Optic nerve sheath diameter correlates with both success and failure of hydrocephalus treatment in pediatric patients with pineal region lesions.

BACKGROUND: Pineal region lesions in children are heterogenous pathologies often symptomatic due to occlusive hydrocephalus and thus elevated intracranial pressure (ICP). MRI-derived parameters to assess hydrocephalus are the optic nerve sheath diameter (ONSD) as a surrogate for ICP and the frontal occipital horn ratio (FOHR), representing ventricle volume. As elevated ICP may not always be associated with clinical signs, the adjunct of ONSD could help decision making in patients undergoing treatment. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with pineal region lesions undergoing surgical treatment with respect to pre- and postoperative ONSD and FOHR as an indicator for hydrocephalus. METHODS: Retrospective data analysis was performed in all patients operated for pineal region lesions at a tertiary care center between 2010 and 2023. Only patients with pre- and postoperative MRI were selected for inclusion. Clinical data and ONSD at multiple time points, as well as FOHR were analyzed. Imaging parameter changes were correlated with clinical signs of hydrocephalus before and after surgical treatment. RESULTS: Thirty-three patients with forty operative cases met the inclusion criteria. Age at diagnosis was 10.9 ± 4.6 years (1-17 years). Hydrocephalus was seen in 80% of operative cases preoperatively (n = 32/40). Presence of hydrocephalus was associated with significantly elevated preoperative ONSD (p = 0.006). There was a significant decrease in ONSD immediately (p < 0.001) and at 3 months (p < 0.001) postoperatively. FOHR showed a slightly less pronounced decrease (immediately p = 0.006, 3 months p = 0.003). In patients without hydrocephalus, no significant changes in ONSD were observed (p = 0.369). In 6/6 patients with clinical hydrocephalus treatment failure, ONSD increased, but in 3/6 ONSD was the only discernible MRI change with unchanged FOHR. CONCLUSIONS: ONSD measurements may have utility in evaluating intracranial hypertension due to hydrocephalus in patients with pineal region tumors. ONSD changes appear to have value in assessing hydrocephalus treatment failure.

Retrospective longitudinal assessment of optic nerve sheath diameter in patients with malignant glioma.

INTRODUCTION: Glioblastoma (GBM) is a tumor with rapid growth and a possible relationship to elevated intracranial pressure (ICP). High ICP may not always be associated with clinical signs. A non-invasive technique for assessment of ICP is measuring the optic nerve sheath diameter (ONSD). Identifying patients who need immediate intervention is of importance in neuro-oncological care. The goal of this study is to assess the available magnetic resonance imaging (MRI) of patients with GBM with respect to pre- and postoperative ONSD. METHODS AND MATERIALS: Retrospective data analysis was performed on all patients operated for GBM at a tertiary care center between 2010 and 2020. Two pre and one postoperative MRI had to be available. Clinical data and ONSD at multiple time points were analyzed and correlated, as well as preoperative volumetrics. RESULTS: Sixty-seven patients met the inclusion criteria. Clinical signs of elevated ICP were seen in 25.4% (n = 17), while significant perifocal edema was present in 67.2% (n = 45) of patients. Clinical signs of preoperatively elevated ICP were associated with significantly elevated ONSD at diagnosis (p < 0.001) as well as preoperative tumor volume (p < 0.001). Significant perifocal edema at the time of diagnosis was associated with elevated ONSD (p = 0.029) and higher tumor volume (p = 0.003). In patients with significant edema, ONSD increased significantly between preoperative MRIs (p = 0.003/005). In patients with clinical signs of raised ICP, ONSD also increased, whereas it was stable in asymptomatic patients (yes: 5.01+/-4.17 to 5.83+/-0.55 mm, p = 0.010, no: 5.17+/-0.46 mm to 5.38+/-0.41 mm, p = 0.81). A significant increase of ONSD from diagnosis to preoperative MRI and a significant decrease until 3 months postoperatively were observed (p < 0.001). CONCLUSIONS: ONSD might help identify high ICP in patients with GBM. In this first-of-its kind study, we observed a significant increase of ONSD preoperatively, likely associated with edema. Postoperatively, ONSD decreased significantly until 3 months after surgery and increased again at 12 months. Further prospective data collection is warranted.

