hydrocephalus remains one of the more common pathologies managed in pediatric neurosurgical units. Endoscopic third ventriculostomy (ETV) has an advantage over ventriculoperitoneal shunting as it enables patients to remain device free. Multiple shunt devices with various valve designs exist, with no one valve proven to be superior to another. The aim of this study was to describe the management of hydrocephalus and its long-term outcome.
The authors retrospectively reviewed the medical records of all patients who had been treated for hydrocephalus at the Hôpital Necker-Enfants Malades in the period from 1985 to 1995.
Nine hundred seventy-five children had been treated for hydrocephalus. The mean follow-up was 11 ± 7.4 years (mean ± standard deviation). The most common cause of hydrocephalus was tumor related (32.3%), followed by malformative (24.5%) and inflammatory (20.9%) causes. Two hundred eighty patients underwent ETV as the first-line treatment. The procedure was effective in controlling hydrocephalus due to posterior fossa tumors and aqueductal stenosis. Six hundred ninety-five children had initial shunt insertion, with the majority receiving an Orbis-Sigma valve (OSV). The overall OSV shunt survival was 70% at 1 year, 58% at 10 years, and 49% at 20 years. The most common cause for mechanical shunt failure was obstruction (50.7%). Overall shunt survival was statistically different between the OSV and the differential-pressure valve (p = 0.009).
Endoscopic third ventriculostomy is effective in the management of childhood hydrocephalus. Its success is directly related to the underlying pathology. In the long term, the OSV has significantly higher event-free shunt survival than the classic differential-pressure valve systems
Kevin Beccaria, Michael Canney, Lauriane Goldwirt, Christine Fernandez, Julie Piquet, Marie-Cécile Perier, Cyril Lafon, Jean-Yves Chapelon and Alexandre Carpentier
The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed.
This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography.
The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source.
Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.
Kevin Beccaria, Michael Canney, Lauriane Goldwirt, Christine Fernandez, Clovis Adam, Julie Piquet, Gwennhael Autret, Olivier Clément, Cyril Lafon, Jean-Yves Chapelon and Alexandre Carpentier
The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma.
Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects.
An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field.
The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.
Thomas Blauwblomme, Federico Di Rocco, Marie Bourgeois, Kevin Beccaria, Giovanna Paternoster, Juliette Verchere-Montmayeur, Christian Sainte-Rose, Michel Zerah and Stéphanie Puget
The ideal treatment for subdural hematomas (SDHs) in infants remains debated. The aim of this study was to analyze the safety and efficiency of subduro-subgaleal drainage in SDH.
The authors conducted a single-center open-label study between August 2011 and May 2012. Data were prospectively collected in a database and retrospectively analyzed.
Eighteen patients (male/female ratio 1.25) with a median age of 5 months were surgically treated. All had preoperative symptoms of intracranial hypertension or seizures. The SDH was bilateral in 16 cases, with a median width of 12 mm. Success of the procedure was noted in 14 of the 18 patients. There was no intraoperative complication or postoperative infection. Drainage failure was attributable to suboptimal positioning of the subdural drain in 2 cases and to migration in 1 case.
Subduro-subgaleal drainage is an efficient treatment that could be proposed as an alternative to external subdural drainage or subduroperitoneal drainage.
Thomas Blauwblomme, Olivier Naggara, Francis Brunelle, David Grévent, Stéphanie Puget, Federico Di Rocco, Kevin Beccaria, Giovanna Paternoster, Marie Bourgeois, Manoelle Kossorotoff, Michel Zerah, Christian Sainte-Rose and Nathalie Boddaert
Arterial spin labeling (ASL)-MRI is becoming a routinely used sequence for ischemic strokes, as it quantifies cerebral blood flow (CBF) without the need for contrast injection. As brain arteriovenous malformations (AVMs) are highflow vascular abnormalities, increased CBF can be identified inside the nidus or draining veins. The authors aimed to analyze the relevance of ASL-MRI in the diagnosis and follow-up of children with brain AVM.
The authors performed a retrospective analysis of 21 patients who had undergone digital subtraction angiography (DSA) and pseudo-continuous ASL-MRI for the diagnosis or follow-up of brain AVM after radiosurgery or embolization. They compared the AVM nidus location between ASL-MRI and 3D contrast-enhanced T1 MRI, as well as the CBF values obtained in the nidus (CBFnidus) and the normal cortex (CBFcortex) before and after treatment.
The ASL-MRI correctly demonstrated the nidus location in all cases. Nidal perfusion (mean CBFnidus 137.7 ml/100 mg/min) was significantly higher than perfusion in the contralateral normal cortex (mean CBFcortex 58.6 ml/100 mg/min; p < 0.0001, Mann-Whitney test). Among 3 patients followed up after embolization, a reduction in both AVM size and CBF values was noted. Among 5 patients followed up after radiosurgery, a reduction in the nidus size was observed, whereas CBFnidus remained higher than CBFcortex.
In this study, ASL-MRI revealed nidus location and patency after treatment thanks to its ability to demonstrate focal increased CBF values. Absolute quantification of CBF values could be relevant in the follow-up of pediatric brain AVM after partial treatment, although this must be confirmed in larger prospective trials.
Sarah Stricker, Grégoire Boulouis, Sandro Benichi, Florent Gariel, Lorenzo Garzelli, Kevin Beccaria, Anais Chivet, Timothee de Saint Denis, Syril James, Giovanna Paternoster, Michel Zerah, Marie Bourgeois, Nathalie Boddaert, Francis Brunelle, Philippe Meyer, Stephanie Puget, Olivier Naggara and Thomas Blauwblomme
Hydrocephalus is a strong determinant of poor neurological outcome after intracerebral hemorrhage (ICH). In children, ruptured brain arteriovenous malformations (bAVMs) are the dominant cause of ICH. In a large prospective cohort of pediatric patients with ruptured bAVMs, the authors analyzed the rates and predictive factors of hydrocephalus requiring acute external ventricular drainage (EVD) or ventriculoperitoneal shunt (VPS).
The authors performed a single-center retrospective analysis of the data from a prospectively maintained database of children admitted for a ruptured bAVM since 2002. Admission clinical and imaging predictors of EVD and VPS placement were analyzed using univariate and multivariate statistical models.
Among 114 patients (mean age 9.8 years) with 125 distinct ICHs due to ruptured bAVM, EVD and VPS were placed for 55/125 (44%) hemorrhagic events and 5/114 patients (4.4%), respectively. A multivariate nominal logistic regression model identified low initial Glasgow Coma Scale (iGCS) score, hydrocephalus on initial CT scan, the presence of intraventicular hemorrhage (IVH), and higher modified Graeb Scale (mGS) score as strongly associated with subsequent need for EVD (all p < 0.001). All children who needed a VPS had initial hydrocephalus requiring EVD and tended to have higher mGS scores.
In a large cohort of pediatric patients with ruptured bAVM, almost half of the patients required EVD and 4.4% required permanent VPS. Use of a low iGCS score and a semiquantitative mGS score as indicators of the IVH burden may be helpful for decision making in the emergency setting and thus improve treatment.