We would like to thank the radiology technicians and nurses&#8217;staff of the Neuroradiology Area, IRCCS Istituto delle Scienze Neurologiche di Bologna, and their Coordinator Dr. Maria Grazia Crepaldi, for their collaboration.

The protocol is following the Local Research Committee&#39;s ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
1. Selection of the patients
<ol>
	<li>Adopt the following inclusion criteria: patients older than 18 years old, fully collaborating, presenting a tumor of the skull base, or pituitary-diencephalic region.</li>
	<li>Exclude patients with contraindication to MRI (i.e., a pacemaker or ferromagnetic material) or presentin...

The application of the presented protocol resulted in a safe and effective treatment of one of the most challenging intracranial tumors such as a craniopharyngioma invading the 3rd ventricle, possibly opening up a new horizon for a lesion that was defined by H. Cushing about a century ago as the most baffling intracranial neoplasm1. The combination of accurate preoperative planning, integrating advanced MRI techniques, and multidisciplinary clinical assessments have permitted us to tail...

The possibility to approach the skull base midline and paramedian regions through an anterior route, adopting the nasal fossae as natural cavities, has a long history, dating back more than one century1. However, in the last 20 years, the visualization and operative technologies have improved enough to expand their possibility of including the treatment of the most complex tumors such as meningiomas, chordomas, chondrosarcomas, and craniopharyngiomas1 due to the (1) introduction of the endoscope, which gives a panoramic and detailed 2D/3D view of these regions to the surgeon, (2) the development of intraoperative neuronavigation systems, and (3) the implementation of dedicated surgical instruments. As painstakingly demonstrated by Kassam et al. and confirmed by multiple reviews and meta-analyses, the advantages of this surgical approach are mainly represented by its chances to resect challenging skull base tumors, avoiding any direct brain retraction or nerve manipulation, thus reducing the risk of surgical complications and long-term neurological and visual sequelae2,3,4,5,6,7,8,9,10,11,12.
For multiple skull base and pituitary-diencephalic tumors, the ideal surgical goal has changed in the last years from the most extensive tumor removal possible to the safest removal with preservation of the neurological functions to preserve the patient&#39;s quality of life3. This limitation could be compensated by innovative and effective adjuvant treatments, such as radiation therapy (adopting massive particles such as proton or carbon ions when appropriate) and, for selected neoplasms, by chemotherapy as inhibitors of the BRAF/MEK pathway for the craniopharyngiomas13,14,15.
However, to pursue these goals, a careful preoperative assessment is crucial, to tailor the surgical strategy to each case&#39;s specific feature2. In most centers, the MRI preoperative protocol is usually performed only with standard structural sequences, which provide the morphological characterization of the lesion. However, with these techniques it is not always possible to assess the anatomical relationship of the tumor with adjacent structures reliably3. Moreover, each patient may present different pathology-induced functional reorganization profiles detectable only with diffusion MRI tractography and functional MRI (fMRI), which can be used to provide guidance both in the surgery planning and in the intraoperative steps16,17.
Currently, fMRI is the most commonly used neuroimaging modality for mapping brain functional activity and connectivity, as guidance for surgical planning18,19 and to improve the patients&#39; outcome20. Task-based fMRI is the modality of choice to identify &#34;eloquent&#34; brain regions that are functionally involved in specific task performance (e.g., finger tapping, phonemic fluency), but is not applicable for the study of skull base tumors.
Diffusion MRI tractography permits in vivo and noninvasive reconstruction of white matter brain connections as well as cranial nerves, investigating the brain hodological structure21. Different tractography algorithms have been developed to reconstruct axonal pathways by linking water molecule diffusivity profiles, evaluated within each brain voxel. Deterministic tractography follows the dominant diffusivity direction, whereas probabilistic tractography evaluates possible pathways&#39; connectivity distribution. Additionally, different models can be applied to evaluate diffusivity within each voxel, and it is possible to define two main categories: single fiber models, such as the diffusion tensor model, where a single fiber orientation is evaluated, and multiple-fiber models, such as spherical deconvolution, where several crossing-fiber orientations are reconstructed22,23. Despite the methodological debate about diffusion MRI tractography, its utility in the neurosurgical workflow is currently established. It is possible to evaluate white matter tract dislocation and distance to the tumor, preserving specific white matter connections. Moreover, diffusion tensor imaging (DTI) maps, especially fractional anisotropy (FA) and mean diffusivity (MD), can be applied to assess microstructural white matter alterations related to possible tumor infiltration and for longitudinal tract monitoring. All these features make diffusion MRI tractography a powerful tool both for pre-surgical planning and intra-operative decision making through neuronavigation systems24.
However, the application of tractography techniques to skull base surgery has been limited by the need for specialized technical knowledge and the time-consuming work-up to optimize diffusion MRI sequence acquisition, analysis protocol, and incorporating tractography results in neuronavigation systems25.Finally, further limitations are due to the technical difficulties extending these analyses from intraparenchymal to extra-parenchymal white matter structures, as cranial nerves. Indeed, only recent studies presented preliminary results attempting to integrate advanced MRI and skull base surgery26,27,28.
The present paper presents a protocol for the multidisciplinary management of pituitary-diencephalic and skull base tumors using diffusion MRI tractography. The implementation of this protocol in the institution resulted from the collaboration between neurosurgeons, neuro-endocrinologists and the neuroimaging team (including clinical and bioinformatics expertise) to offer an effective integrated multi-axial approach to these patients.
In the center, we have integrated multidisciplinary protocols for managing patients with skull base tumors, to provide the most informative description possible, and to tailor and personalize the surgical plan. We show that this protocol can be adopted both in the clinical and the research setting for any patient with a skull base tumor to guide the treatment strategy and to improve the knowledge on the brain modifications induced by these lesions.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>BRAF V600E-specific clone VE1</td>
			<td>Ventana</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Dural Substitute</td>
			<td>Biodesign, Cook Medical</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Endoscope</td>
			<td>Karl Storz, 4mm in diameter, 18 cm in length, Hopkins II &#8211; Karl Storz Endoscopy</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Immunohistochemical staining instrument&#160;</td>
			<td>Ventana Benchmark, Ventana Medical Systems</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>MRI</td>
			<td>3T Magnetom Skyra, Siemens Health Care</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Neuronavigator</td>
			<td>Stealth Station S8 Surgical Navigation System, MEDTRONIC</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