Monitoring of cerebrovascular pressure reactivity in children may predict neurologic outcome after hypoxic-ischemic brain injury.

OBJECTIVES: Impaired cerebral blood flow is a first-line reason of ischemic-hypoxic brain injury in children. The principal goal of intensive care management is to detect and prevent further cerebral blood flow deficits. This can be achieved by actively managing cerebral perfusion pressure (CPP) using input from cerebrovascular autoregulation (CAR). The main objective of the current study was to investigate CAR after cardiac arrest in children. METHODS: Nineteen consecutive children younger than 18 years after cardiopulmonary resuscitation, in whom intracranial pressure (ICP) was continuously measured, were included. Blood pressure and ICP were continuously monitored via ICM + software and actively managed using the pressure reactivity index (PRx) to achieve and maintain an optimal CPP. Outcome was scored using the extended Glasgow outcome scale (eGOS) at discharge and 6 months. RESULTS: Eight children died in hospital. At 6 months, further 4 children had an unfavorable (eGOS1-4) and 7 a favorable (eGOS5-8) outcome. Over the entire monitoring period, we found an elevated ICP (24.5 vs 7.4 mmHg), a lower CPP (50.3 vs 66.2 mmHg) and a higher PRx (0.24 vs - 0.01), indicating impaired CAR, in patients with unfavorable outcome. The dose of impaired autoregulation was significantly higher in unfavorable outcome (54.6 vs 29.3%). Analyzing only the first 72 h after cardiac arrest, ICP ≥ 10 mmHg and PRx > 0.2 correlated to unfavorable outcome. CONCLUSIONS: Significant doses of impaired CAR within 72 h after resuscitation are associated with unfavorable outcome. The inability to restore autoregulation despite active attempts to do so as well as an elevated ICP may serve as a bad prognostic sign indicating a severe initial hypoxic-ischemic brain injury.

Comparison of B-Scan Ultrasound and MRI-Based Optic Nerve Sheath Diameter (ONSD) Measurements in Children.

BACKGROUND: Qualitative, noninvasive assessment of intracranial pressure is of eminent importance in pediatric patients in many clinical situations and can reliably be performed using transorbital ultrasonographic measurement of the optic nerve sheath diameter (ONSD). MRI-based determination of ONSD can serve as an alternative if ultrasound (US) is not possible or available for various reasons, for example, in small, incompliant children. This study investigates repeatability and observer reliability of US ONSD and correlation and bias of US- versus MRI-based ONSD assessment in pediatric patients. METHODS: One hundred fifty children diagnosed with tumor (n = 40), hydrocephalus (n = 42), and other cranial pathologies (n = 68) were included. Bilateral ONSD was quantified by US using a 12-MHz linear array transducer. This was compared with ONSD measured in simultaneously acquired (≤24 h) T2-weighted MRI scans of the orbit. RESULTS: Repeatability of individual US values and intraobserver ONSD was outstanding (Cronbach's α = 0.984 and 0.996, respectively). Overall mean values for ONSD were 5.8 ± 0.88 mm and 5.7 ± 0.89 mm for US and MRI, respectively. Correlation between US and MRI-based ONSD was strong (r = 0.976, P < 0.01). Bland and Altman analysis showed a mean bias of 0.078 mm. A repeated-measures correlation (rrm) in 9 patients showed an excellent value (rrm = 0.94, P < 0.01). CONCLUSIONS: Repeatability and reliability of US ONSD determination is excellent. In case US ONSD assessment is not possible or available, MRI scans can serve as an excellent alternative. The difference of US and MRI ONSD is minimal and insignificant, and thus, both techniques can complement each other.

Semantic segmentation of cerebrospinal fluid and brain volume with a convolutional neural network in pediatric hydrocephalus-transfer learning from existing algorithms.

