Surface Cranial Ultrasound: The Natural Heir to X-Ray for the Screening of Skull Deformities in Infants.

PURPOSE: Volumetric tomography (3D-CT) is currently considered the gold standard for the diagnosis of craniosynostosis, but its use as the first-line examination for cranial deformities is a topic of debate, because of skull X-ray radiation and low sensitivity and specificity. Cranial ultrasound is an emerging noninvasive radiation-free alternative, but its diagnostic accuracy still needs confirmation. MATERIALS AND METHODS: The present prospective study included 350 infants with skull deformities, who underwent cranial ultrasound as the first-line examination, followed by 3D-CT if the echography results was positive or unclear. If the results were negative, infants underwent physical treatment and follow-up. To evaluate ultrasound reliability, we focused on cases that underwent both the index test and the gold standard and performed a double-blind comparison of the echography and 3D-CT results. RESULTS: Ultrasound documented patent sutures in 293 infants and 9 had inconclusive results. The 293 ultrasound-negative infants were followed clinically: all improved, except 28 that underwent 3D-CT. In all of these cases, 3D-CT confirmed the ultrasonography results (no false negatives). 48 infants showed premature suture closure and underwent 3D-CT: 47 were confirmed (true positive), 1 was false positive. The sensitivity was 100%, the specificity was 99.7%, the positive and negative predictive values were 97.9% and 100%, respectively, the accuracy was 99.7%, and the diagnostic test evaluation was conclusive. CONCLUSION: The study documented the high sensitivity and specificity of echography for the diagnosis of craniosynostosis in a referral center, with better results being achieved before 6 months of age. Major limitations are the loss of diagnostic significance as the child grows and the learning curve needed. The advantages are avoidance of radiation and chance to evaluate the brain at the same time.

Sonodynamic therapy for gliomas.

INTRODUCTION: Glioma remains incurable and a life limiting disease with an urgent need for effective therapies. Sonodynamic therapy (SDT) involves systemic delivery of non-toxic chemical agents (sonosensitizers) that accumulate in tumor cells or environment and are subsequently activated by exposure to low-frequency ultrasound to become cytotoxic agents. Herein, we discuss proposed mechanisms of action of SDT and provide recommendation for future research and clinical applications of SDT for gliomas. METHODS: Review of literature of SDT in glioma cell cultures and animal models published in Pubmed/MEDLINE before January, 2021. RESULTS: Different porphyrin and xanthene derivatives have proven to be effective sonosensitizers. Generation of reactive oxygen species and free radicals from water pyrolysis or sonosensitizers, or physical destabilization of cell membrane, have been identified as mechanisms of SDT leading to cell death. Numerous studies across glioma cell lines using various sonosensitizers and ultrasound parameters have documented tumoricidal effects of SDT. Studies in small animal glioma xenograft models have also consistently documented that SDT is associated with improved tumor control and longer survival of animals treated with SDT while avoiding damage of surrounding brain. There are no clinical trials completed to date regarding safety and efficacy of SDT in patients harboring gliomas, but some are beginning. CONCLUSIONS: Pre-clinical studies cell cultures and animal models indicate that SDT is a promising treatment approach for gliomas. Further studies should define optimal sonication parameters and sonosensitizers for gliomas. Clinical trials of SDT in patients harboring gliomas and other malignant brain tumors are currently underway.

Cranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery).

INTRODUCTION: Ultrasound (US) is a versatile technology, able to provide a real-time and multiparametric intraoperative imaging, and a promising way to treat neuro-oncological patients outside the operating room. Anyhow, its potential is limited both in imaging and therapeutic purposes by the existence of the bone shielding. To enhance the spectrum of uses, our group has designed a dedicated US-translucent cranial prosthesis. Herein, we provide the proof of concept of a long-term US-based follow-up and a potential bedside therapeutic exploitation of US. METHODS: The prosthesis was first implanted in a cadaveric specimen to record any issue related to the cranioplasty procedure. Hence, the device was implanted in a patient undergoing surgery for a multi-recurrent anaplastic oligodendroglioma. US multiparametric scans through the device were acquired at 3, 6, 9, and 30 months after the procedure. RESULTS: The prosthesis could be modeled and implanted through ordinary instruments, with no concerns over safety and feasibility. Trans-prosthesis multiparametric US imaging was feasible, with image quality comparable to intraoperative US. Long-term follow-up in an outpatient setting was possible with no adverse events. Trans-prosthesis mechanical interaction with microbubbles was also feasible during follow-up. CONCLUSIONS: This report provides the first proof of concept for a potential breakthrough in the management of neuro-oncological patients. Indeed, through the implantation of an artificial acoustic window, the road is set to employ US both for a more dynamic long-term follow-up, and for US-guided therapeutic applications.