role of diffusion mri tractography in endoscopic endonasal skull base surgery

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of benign and malignant lesions through a natural anatomical extra-cranial pathway, represented by the nasal cavities, avoiding brain retraction and neurovascular manipulation. This is reflected by the patients' prompt clinical recovery and the low risk of permanent neurological sequelae, representing the main caveat of conventional skull base surgery. This surgery must be tailored to each specific case, considering its features and relationship with surrounding neural structures, mostly based on preoperative neuroimaging. Advanced MRI techniques, such as tractography, have been rarely adopted in skull base surgery due to technical issues: lengthy and complicated processes to generate reliable reconstructions for inclusion in the neuronavigation system. 
This paper aims to present the protocol implemented in the institution and highlights the synergistic collaboration and teamwork between neurosurgeons and the neuroimaging team (neurologists, neuroradiologists, neuropsychologists, physicists, and bioengineers) with the final goal of selecting the optimal treatment for each patient, improving the surgical results and pursuing the advancement of personalized medicine in this field.

A 55-year-old woman presented with progressive visual deficits. Her medical history was unremarkable. On ophthalmological evaluation, bilateral reduction of visual acuity (6/10 in the right eye and 8/10 in the left eye) was revealed, and the computerized visual field showed complete bitemporal hemianopia. No further deficits were evident on neurological examination, but the patient reported persistent asthenia and an increase in hunger and thirst sensation in the previous 2-3 months, with...

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Role of Diffusion MRI Tractography in Endoscopic Endonasal Skull Base Surgery

We present a protocol to integrate diffusion MRI tractography in patient work-up to endoscopic endonasal surgery for a skull base tumor. The methods for adopting these neuroimaging studies in the pre- and intra-operative phases are described.

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of ...