BACKGROUND: For the segmentation of medical imaging data, a multitude of precise but very specific algorithms exist. In previous studies, we investigated the possibility of segmenting MRI data to determine cerebrospinal fluid and brain volume using a classical machine learning algorithm. It demonstrated good clinical usability and a very accurate correlation of the volumes to the single area determination in a reproducible axial layer. This study aims to investigate whether these established segmentation algorithms can be transferred to new, more generalizable deep learning algorithms employing an extended transfer learning procedure and whether medically meaningful segmentation is possible. METHODS: Ninety-five routinely performed true FISP MRI sequences were retrospectively analyzed in 43 patients with pediatric hydrocephalus. Using a freely available and clinically established segmentation algorithm based on a hidden Markov random field model, four classes of segmentation (brain, cerebrospinal fluid (CSF), background, and tissue) were generated. Fifty-nine randomly selected data sets (10,432 slices) were used as a training data set. Images were augmented for contrast, brightness, and random left/right and X/Y translation. A convolutional neural network (CNN) for semantic image segmentation composed of an encoder and corresponding decoder subnetwork was set up. The network was pre-initialized with layers and weights from a pre-trained VGG 16 model. Following the network was trained with the labeled image data set. A validation data set of 18 scans (3289 slices) was used to monitor the performance as the deep CNN trained. The classification results were tested on 18 randomly allocated labeled data sets (3319 slices) and on a T2-weighted BrainWeb data set with known ground truth. RESULTS: The segmentation of clinical test data provided reliable results (global accuracy 0.90, Dice coefficient 0.86), while the CNN segmentation of data from the BrainWeb data set showed comparable results (global accuracy 0.89, Dice coefficient 0.84). The segmentation of the BrainWeb data set with the classical FAST algorithm produced consistent findings (global accuracy 0.90, Dice coefficient 0.87). Likewise, the area development of brain and CSF in the long-term clinical course of three patients was presented. CONCLUSION: Using the presented methods, we showed that conventional segmentation algorithms can be transferred to new advances in deep learning with comparable accuracy, generating a large number of training data sets with relatively little effort. A clinically meaningful segmentation possibility was demonstrated.

Changes of third ventricle diameter (TVD) mirror changes of the entire ventricular system at acute shunt failure and after shunt revision in pediatric hydrocephalus.

PURPOSE: In hydrocephalic children, regular investigations of the ventricles are important for initial diagnosis and after initial treatment. Our recent study showed that changes of the third ventricle diameter (TVD) reliably reflect changes of the entire ventricular system at diagnosis and following initial therapy. This study compares changes of TVD with changes of ventricle indices at acute shunt failure and after shunt revision in hydrocephalic children. METHODS: A total of 117 children with hydrocephalus were included in this study. MRI/CT images of 30 children were evaluated at the time of acute shunt dysfunction and after subsequent shunt revision. Measurements included axial TVD and three standard measures of lateral ventricles (Evans index, frontal occipital horn ratio (FOHR), and cella media index (CMI)). In 97 children, correlation between axial and coronal/diagonal TVD was evaluated at the time of initial diagnosis of hydrocephalus. RESULTS: At acute shunt dysfunction, the best linear correlation was found between TVD and CMI (r = 0.702, p < 0.01). Changes of TVD correlated very well to changes of FOHR (r = 0.74, p < 0.01) after shunt revision. The correlation between axial and coronal/diagonal TVD was outstanding (r = 0.995, p < 0.01). CONCLUSION: TVD showed a significant correlation with all lateral ventricle indices at acute shunt dysfunction and after shunt revision. It is therefore not only an excellent mirror of ventricular changes at initial hydrocephalus diagnosis and therapy, but it can also reliably reflect changes of the ventricular system in relevant clinical situations associated with the lifelong treatment of pediatric hydrocephalus.

The relation of optic nerve sheath diameter (ONSD) and intracranial pressure (ICP) in pediatric neurosurgery practice - Part I: Correlations, age-dependency and cut-off values.

PURPOSE: It is assumed that the width of the optic nerve sheath diameter (ONSD) is dependent on intracranial pressure (ICP) and pulsatility and thus constitutes a non-invasively accessible "window" for qualitative assessment of ICP. Data on the correlation to invasively measured ICP in children are scarce and have often been obtained from sedated patients in intensive care unit (ICU) or intraoperatively. We report on a mixed cohort of pediatric neurosurgical patients, ICP and ONSD measurements were available from both sedated and awake children, only a minority from ICU patients. METHODS: Seventy-two children were investigated. Ultrasound ONSD determination was performed immediately prior to invasive ICP measurement and the mean binocular ONSD was compared with ICP. The investigations were performed in children awake, sedated, or under general anesthesia. RESULTS: In the entire patient cohort, the correlation between ONSD and ICP was good (r = 0.52, p < 0.01). Children > 1 year revealed a better correlation (r = 0.63; p < 0.01) and those ≤ 1 year did worse (r = 0.21). Infants with open fontanelle had no correlation. In the entire cohort, the best ONSD cut-off value for detecting ICP ≥ 15 and ≥ 20 mmHg was 5.28 and 5.57 mm (OR 22.5 and 7.2, AUC 0.782 and 0.733). CONCLUSION: Transorbital ultrasound measurement of ONSD is a reliable non-invasive technique to assess increased ICP in children in every clinical situation; however, the impact of age and fontanelle status needs to be considered. ONSD thresholds enable qualitative first orientation regarding ICP categories with a very satisfying diagnostic accuracy.

