Multimodality Structural and Functional Monitoring in Brain Tumor Surgery: The Role of IONM and IOUS.

Brain tumor surgery represents the pinnacle of technical and technological advances in the neurosurgery. The goal remains optimized extent of resection with preservation of neurological function. The benefit of a multimodal structural and functional intra-operative monitoring approach is to improve the ability of the surgeon to achieve the goal of optimized surgical resection. Despite significant technological advances, challenges in defining tumor and functional neural tissue interface remain a significant barrier. The opportunity to address this challenge, however, presents us with an exciting path ahead.

Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas: accumulated experience from 4 centers.

PURPOSE: Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) in pLGG is the most important prognostic factor. There are multiple intraoperative tools to optimize the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the surgical treatment of pLGG. METHODS: The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers. RESULTS: We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep-seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (chi-square test, p < 0.01). CONCLUSION: iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long-term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent and iMRI if locally available.

Noninvasive Assessment of Intracranial Pressure: Deformability Index as an Adjunct to Optic Nerve Sheath Diameter to Increase Diagnostic Ability.

BACKGROUND: Today, invasive intracranial pressure (ICP) measurement remains the standard, but its invasiveness limits availability. Here, we evaluate a novel ultrasound-based optic nerve sheath parameter called the deformability index (DI) and its ability to assess ICP noninvasively. Furthermore, we ask whether combining DI with optic nerve sheath diameter (ONSD), a more established parameter, results in increased diagnostic ability, as compared to using ONSD alone. METHODS: We prospectively included adult patients with traumatic brain injury with invasive ICP monitoring, which served as the reference measurement. Ultrasound images and videos of the optic nerve sheath were acquired. ONSD was measured at the bedside, whereas DI was calculated by semiautomated postprocessing of ultrasound videos. Correlations of ONSD and DI to ICP were explored, and a linear regression model combining ONSD and DI was compared to a linear regression model using ONSD alone. Ability of the noninvasive parameters to distinguish dichotomized ICP was evaluated using receiver operating characteristic curves, and a logistic regression model combining ONSD and DI was compared to a logistic regression model using ONSD alone. RESULTS: Forty-four ultrasound examinations were performed in 26 patients. Both DI (R = - 0.28; 95% confidence interval [CI] R < - 0.03; p = 0.03) and ONSD (R = 0.45; 95% CI R > 0.23; p < 0.01) correlated with ICP. When including both parameters in a combined model, the estimated correlation coefficient increased (R = 0.51; 95% CI R > 0.30; p < 0.01), compared to using ONSD alone, but the model improvement did not reach statistical significance (p = 0.09). Both DI (area under the curve [AUC] 0.69, 95% CI 0.53-0.83) and ONSD (AUC 0.72, 95% CI 0.56-0.86) displayed ability to distinguish ICP dichotomized at ICP ≥ 15 mm Hg. When using both parameters in a combined model, AUC increased (0.80, 95% CI 0.63-0.90), and the model improvement was statistically significant (p = 0.02). CONCLUSIONS: Combining ONSD with DI holds the potential of increasing the ability of optic nerve sheath parameters in the noninvasive assessment of ICP, compared to using ONSD alone, and further study of DI is warranted.

Transorbital neuroendoscopy-assisted resection of a giant optic pathway glioma in a neonate.

Congenital giant orbital tumors in infancy are relatively rare, especially when the tumors are associated with significant intracranial extension. We describe the use of a transorbital neuroendoscopy-assisted resection of such a lesion. While this approach is increasingly gaining popularity for certain anterior and middle skullbase lesions in adults, this report represents the youngest patient reported on where this minimally invasive approach has been successfully used to resect the intracranial tumor. This surgical approach obviated the need for a separate craniotomy, with the additional benefit of minimizing blood loss.

ICP-based decision-making in pediatric neurosurgery.

Decision-making in pediatric neurosurgery routinely involves assessing intracranial pressure (ICP). The level of injury and severity of disease play an important role in determining which method of ICP measurement is preferred. Invasive and non-invasive techniques have described indications, advantages and shortcomings. This collection of papers from some of the world's leading thinkers in this field is a refreshing perspective on some mundane techniques and a few innovative and promising advances.