A preclinical study of diffusion-weighted MRI contrast as an early indicator of thermal ablation.

PURPOSE: Intraoperative T2 -weighted (T2-w) imaging unreliably captures image contrast specific to thermal ablation after transcranial MR-guided focused ultrasound surgery, impeding dynamic imaging feedback. Using a porcine thalamotomy model, we test the unproven hypothesis that intraoperative DWI can improve dynamic feedback by detecting lesioning within 30 minutes of transcranial MR-guided focused ultrasound surgery. METHODS: Twenty-five thermal lesions were formed in six porcine models using a clinical transcranial MR-guided focused ultrasound surgery system. A novel diffusion-weighted pulse sequence monitored the formation of T2-w and diffusion-weighted lesion contrast after ablation. Using postoperative T2-w contrast to indicate lesioning, apparent intraoperative image contrasts and diffusion coefficients at each lesion site were computed as a function of time after ablation, observed peak temperature, and observed thermal dose. Lesion sizes segmented from imaging and thermometry were compared. Image reviewers estimated the time to emergence of lesion contrast. Intraoperative image contrasts were analyzed using receiver operator curves. RESULTS: On average, the apparent diffusion coefficient at lesioned sites decreased within 5 minutes after ablation relative to control sites. In-plane lesion areas on intraoperative DWI varied from postoperative T2-w MRI and MR thermometry by 9.6±9.7 mm2 and -4.0±7.1 mm2 , respectively. The 0.25, 0.5, and 0.75 quantiles of the earliest times of observed T2-w and diffusion-weighted lesion contrast were 10.7, 21.0, and 27.8 minutes and 3.7, 8.6, and 11.8 minutes, respectively. The T2-w and diffusion-weighted contrasts and apparent diffusion coefficient values produced areas under the receiver operator curve of 0.66, 0.80, and 0.74, respectively. CONCLUSION: Intraoperative DWI can detect MR-guided focused ultrasound surgery lesion formation in the brain within several minutes after treatment.

Contrast-enhanced ultrasound of the pediatric brain.

Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic-ischemic injury and focal lesions such as tumors and vascular malformations. It can be applied not only in infants with open fontanelles but also in older children and adults via a transtemporal window or surgically created acoustic window. Advancements in CEUS technology and post-processing methods for quantitative analysis of UCA kinetics further elucidate cerebral microcirculation. In this review article we discuss the CEUS examination protocol for brain imaging in children, current clinical applications and future directions for research and clinical uses of brain CEUS.

Fluorescein-mediated sonodynamic therapy in a rat glioma model.

INTRODUCTION: Malignant gliomas have a dismal prognosis and significant efforts are being made to develop more effective treatments. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. The aim of this study is to demonstrate the efficacy of SDT with fluorescein (FL) and low-intensity focused ultrasound in inhibiting the growth of ectopic gliomas implanted in the rat's subcutaneous tissue. METHODS: In vivo cytotoxicity of FL-SDT was evaluated in C6 rat glioma cells which were inoculated subcutaneously. Tumor specific extracellular FL extravasation and accumulation was assessed with IVIS imaging in rats receiving systemic FL. Effects of FL-SDT with focused low-intensity ultrasound on tumor growth, and histological features of the rat's tumors were investigated. Treatment related apoptosis and necrosis were analyzed using hematoxylin & eosin, and apoptosis-specific staining. RESULTS: IVIS imaging revealed a high degree of FL accumulation within the tumor, with a nearly threefold increase in tumoral epifluorescence signal over background. SDT significantly inhibited outgrowth of ectopic C6 gliomas across all three FUS exposure conditions. TUNEL and active caspase-3 staining did not reveal conclusive trends across control and SDT condition for apoptosis. CONCLUSION: Our results suggest that SDT with FL and low-intensity FUS is effective in inhibiting the growth of ectopic malignant gliomas in rats. The selective FL extravasation and accumulation in the tumor areas where the blood-brain barrier is damaged suggests the tumor-specificity of the treatment. The possibility to use this treatment in intracranial models and in human gliomas will have to be explored in further studies.

Ablative brain surgery: an overview.