The relation of optic nerve sheath diameter (ONSD) and intracranial pressure (ICP) in pediatric neurosurgery practice - Part II: Influence of wakefulness, method of ICP measurement, intra-individual ONSD-ICP correlation and changes after therapy.

PURPOSE: Previous studies correlating ultrasound (US)-based optic nerve sheath diameter (ONSD) and intracranial pressure (ICP) in children were performed under general anesthesia. To apply ONSD in daily clinical routine, it is necessary to investigate patients awake. It is furthermore essential for ICP-assessment with ONSD to know if ONSD-ICP correlation varies within individuals. In this study, we report on the influence of wakefulness, method of ICP measurement, intraindividual correlations, and dynamic changes of ONSD and ICP after ICP decreasing therapy. METHODS: The overall study included 72 children with a median age of 5.2 years. US ONSD determination was performed immediately prior to invasive ICP measurement, and the mean binocular ONSD was compared to ICP. In 10 children, a minimum of 3 ONSD/ICP measurements were performed to investigate a correlation within subjects. In 30 children, measurements were performed before and after therapy. RESULTS: Twenty-eight children were investigated awake with an excellent correlation of ONSD and ICP (r = 0.802, p < 0.01). In 10 children, at least three simultaneous ONSD and ICP measurements were performed. The intraindividual correlations were excellent (r = 0.795-1.0) however with strongly differing individual regression curves. The overall correlation within subjects was strong (r = 0.78, p < 0.01). After ICP decreasing therapy, all ONSD values decreased significantly (p < 0.01); however, there was no correlation between ∆ICP and ∆ONSD. CONCLUSION: Awake investigation does not impair the correlation between ONSD and ICP. Even if there is a good overall ONSD-ICP correlation, every individual has its own distinctive and precise correlation line. The relationship between ONSD and ICP is furthermore not uniform between individuals. Strong ICP decreases can lead to smaller ONSD changes and vice versa. This should be kept in mind when using this technique in the clinical daily routine.

Planar single plane area determination is a viable substitute for total volumetry of CSF and brain in childhood hydrocephalus.

BACKGROUND: In the treatment of childhood hydrocephalus, 3D volumetry seems to have many advantages over classical planar index measurements for dedicated monitoring of changes in cerebrospinal fluid and brain volume. Nevertheless, this method requires extensive technical effort and access to the complete three-dimensional data set. Against this background, we evaluated the possibility of planar area determination in a single plane and the correlation to volumetry. METHODS: 138 routinely performed true FISP MRI sequences (1 mm isovoxel) were analyzed retrospectively in 68 patients with pediatric hydrocephalus. After preprocessing, the 3D-data sets were skull stripped to estimate the inner skull volume. A 2-class segmentation into different tissue types (brain matter and CSF) was performed, and the volumes of CSF (VCSF) and brain matter (VBrain) were calculated. A plane at the level of the foramina of Monro was manually identified in the ac-pc oriented data. In this plane, the areas of brain (ABrain) and CSF (ACSF) in cm2 were calculated and used for further correlation analysis. RESULTS: Mean VCSF was 340 ± 145 cm3 and VBrain 1173 ± 254 cm3. In the selected plane, ACSF was 26 ± 14 cm2, and ABrain was 107 ± 25 cm2. There was a very strong positive correlation between both ACSF and VCSF (r = 0.895) and between ABrain and VBrain (r = 0.846). The prediction equations for VBrain and VCSF were highly significant. CONCLUSION: Planar area determination of brain and CSF correlates excellently with both VCSF and VBrain. Thus, areas can serve as a surrogate marker for total brain and CSF volumes for a quantitated objective tracking of changes during treatment of childhood hydrocephalus.