Non-invasive assessment of ICP in children: advances in ultrasound-based techniques.

The assessment of intracranial pressure (ICP) in children with neurological disease remains a cornerstone in their routine management. The quest for a reliable, reproducible and radiation-free non-invasive technique for assessing ICP in children remains somewhat of a holy grail for neurosurgery. This work assesses some of the recent advances in ultrasound-based techniques, addressing both novel processes and modifications aimed at improving the accuracy of existing techniques.

Hydatid disease (Echinococcus) of the central nervous system.

Hydatid disease of the central nervous system is rare and comprises about 2-3% of all the hydatid cyst cases reported in the world. Spinal hydatid is still rare. It is endemic in sheep and cattle-raising regions, seen mainly in Mediterranean countries including Turkey and Syria. Pediatric neurosurgeons in nonendemic countries face a challenge when they are encountered with hydatid cyst of the central nervous system due to lack of awareness and diagnostic dilemmas. It is also a mammoth economic problem in developing countries due to improper hygiene and lack of dedicated veterinary practice. The clinical features are largely nonspecific. However, with the advent of MR imaging, the diagnostic accuracy has increased. Intact removal of the cyst without causing any spillage is the goal and key to cure. In this manuscript, the current literature on hydatid cyst of the brain and spine is reviewed to understand the epidemiological, diagnostic accuracy and advances in therapeutics. A heightened clinical suspicion about hydatid disease, role of MR imaging and improving surgical strategies is discussed. A nationwide prevention of the disease is the ultimate goal.

Infections in the immunocompromised child.

Prevention and management of opportunistic infections in children is particularly relevant in an era demonstrating an increased prevalence of immunocompromising conditions. The presence of an unusual organism which results in serious infection in a child should therefore always raise the consideration of immune compromise. The more common opportunistic infections have become easier to recognize in recent times due to improved awareness and more refined diagnostic testing. Targeted treatment is usually followed by long-term prophylactic medication. The impact of these conditions on patient outcome is of clear significance and certainly warrants further discussion.

Clinical characteristics and neurodevelopmental outcomes of children with tuberculous meningitis and hydrocephalus.

AIM: Tuberculous meningitis (TBM) is a lethal and commonly occurring form of extra-pulmonary tuberculosis in children, often complicated by hydrocephalus which worsens outcome. Despite high mortality and morbidity, little data on the impact on neurodevelopment exists. We examined the clinical characteristics, and clinical and neurodevelopmental outcomes of TBM and hydrocephalus. METHOD: Demographic and clinical data (laboratory and radiological findings) were prospectively collected on children treated for probable and definite TBM with hydrocephalus. At 6 months, clinical outcome was assessed using the Paediatric Cerebral Performance Category Scale and neurodevelopmental outcome was assessed with the Griffiths Mental Development Scale - Extended Version. RESULTS: Forty-four patients (median age 3y 3mo, range 3mo-13y 1mo, [SD 3y 5mo]) were enrolled. The mortality rate was 16%, three patients (6.8%) were in a persistent vegetative state, two were severely disabled (4.5%), and 11 (25%) suffered mild-moderate disability. All cases demonstrated neurodevelopmental deficits relative to controls. Multiple or large infarcts were prognostic of poor outcome. INTERPRETATION: Neurological and neurodevelopmental deficits are common after paediatric TBM with hydrocephalus, and appear to be related to ongoing cerebral ischaemia and consequent infarction. The impact of TBM on these children is multidimensional and presents short- and long-term challenges.

Non-invasive intracranial pressure assessment.

Assessing intracranial pressure (ICP) remains a cornerstone in neurosurgical care. Invasive techniques for monitoring ICP remain the gold standard. The need for a reliable, safe and reproducible technique to non-invasively assess ICP in the context of early screening and in the neurocritical care environment is obvious. Numerous techniques have been described with several novel advances. While none of the currently available techniques appear independently accurate enough to quantify raised ICP, there is some promising work being undertaken.

The relationship between transorbital ultrasound measurement of the optic nerve sheath diameter (ONSD) and invasively measured ICP in children. : Part II: age-related ONSD cut-off values and patency of the anterior fontanelle.