Background: Ablative therapies have been used for the treatment of neurological disorders for many years. They have been used both for creating therapeutic lesions within dysfunctional brain circuits and to destroy intracranial tumors and space-occupying masses. Despite the introduction of new effective drugs and neuromodulative techniques, which became more popular and subsequently caused brain ablation techniques to fall out favor, recent technological advances have led to the resurgence of lesioning with an improved safety profile. Currently, the four main ablative techniques that are used for ablative brain surgery are radiofrequency thermoablation, stereotactic radiosurgery, laser interstitial thermal therapy and magnetic resonance-guided focused ultrasound thermal ablation. Object: To review the physical principles underlying brain ablative therapies and to describe their use for neurological disorders. Methods: The literature regarding the neurosurgical applications of brain ablative therapies has been reviewed. Results: Ablative treatments have been used for several neurological disorders, including movement disorders, psychiatric disorders, chronic pain, drug-resistant epilepsy and brain tumors. Conclusions: There are several ongoing efforts to use novel ablative therapies directed towards the brain. The recent development of techniques that allow for precise targeting, accurate delivery of thermal doses and real-time visualization of induced tissue damage during the procedure have resulted in novel techniques for cerebral ablation such as magnetic resonance-guided focused ultrasound or laser interstitial thermal therapy. However, older techniques such as radiofrequency thermal ablation or stereotactic radiosurgery still have a pivotal role in the management of a variety of neurological disorders.

The neurosurgical treatment of craniofacial pain syndromes: current surgical indications and techniques.

Craniofacial pain syndromes are comprised of multiple pathological entities resulting in pain referred to the scalp, face, or deeper cranial structures. In a small subset of patients affected by those syndromes, pharmacological and physical therapies fail in alleviating pain. In some of those refractory patients surgical procedures aimed at relieving pain are indicated and have been adopted with variable results and safety profiles. In this review, the authors describe craniofacial pain syndromes that most commonly fail to respond to pharmacological therapies and may be amenable to tailored surgical procedures. In particular, trigeminal, glossopharyngeal, and occipital neuralgias are considered, as well as some primary headache syndromes such as cluster headache, short unilateral neuralgiform headache with conjunctival injection and tearing/short unilateral neuralgiform headache with autonomic symptoms, and migraine. Surgical techniques, including the implantation of deep brain or peripheral nerve electrodes with subsequent chronic stimulation, microvascular decompression of neurovascular conflicts, and percutaneous lesioning of neural structures are described. Finally, surgical indications, outcomes, and safety of these procedures are presented.

The role of contrast-enhanced ultrasound in neurosurgical disease.

Contrast-enhanced ultrasound (CEUS) is a relatively new imaging modality in the realm of neurosurgical disease. CEUS permits the examination of blood flow through arteries, veins, and capillaries via intravascular contrast agents and allows vascular architectural mapping with extreme sensitivity and specificity. While it has established utility in other organ systems such as the liver and kidneys, CEUS has not been studied extensively in the brain. This report presents a review of the literature on the neurosurgical applications of CEUS and provides an outline of the imaging modality's role in the diagnosis, evaluation, and treatment of neurosurgical disease.

Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy for tremor: technical note.

Although the use of focused ultrasound (FUS) in neurosurgery dates to the 1950s, its clinical utility was limited by the need for a craniotomy to create an acoustic window. Recent technological advances have enabled efficient transcranial delivery of US. Moreover, US is now coupled with MRI to ensure precise energy delivery and monitoring. Thus, MRI-guided transcranial FUS lesioning is now being investigated for myriad neurological and psychiatric disorders. Among the first transcranial FUS treatments is thalamotomy for the treatment of various tremors. The authors provide a technical overview of FUS thalamotomy for tremor as well as important lessons learned during their experience with this emerging technology.

Dynamic assessment of venous anatomy and function in neurosurgery with real-time intraoperative multimodal ultrasound: technical note.

The relevance of the cerebral venous system is often underestimated during neurosurgical procedures. Damage to this draining system can have catastrophic implications for the patient. Surgical decision-making and planning must consider each component of the venous compartment, from the medullary draining vein to the dural sinuses and extracranial veins. Intraoperative ultrasound (ioUS) permits the real-time study of venous compartments using different modalities, thus allowing complete characterization of their anatomical and functional features. The B-mode (brightness mode) offers a high-resolution anatomical representation of veins and their relationships with lesions. Doppler modalities (color, power, spectral) allow the study of blood flow and identification of vessels to distinguish their functional characteristics. Contrast-enhanced US allows one to perform real-time angiosonography showing both the functional and the anatomical aspects of vessels. In this technical report, the authors demonstrate the different applications of multimodal ioUS in neurosurgery for identifying the anatomical and functional characteristics of the venous compartment. They discuss the general principles and technical nuances of ioUS and analyze their potential implications for the study of various venous districts during neurosurgical procedures.

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Long Version).

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version).

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

Contrast-enhanced MR Imaging versus Contrast-enhanced US: A Comparison in Glioblastoma Surgery by Using Intraoperative Fusion Imaging.

Purpose To compare contrast material enhancement of glioblastoma multiforme (GBM) with intraoperative contrast-enhanced ultrasonography (US) versus that with preoperative gadolinium-enhanced T1-weighted magnetic resonance (MR) imaging by using real-time fusion imaging. Materials and Methods Ten patients with GBM were retrospectively identified by using routinely collected, anonymized data. Navigated contrast-enhanced US was performed after intravenous administration of contrast material before tumor resection. All patients underwent tumor excision with navigated intraoperative US guidance with use of fusion imaging between real-time intraoperative US and preoperative MR imaging. With use of fusion imaging, glioblastoma contrast enhancement at contrast-enhanced US (regarding location, morphologic features, margins, dimensions, and pattern) was compared with that at gadolinium-enhanced T1-weighted MR imaging. Results Fusion imaging for virtual navigation enabled matching of real-time contrast-enhanced US scans to corresponding coplanar preoperative gadolinium-enhanced T1-weighted MR images in all cases, with a positional discrepancy of less than 2 mm. Contrast enhancement of gadolinium-enhanced T1-weighted MR imaging and contrast-enhanced US was superimposable in all cases with regard to location, margins, dimensions, and morphologic features. The qualitative analysis of contrast enhancement pattern demonstrated a similar distribution in contrast-enhanced US and gadolinium-enhanced T1-weighted MR imaging in nine patients: Seven lesions showed peripheral inhomogeneous ring enhancement, and two lesions showed a prevalent nodular pattern. In one patient, the contrast enhancement pattern differed between the two modalities: Contrast-enhanced US showed enhancement of the entire bulk of the tumor, whereas gadolinium-enhanced T1-weighted MR imaging demonstrated peripheral contrast enhancement. Conclusion Glioblastoma contrast enhancement with contrast-enhanced US is superimposable on that provided with preoperative gadolinium-enhanced T1-weighted MR imaging regarding location, margins, morphologic features, and dimensions, with a similar enhancement pattern in most cases. Thus, contrast-enhanced US is of potential use in the surgical management of GBM. © RSNA, 2017 Online supplemental material is available for this article.

Differentiating brain radionecrosis from tumour recurrence: a role for contrast-enhanced ultrasound?

Differentiating radionecrosis from tumour recurrence is a major issue in neuro-oncology. Conventional imaging is far from being validated as an alternative to histological assessment. We report the case of a patient operated on for suspected recurrence of brain metastasis 9 months after cyberknife radiosurgery. While magnetic resonance imaging showed strong enhancement of the lesion, intraoperative contrast-enhanced ultrasonography (CEUS) surprisingly did not-different from what is expected for brain metastases. Histopathological examination documented radionecrosis. For the first time, we describe radionecrosis with CEUS; further investigation is needed; however, the lack of enhancement could represent an important hallmark in differential diagnosis with neoplastic tissue.

Brain ultrasound rehearsal before surgery: A pilot cadaver study.

It has been shown that brain ultrasonography (US) is an efficient tool for improving three-dimensional (3D) spatial orientation during neurosurgical interventions. However, it necessitates specific training as it is highly operator-dependent. To date, neurosurgeons have relied solely on intraoperative practice to improve their mastery of brain US; this has obvious limitations. Herein, we consider whether a study of brain US on human cadavers could enable a training platform for neurosurgeons and residents to be developed. Standard two-dimensional (2D) brain US was performed on two human cadavers (one fresh-frozen and one Thiel-prepared) through left frontoparietal, left frontal, right temporal, and left parietal craniotomies. US workflow and image quality were assessed in both preparations. It was possible to assess US in both cadaver preparations; however, the specimen prepared with Thiel-fixation performed better, with superior image quality and specimen usability at room temperature. US images were obtainable through all surgical corridors with the main intracranial anatomical landmarks easily identifiable. US of cadaveric brains is feasible and delivers good quality results. This technique could allow neurosurgeons to develop the expertise required for a successful clinical application preoperatively. Clin. Anat. 30:1017-1023, 2017. © 2017 Wiley Periodicals, Inc.

Neurosurgical tools to extend tumor resection in hemispheric low-grade gliomas: conventional and contrast enhanced ultrasonography.

PURPOSE: Pediatric low-grade gliomas (LGGs) are the most frequent solid tumor in childhood. Based on an increasing number of literature reports, maximal safe resection is recommended as the first line of treatment whenever possible. However, distinguishing tumor tissue from the surrounding normal brain is often challenging with infiltrating neoplasms, even with the assistance of intraoperative, microscopic and conventional neuronavigation systems. Therefore, any technique that enhances the detection and visualization of LGGs intraoperatively is certainly desirable. METHODS: In this paper, we reviewed the role of intraoperative conventional ultrasound and contrast-enhanced ultrasound (CEUS) as a tool for extending tumor resection in LGGs. Moreover, our experience with this technology is reported and discussed. RESULTS: Both B-mode and CEUS are helpful in highlighting LGGs, detecting tumor margins and providing additional information such as vascularization, thus improving the safety of a more radical resection. CONCLUSIONS: Although the full potentialities of the method are yet to be explored, intraoperative ultrasound is a promising tool in oncologic surgery and LGG surgery.

Identification of residual tumor with intraoperative contrast-enhanced ultrasound during glioblastoma resection.

OBJECTIVE: The purpose of this study was to assess the capability of contrast-enhanced ultrasound (CEUS) to identify residual tumor mass during glioblastoma multiforme (GBM) surgery, to increase the extent of resection. METHODS: The authors prospectively evaluated 10 patients who underwent surgery for GBM removal with navigated ultrasound guidance. Navigated B-mode and CEUS were performed prior to resection, during resection, and after complete tumor resection. Areas suspected for residual tumors on B-mode and CEUS studies were localized within the surgical field with navigated ultrasound and samples were sent separately for histopathological analysis to confirm tumor presence. RESULTS: In all cases tumor remnants were visualized as hyperechoic areas on B-mode, highlighted as CEUS-positive areas, and confirmed as tumoral areas on histopathological analysis. In 1 case only, CEUS partially failed to demonstrate residual tumor because the residual hyperechoic area was devascularized prior to ultrasound contrast agent injection. In all cases CEUS enhanced B-mode findings. CONCLUSIONS: As has already been shown in other neoplastic lesions in other organs, CEUS is extremely specific in the identification of residual tumor. The ability of CEUS to distinguish between tumor and artifacts or normal brain on B-mode is based on its capacity to show the vascularization degree and not the echogenicity of the tissues. Therefore, CEUS can play a decisive role in the process of maximizing GBM resection.

Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative glioma: technical note and case report.

Hemangioblastomas are benign, highly vascularized intramedullary lesions that may also extend into the intradural space. Surgery represents the standard therapy, with the goal of obtaining complete resection even at the risk of neurological morbidity. MRI is the gold standard for diagnosis and assessment of intramedullary tumors. Nevertheless, sometimes MRI may not accurately differentiate between different types of intramedullary tumors, in particular if they are associated with syringes or intra- and peritumoral cysts. This could subsequently affect surgical strategies. Intraoperative ultrasound (ioUS) has become in the last few years a very useful tool for use during neurosurgical procedures. Various ioUS modalities such as B-mode and Doppler have been applied during neurosurgical procedures. On the other hand, the use of contrast-enhanced ultrasound (CEUS) is not yet well defined and standardized in this field. We report a case of a young patient harboring a cervicothoracic intramedullary tumor, for which the preoperative neuroradiologi-cal diagnosis was in favor of a diffuse astrocytoma with nodular components whereas ioUS demonstrated 3 distinct intramedullary nodules. CEUS showed highly vascularized lesions, compatible with hemangioblastomas. These findings, particularly those obtained with CEUS, allowed better definition of the lesions for diagnosis, enhanced understanding of the physiopathological aspects, and permitted the localization of all 3 nodules, thus limiting spinal cord manipulation and allowing complete resection of the lesions, with an uneventful postoperative neurological course. To the best of our knowledge, this is the first report of the use of intraoperative CEUS in a case of intramedullary hemangioblastoma.