Automatic volumetry of cerebrospinal fluid and brain volume in severe paediatric hydrocephalus, implementation and clinical course after intervention.

BACKGROUND: In childhood hydrocephalus, both the amount of cerebrospinal fluid and the brain volume are relevant for the prognosis of the development and for therapy monitoring. Since classical planar measurements of ventricular size are subject to strong limitations, imprecise and neglect brain volume, 3D volumetry is most desirable. We used and evaluated the robust segmentation algorithms of the freely available FSL-toolbox in paediatric hydrocephalus patients before and after specific therapy. METHODS: Retrospectively 76 pre- and postoperative high-resolution T2-weighted MRI sequences (true FISP, 1 mm isovoxel) were analyzed in 38 patients with paediatric hydrocephalus (mean 4.4 ± 5.1 years) who underwent surgical treatment (ventriculo-peritoneal (VP) shunt n = 22, endoscopic third ventriculostomy (ETV) n = 16). After preprocessing, the 3D-datasets were skull stripped to estimate the inner skull surface. Following, a 2 class segmentation into different tissue types (brain matter and CSF) was performed. The volumes of CSF and brain were calculated. RESULTS: The method could be implemented in an automated fashion in all 76 MRIs. In the VP shunt cohort, the amount of CSF (p < 0.001) decreased. Consecutively brain volume increased significantly (p < 0.001). Following ETV, CSF volume (p = 0.019) decreased significantly (p = 0.012) although the reduction was less pronounced than after shunt implantation. Brain volume expanded (p = 0.02). CONCLUSION: A reliable automated segmentation of CSF and brain could be performed with the implemented algorithm. The method was able to track changes after therapy and detected significant differences in CSF and brain volumes after shunting and after ETV.

Transtemporal Ultrasound (US) Assessment of Third Ventricle Diameter (TVD): Comparison of US and MRI TVD in Pediatric Patients.

INTRODUCTION: In a retrospective magnetic resonance imaging (MRI)-based study, we showed that changes of the third ventricle diameter (TVD) are a reliable mirror of changes of the entire ventricular system. The third ventricle is easily accessible in more than 90% of children and adults using ultrasound (US) via the transtemporal bone-window; thus it can be assessed quickly and free of radiation. In order to use transtemporal US determination of TVD instead of MRI/CT in clinical practice, it is important to know if there is a correlation and bias between both methods, which is addressed in this study. MATERIALS AND METHOD: This prospective study investigates 122 children (newborn-18 years). Diagnoses encompassed hydrocephalus (50%), tumors (14.8%), and other intracranial pathologies (35.2%). US-based TVD was measured via the transtemporal bone-window using a phased array 1 to 4MHz transducer. Results were compared with TVD measured on simultaneously acquired axial T1-weighted axial MRI or computed tomography (CT) scans. RESULTS: Overall mean values for TVD were 6.56 ± 5.84 and 6.47 ± 5.64 mm for US and MRI, respectively. There was an outstanding correlation between TVD measured by MRI and US (r = 0.991, p < 0.01). Bland-Altman analysis showed a mean bias of 0.096 mm with limits of agreement of -0.99 and 1.18 mm. CONCLUSION: US- and MRI-based TVD measurements correlate excellently and measure almost identical TVD values. US-based TVD is in mean ∼0.096 mm larger than MRI-based TVD due to a more angulated measurement plane. US is equal to the gold-standard MRI, a fact, opening new avenues for US-based TVD as a first-line assessment tool of ventricular width.

Changes of third ventricle diameter (TVD) mirror changes of the entire ventricular system after initial therapy and during follow-up in pediatric hydrocephalus.