PURPOSE: To analyse the diagnostic accuracy of age-related optic nerve sheath diameter (ONSD) cut-off values in children for detecting raised intracranial pressure (ICP) and to assess the benefit of using patency of the anterior fontanelle in describing a different set of cut-off values. METHODS: The ONSD measurement was performed prior to invasive ICP measurement in children under general anesthesia. The diagnostic accuracy of the ONSD measurement was compared to ICP at thresholds of 20, 15, 10, and 5 mmHg. This was further analysed in children above and below the age of 1 year, with a subgroup analysis of age at 4 years, and assessment of the anterior fontanelle (AF) as a reliable physiological marker in part II of this study. RESULTS: Data from 174 children were analysed. In children ≤1 year old, the ONSD measurement with the best diagnostic accuracy for detecting ICP ≥ 20 mmHg was 5.16 mm, compared to 5.75 mm in children >1 year old (p < 0.001). In addition, patency of the anterior fontanelle (AF) was found to be a useful clinical marker for defining different ONSD cut-off values at ICP thresholds of 20, 15, 10 and 5 mmHg. CONCLUSION: Transorbital ultrasound measurement of the ONSD is a reliable non-invasive marker of ICP particularly at higher thresholds of 20 and 15 mmHg. Patency of the AF is a useful clinical marker for defining different ONSD cut-off values in children.

The relationship between transorbital ultrasound measurement of the optic nerve sheath diameter (ONSD) and invasively measured ICP in children : Part I: repeatability, observer variability and general analysis.

PURPOSE: The aim of this study was to investigate the relationship between optic nerve sheath diameter (ONSD) measurement and invasively measured intracranial pressure (ICP) in children. METHODS: ONSD measurement was performed prior to invasive measurement of ICP. The mean binocular ONSD measurement was compared to the ICP reading. Physiological variables including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse rate, temperature, respiratory rate and end tidal carbon dioxide (ETCO2) level were recorded at the time of ONSD measurement. Diagnostic accuracy analysis was performed at various ICP thresholds and  repeatability, intra- and inter-observer variability, correlation between measurements in different imaging planes as well the relationship over the entire patient cohort were examined in part I of this study. RESULTS: Data from 174 patients were analysed. Repeatability and intra-observer variability were excellent (α = 0.97-0.99). Testing for inter-observer variability revealed good correlation (r = 0.89, p < 0.001). Imaging in the sagittal plane demonstrated a slightly better correlation with ICP (r = 0.66, p < 0.001). The ONSD measurement with the best diagnostic accuracy for detecting an ICP ≥ 20 mmHg over the entire patient cohort was 5.5 mm, sensitivity 93.2 %, specificity 74 % and odds ratio (OR) of 39.3. CONCLUSION: Transorbital ultrasound measurement of the OSND is a reliable and reproducible technique, demonstrating a good relationship with ICP and high diagnostic accuracy for detecting raised ICP.

Change in optic nerve sheath diameter as a radiological marker of outcome from endoscopic third ventriculostomy in children.

PURPOSE: The purpose of this study was to investigate the value of the change in optic nerve sheath diameter (ONSD) as a radiological marker of endoscopic third ventriculostomy (ETV) outcome in children. METHODS: Magnetic resonance imaging (MRI) scans of patients on whom ETVs were performed between the periods of January 2009 and June 2013 were reviewed. ONSD measurements on pre- and post-operative images were performed by two blinded observers, and the relationship between the change in these measurements and outcome from ETV were investigated. These findings were then also compared to conventional imaging features associated with ETV outcome. RESULTS: MRI scans of 24 patients were adequate to measure the ONSD pre- and post-operatively. In patients with successful ETV (n = 19), the mean change in ONSD was 0.73 mm and in patients with a failed ETV (n = 5), the mean change in ONSD was 0.18 mm (p = 0.0007). A change in ONSD of 7.5 % of the initial measurement demonstrated a sensitivity of 92.9 % and a sensitivity of 85.7 % for ETV outcome (area under the receiver operating characteristic curve (AUROC) = 0.96). CONCLUSION: Change in ONSD is a useful radiological marker of ETV outcome and may be used in combination with conventional radiological parameters to aid decision-making in this difficult group of patients.