Using an integrated neuroimaging and neurosurgery protocol, it is possible to merge different expertise in a synergic framework to tailor a patient-specific tumor resection surgery. Using MRI tractography, it is possible to visualize white matter tract dislocation and tumor distance. Its versatility in glioma surgery has been established and can also be applied in drug-resistant focal epilepsy.The integration of advanced neuroimaging techniques in endoscopic endonasal surgery for pituitary, diencephalic, and skull-based tumors is effective at increasing surgical safety, reducing the complications, and improving patient outcomes and quality of life. MRI tractography combined with task fMRI allows the monitoring of brain structural and functional reorganization after surgery. In addition, correlation with clinical outcomes are useful for clinical and research proposals.Both endoscopic endonasal surgery and advanced neuroimaging require a long training period. We suggest an observership or a fellowship in academic tertiary referral centers at which these techniques are being implemented. Through visible demonstration, it's possible to make the steps of this method that have not been standardized yet and to clarify how to integrate different expertise.Using a standardized multimodal MRI protocol high-field scanner, acquire high resolution and volumetric anatomical sequences using T1-weighted pre and post-gadolinium contrast agent administration and FLAIR T2-weighted imaging. Acquire continuous sagittal slices providing an isotropic resolution of a one by one by one cubic millimeter scanning time of about five minutes per sequence. Acquire a high-resolution T2-weighted sequence to localize the tumor area for cranial nerve visualization with the volumetric constructive interference and steady-state voxel dimension of 0.5 by 0.5 by 0.5 cubic millimeters and a scanning time of about nine minutes.Acquire diffusion-weighted sequences using single shot echo planar images, a two by two by two cubic millimeter voxel dimension, 64 magnetic gradient directions with a 2, 000 second per square millimeter B value, 98 millisecond echo time, and 4, 300 millisecond relaxation time. Acquire five volumes with a null B value at the beginning of the diffusion-weighted acquisition with the phase encoding direction set to anterior-posterior and a scanning time of five minutes. Then acquire three volumes with a null B value, but reversed posterior-anterior phase encoding direction to correct any imaging distortions due to the echo planar image acquisition and a scanning time of 42 seconds.Continuous near axial slices will be acquired. For segmentation of the tumor, load the images into the ITK-SNAP software and inspect the tumor in the t1. nii, flair.nii, and t1_contrast. nii images. Then select the anatomical plane to follow when drawing the lesion.For tractographic analysis of the segmented tumor, run the fsl-dtifit function to model diffusivity in the different spatial directions and obtain the fa. nii, md. ii, and v1.nii diffusion tensor maps. Evaluate the diffusion tensor imaging maps to assess any abnormal diffusivity values that may occur in the presence of tumor edema or infiltration and select the seed_image and include options based on a priori anatomical knowledge to adopt a seed target approach. Then manually draw regions of interest to set the seed or target for tractography.For an accurate description of the diffusion tensor imaging parameters, use long tract algorithm such as the MATLAB-based algorithm that model the surface tract geometry with the Laplacian operator properties. To visualize the 3D volume rendering, in the Surf Ice software, click file and open in the command panel and select the obj file. Before scheduling the procedure, perform a neurological physical examination with a collection of anamnestic information about weight gain, the sensation of hunger, continuous monitoring of the rectal temperature every two minutes for 24 hours, and a 24-hour sleep/wake cycle recording.Based on the results of tumor segmentation and the relationship with the functional eloquent neural structures, discuss the patient candidacy for surgery in a collegial team meeting to determine the most appropriate surgical approach. After selecting the surgical corridor with the most minimal risk of injury to the neural structures, define the safe resection area for each case, localizing the critical neural structure under which the proximity the resection must be arrested to avoid permanent damage. Then merge the most relevant MRI sequences and import the sequences, including the tractography reconstructions, into the operative phase neuro navigation system.Before beginning the procedure, select the brain surgery electromagnetic registration modality. Register the neuro navigation system on the patient, adopting a free tracking technique or external markers and control the accuracy of the achieved registration, checking the position of the external markers on the imported MRI. When the patient is ready, use a zero degree endoscope to harvest the nasoseptal flap.Next, perform an anterior sphenoidectomy and a posterior septostomy and ethmoidectomy, preserving the middle turbinate as possible. Open the cellar and tuberculum bones. After coagulation of the superior intracavernous sinus, make an H-shaped incision in the dura layer.Leave the tumor by the arachnoidal plane and centrally de-bulk the tumor. Remove the tumor capsule from the surrounding diencephalic neural structures and use angled optics to explore the surgical cavity for any remaining pieces of tumor. When all of the tumor has been removed, use an intradural intracranial layer of dural substitute to close the osteo-meningeal opening.Then place an extradural intracranial layer of dural substitute scaffolded with abdominal fat and eventually bone and cover the closure with the nasoseptal flap. In this representative patient, brain MRI revealed a suprasellar tumor occupying the optochiasmatic cistern and invading the third ventricle with an irregular polycystic morphology. The optic pathway tractography and bilateral optic cranial nerves were reconstructed, but susceptibility artifacts within the interface between the brain bones and blood vessels did not allow a complete reconstruction of the fibers connecting the optic chiasm to the optic nerves.Investigation of the pyramidal tract diffusivity profile and a long tract diffusion tensor imaging map statistics showed the presence of a focal FLAIR T2-weighted hyperintensity at the level of the right posterior limb of the internal capsule, corresponding to a 5%increase of the right mean diffusivity measure compared to the left side. Using an endoscopic endonasal extended transplant transtuberculum approach, the tumor was centrally de-bulked in conjunction with the draining of its cystic component. The craniopharyngioma was then able to be progressively detached from the neural structures to adopt the arachnoid as a cleavage plane.At the end of the surgery, complete tumor removal with preservation of the hypothalamic anatomy was achieved. The repair of the osteo-dural defect was then performed using abdominal fat and the nasoseptal flap. Three months after the surgery, a complete tumor removal with no remnant or recurrence was observed.In the preoperative workup, the most relevant steps are:an accurate diffusion-weighted sequences acquisition and tumor segmentation. During surgery, the key point is an accurate identification of the neural structures. The visualization of the neural structures provided by this method can be adopted for all skull-based regions, reducing the risk of permanent disabilities for many other tumors.The tractographic reconstruction of cranial nerves and neuro pathways can facilitate our understanding of the relationship between tumors and the structures, potentially providing an innovative outcome predictor for patient symptoms.

Role of Diffusion MRI Tractography in Endoscopic Endonasal Skull Base Surgery

Abstract