PURPOSE: Regular measurement of ventricular size is important in children with hydrocephalus. After closure of the fontanelle this is currently addressed by repetitive cranial MRI or CT imaging, coming along with risks of anaesthesia or radiation. As the third ventricle is accessible via the temporal bone window using ultrasound, determination of its diameter might be an easy and radiation-free alternative to assess the ventricular system. An essential precondition is that changes of the third ventricle diameter (TVD) mirror changes of the whole ventricular system. This study compares changes of TVD with changes of ventricular indices before and after initial treatment of hydrocephalus and during the following evolution. METHODS: MRT/CT images from 117 children with hydrocephalus were evaluated at time of diagnosis, after initial therapy and during follow-up with functional shunts. Measurements included axial TVD and three standard linear measures of the lateral ventricles (Evans Index - EI, fronto-occipital horn ratio - FOHR Index, and Cella Media Index - CMI). Furthermore, a correlation within subjects was calculated in 8 patients over the entire available follow-up. RESULTS: Relative changes of TVD were significantly correlated to relative changes of all ventricular indices (r = 0.48, r = 0.68 and r = 0.701 for EI, FOHR and CMI, respectively, p < 0.01). The correlation within subjects was outstanding for EI (r = 0.988), FOHR (r = 0.99) and CMI (r = 0.99). CONCLUSION: TVD showed a significant correlation with all three linear indices at the time of diagnosis and during follow-up changes independently of age, aetiology and ventricular width. TVD and its changes are therefore a reliable surrogate of changes in ventricular size in pediatric hydrocephalus undergoing treatment.

Cerebro-venous hypertension: a frequent cause of so-called "external hydrocephalus" in infants.

INTRODUCTION: External hydrocephalus (eHC) is commonly defined as a subtype of infant "hydrocephalus" consisting of macrocepahly associated with enlarged subarachnoid space and no or mild ventriculomegaly. This status is thought to be related to impaired CSF absorption because of arachnoid villi immaturity. However, other factors like the venous system might be involved in the development of the clinical picture. METHODS: All patients diagnosed with eHC received prospectively contrast-enhanced 3D MR phlebography. Venous sis abnormalities were graded depending on the number of affected sinus segments and type. External CSF space volume was quantified planimetrically. RESULTS: Seventeen patients with the typical clinical feature of eHC were included. In 15, venous sinus abnormalities were found. There was a significant correlation between the volume of the widened cortical subarachnoid space (CSAS) and the number of venous sinus segments affected. Conversely, ventricular volume was not correlated. CONCLUSION: These results support the hypothesis that impaired venous outflow plays a major role in external hydrocephalus development. Raised venous pressure increases intracranial pressure accelerating head growth, resulting in an enlargement of the cortical subarachnoid space. Increased venous pressure increases the capillary bed pressure and brain turgor preventing ventricular space to enlarge forcing displacement of ventricular CSF to the subarachnoid space. As a result, ventriculomegaly is rarely found. The descriptive term "external hydrocephalus" implying a primary etiology within the CSF system is misleading and this work supports the notion that venous hypertension is the leading cause of the clinical picture.

Fibrolipomatous hamartomas of the median nerve in infancy and early childhood-imaging hallmarks, symptomatology, and treatment.

A fibrolipomatous hamartoma (FLH) is a rare lesion leading to an enlargement of the affected nerve and commonly manifests at the median nerve. Symptomatic patients are mostly adolescents or adults. In children below 10 years, this entity is rather unknown and likely to be misdiagnosed. We report three children with FLH, two severely and one mildly symptomatic, all below 4 years of age at the time of first presentation. Two of three children were initially misdiagnosed. We provide a review of the pertinent clinical and radiological findings of the entity. Two patients had a characteristic macrodactyly. The two symptomatic children underwent surgical carpal tunnel decompression. The intervention relived their symptoms with a long-lasting effect. Surgical reduction of the hamartoma mass is not indicated and medical treatment non-existent. CONCLUSION: A symptomatic FLH of the median nerve is rare in children below the age of 5 years but has to be kept in mind as differential diagnosis in case of wrist and/or palm swelling, macrodactyly, and pain in hand or forearm. MRI is diagnostic, with very characteristic features, which can also be identified in high-resolution nerve ultrasound. This article aims to increase the knowledge about the entity including the diagnostic features and the management options. What is Known: • Fibrolipomatous hamartomas (FLHs) of the median nerve are rare, possibly associated with macrodactyly and tissue growth at the wrist and thenar side of the palm. • An associated carpal tunnel syndrome typically occurs, if at all, in adulthood. What is New: • We describe two children below 4 years with symptomatic carpal tunnel syndrome, experiencing a long-lasting favorable outcome after carpal tunnel decompression. In this age group, only one other child undergoing surgery has been published so far. • MRI and high-resolution ultrasound demonstrate the characteristic features of FLHs and are the diagnostic modalities of choice. Biopsy is not recommended.