Noninvasive intracranial pressure assessment by optic nerve sheath diameter: Automated measurements as an alternative to clinician-performed measurements.

Introduction: Optic nerve sheath diameter (ONSD) has shown promise as a noninvasive parameter for estimating intracranial pressure (ICP). In this study, we evaluated a novel automated method of measuring the ONSD in transorbital ultrasound imaging. Methods: From adult traumatic brain injury (TBI) patients with invasive ICP monitoring, bedside manual ONSD measurements and ultrasound videos of the optic nerve sheath complex were simultaneously acquired. Automatic ONSD measurements were obtained by the processing of the ultrasound videos by a novel software based on a machine learning approach for segmentation of the optic nerve sheath. Agreement between manual and automated measurements, as well as their correlation to invasive ICP, was evaluated. Furthermore, the ability to distinguish dichotomized ICP for manual and automatic measurements of ONSD was compared, both for ICP dichotomized at ≥20 mmHg and at the 50th percentile (≥14 mmHg). Finally, we performed an exploratory subgroup analysis based on the software's judgment of optic nerve axis alignment to elucidate the reasons for variation in the agreement between automatic and manual measurements. Results: A total of 43 ultrasound examinations were performed on 25 adult patients with TBI, resulting in 86 image sequences covering the right and left eyes. The median pairwise difference between automatically and manually measured ONSD was 0.06 mm (IQR -0.44 to 0.38 mm; p = 0.80). The manually measured ONSD showed a positive correlation with ICP, while automatically measured ONSD showed a trend toward, but not a statistically significant correlation with ICP. When examining the ability to distinguish dichotomized ICP, manual and automatic measurements performed with similar accuracy both for an ICP cutoff at 20 mmHg (manual: AUC 0.74, 95% CI 0.58-0.88; automatic: AUC 0.83, 95% CI 0.66-0.93) and for an ICP cutoff at 14 mmHg (manual: AUC 0.70, 95% CI 0.52-0.85; automatic: AUC 0.68, 95% CI 0.48-0.83). In the exploratory subgroup analysis, we found that the agreement between measurements was higher in the subgroup where the automatic software evaluated the optic nerve axis alignment as good as compared to intermediate/poor. Conclusion: The novel automated method of measuring the ONSD on the ultrasound videos using segmentation of the optic nerve sheath showed a reasonable agreement with manual measurements and performed equally well in distinguishing high and low ICP.

The frequency of cerebral ischemia/hypoxia in pediatric severe traumatic brain injury.

INTRODUCTION: The frequency of adverse events, such as cerebral ischemia, following traumatic brain injury (TBI) is often debated. Point-in-time monitoring modalities provide important information, but have limited temporal resolution. PURPOSE: This study examines the frequency of an adverse event as a point prevalence at 24 and 72 h post-injury, compared with the cumulative burden measured as a frequency of the event over the full duration of monitoring. METHODS: Reduced brain tissue oxygenation (PbtO(2) < 10 mmHg) was the adverse event chosen for examination. Data from 100 consecutive children with severe TBI who received PbtO(2) monitoring were retrospectively examined, with data from 87 children found suitable for analysis. Hourly recordings were used to identify episodes of PbtO(2) less than 10 mmHg, at 24 and 72 h post-injury, and for the full duration of monitoring. RESULTS: Reduced PbtO(2) was more common early than late after injury. The point prevalence of reduced PbtO(2) at the selected time points was relatively low (10 % of patients at 24 h and no patients at the 72-h mark post-injury). The cumulative burden of these events over the full duration of monitoring was relatively high: 50 % of patients had episodes of PbtO(2) less than 10 mmHg and 88 % had PbtO(2) less than 20 mmHg. CONCLUSION: Point-in-time monitoring in a dynamic condition like TBI may underestimate the overall frequency of adverse events, like reduced PbtO(2), particularly when compared with continuous monitoring, which also has limitations, but provides a dynamic assessment over a longer time period.

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination.

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.

Microbiomics in Collusion with the Nervous System in Carcinogenesis: Diagnosis, Pathogenesis and Treatment.

The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood-brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination.