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 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.
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'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'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' outcome20. Task-based fMRI is the modality of choice to identify "eloquent" 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' 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.
The protocol is following the Local Research Committee's ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
1. Selection of the patients
2. Preparation for the MRI exam
3. Positioning of the patient in the scanner
4. Brain MRI protocol setting and acquisition parameters
5. Brain MR images pre-processing
6. Tumor segmentation
7. Tractography analysis
8. Tractography: along-tract analysis
9. 3D-rendering visualization
10. Preoperative clinical examinations
11. Surgical planning
12. Surgery preparation
13. Endoscopic endonasal surgery
14. Histological examination
15. Post-surgical patient management
16. Early follow-up
17. Adjuvant therapy
18. Long-term follow-up
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 a weight gain of 4-5 kg and frequent awakenings in the night for the need to urinate. On endocrinological evaluation, central hypercorticism and diabetes insipidus were revealed. The patient was treated with corticosteroids (hydrocortisone 30+15 mg/day and desmopressin 30+30 µg/day). On 24 h sleep-wake cycle and temperature monitoring, no significant alterations were noticed after the hormonal substitute therapy's optimization.
Brain MRI demonstrated a suprasellar tumor occupying the opto-chiasmatic cistern and invading the 3rd ventricle, with an irregular polycystic morphology, enhancing after gadolinium, suspected as the first hypothesis for a craniopharyngioma (Figure 1A-C). Advanced imaging analyses were performed, as illustrated in the current protocol. The tumor core segmentation highlighted the gadolinium uptake and corresponded to a volume of 7.92 cm3 (Figure 1D-E).
The visual pathways were the most critical to evaluate in the pre-surgical planning of this patient. The pyramidal tracts were also reconstructed to assess the microstructural correlate of the signal increase detected on the FLAIR T2-weighted image at the level of the right tract.
The optic pathway tractography reconstruction was investigated, particularly the optic chiasm dislocation in the presence of the tumor mass. The bilateral optic cranial nerves were also reconstructed. In the interface between the brain, bones, and blood vessels, susceptibility artifacts did not allow for full reconstruction of the fibers connecting the optic chiasm to the optic nerves (Figure 2).
The pyramidal tracts diffusivity profile was investigated with along-tract DTI map statistics. At the level of the right posterior limb of the internal capsule, a focal FLAIR T2-weighted hyperintensity was present, corresponding to a 5% increase of the right MD measure (5th-7th segments) compared to the left side (Figure 3).
By considering such relationships between tumor and neural structures, the endoscopic endonasal extended transplant/transtuberculum approach was chosen36. The tumor removal was performed with a microsurgical two-hands technique. Initially, the tumor was centrally debulked, also draining its cystic component (Figure 4). Afterward, it was possible to progressively detach the craniopharyngioma from the neural structures, adopting the arachnoid as a cleavage plane (Figure 5). At the end of the surgery, complete tumor removal with the hypothalamus's anatomical preservation was achieved (Figure 6). The repair of the osteo-dural defect was performed with abdominal fat and naso-septal flap (Figure 7).
The postoperative course was uneventful, and the patient was discharged after four days in the right clinical conditions. The tumor turned out to be an adamantinomatous craniopharyngioma (WHO grade 1) on histological examination.
The patient developed complete panhypopituitarism at follow-up and was under complete substitution therapy with hydrocortisone, desmopressin, and levothyroxine. Visual deficits wholly regressed, and no alterations on neurological examination, 24 h sleep-wake cycle, and temperature monitoring were detected. Three months of brain MRI demonstrated a complete tumor removal, with no remnant or recurrence. Therefore, no adjuvant treatment was advised, and the patient is followed up with yearly clinical and neuroradiological examinations (Figure 8).
Figure 1. Preoperative anatomical MRI sequences (F/55 years). Axial view of T1-weighted (A) and FLAIR T2-weighted (B); axial (C, D) and sagittal (E) T1- after gadolinium administration (0.1 mm/kg). The tumor segmentation (red) overlaid to the gadolinium-enhanced T1-weighted image is shown in D and E. Please click here to view a larger version of this figure.
Figure 2. Preoperative 3D rendering of optic pathways tractography and tumor segmentation. (A) Axial slice of the FLAIR T2-weighted image overlays the optic chiasm tractography, localized anteriorly to the tumor. (B) 3D volume rendering of the FLAIR T2-weighted image, selecting an axial plane and overlaid the optic pathways tractography. (C) 3D volume rendering of the brain surface, optic pathways tractography, and tumor segmentation in red. All the panels' tractography streamlines are colored by the RGB directionality color map (red: lateral-lateral, green: anterior-posterior, and blue: inferior-superior). Please click here to view a larger version of this figure.
Figure 3. Pyramidal along-tract DTI measure analysis. (A) 3D rendering of the bilateral pyramidal tracts or corticospinal tract (CST), colored based on the Laplacian inferior-superior segmentation gradient. (B) Right (red) and left (blue) CST mean diffusivity (MD) profiles resulting from the partitioning of the tract into twenty segments displayed in the color maps in A; segments start at the level of the pons towards the precentral gyrus (PrCr). The black box highlights the segments at the posterior limb of the internal capsule (PLIC) (5th-7th). (C) Axial view of FLAIR T2-weighted image at the PLIC level, with and without the right CST connectivity map, where a brighter red intensity corresponds to a higher streamline density. Please click here to view a larger version of this figure.
Figure 4. Intraoperative endoscopic images. (A) 0° scope, after dural opening, the tumor was initially detached by the chiasm, adopting the arachnoid as a cleavage plane. (B) and (C), afterward, it was centrally debulked, and the cyst was progressively drained. Please click here to view a larger version of this figure.
Figure 5. Intraoperative endoscopic images. (A) 0° scope, the craniopharyngioma is cleaved by the arachnoidal plane with the help of neuronavigation, showing the tumor and the neural structures (identified according to our current protocol). Therefore, the mammillary bodies can be spared to avoid permanent hypothalamic damages. (B) and (C) afterward, it was possible to resect the tumor by the medial hypothalamic surfaces, avoiding any tractions not to injure such neural structure. (D) During the removal of the tumor's intra-ventricular portion, particular care was paid in re-opening the cerebral aqueduct and Monro foramina to avoid postoperative acute hydrocephalus. Please click here to view a larger version of this figure.
Figure 6. Intraoperative endoscopic images. (A) and (B) 30° scope, at the end of the surgery, the neural structure of the 3rd ventricle has been explored with angled optics to confirm the complete tumor removal and demonstrate its anatomical integrity. (C) At the bottom of the surgical field, it was possible to identify the CN III, under the Liliequist membrane: its function, as the MEPs, SEPs, and other CNs, had been continuously controlled with intraoperative neurophysiological monitoring. Please click here to view a larger version of this figure.
Figure 7. Intraoperative endoscopic images. (A) 0° scope, closure of osteo-dural defect requires a multilayer technique, adopting dural substitute, abdominal fat, eventually bone, and naso-septal flap. The first layer is constituted by intracranial intradural positioning of the first layer of a dural substitute. (B) The following step is represented by abdominal fat placement to fill the surgical cavity; particular care should be paid to avoid overpacking. (C) The second layer of dural substitute is adopted to cover the fat, and it can be maintained in position thanks to a rigid scaffold, as a piece of bone or cartilage (gasket seal technique). (D) Finally, the naso-septal flap or a free graft of septum or middle turbinate is used to cover the multilayer closure. Please click here to view a larger version of this figure.
Figure 8. MRI, sagittal view T1-weighted after gadolinium administration (0.1 mm/kg). (A) Preoperative MRI demonstrates the tumor. (B) Post-operatively, the complete tumor removal with the mammillary bodies' anatomical preservation and the hypothalamic structures are visible. Please click here to view a larger version of this figure.
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 tailor the surgical strategy, identifying the most appropriate surgical corridor and minimizing the risk of neural structure damage2,49,50,51. Unlike other MRI protocols reported in the literature, the inclusion of fast sequences, such as phase reverse encoding scans for diffusion-weighted images, allows advanced post-processing corrections52. This procedure should always be adopted, especially at high intensity field (e.g., 3 T or higher) where imaging distortions are present.
Moreover, the use of a probabilistic tractography approach based on constrained spherical deconvolution allowed an increase in fiber reconstruction quality compared to other deterministic tractography models53. Besides, the proposed 3D rendering, and quantitative analyses increased the accuracy of the preoperative patient assessment. This neuroimaging study, together with neurophysiological monitoring, represented a guide for the surgeon, helping him/her to decide whether and where to stop the surgical resection with the final goal of avoiding patients' permanent neurological deficits.
Indeed, the most aggressive tumor resection for craniopharyngiomas has been recently progressively abandoned in favor of a hypothalamic-sparing technique, consisting of arresting the tumor removed before any permanent neural damage54. However, in standard clinical practice, it is often complicated for the neurosurgeon to decide when to stop the tumor removal from achieving the maximal safe resection, exposing the patient to the risk, on the one hand, of leaving a tumor remnant larger than planned or, on the other hand, of inducing a permanent hypothalamic injury, with consequent quality of life detriment.
The presented protocol has provided a model of integrating clinical and neuroradiological data intending to provide a practical and easy-to-adopt method for the management of pituitary-diencephalic and skull base tumors. However, we underline that it presents some critical points: the need for adequate equipment, such as high field (3 T) magnet, high-resolution channel coil, and advanced pre/processing imaging software.
The MRI sequences in the presented protocol are also acquirable at 1.5 T, but acquisition parameters reported in Step 4 have to be modified to achieve a good signal to noise ratio: for the diffusion-weighted sequences, a lower b-value is suggested (e.g., 1000 s/mm2). Moreover, the implementation of the proposed neuroimaging analyses and their introduction in the clinical practice required both clinical and MRI technical and computer science expertise, in particular for the imaging processing. The majority of the reported software is freely available (e.g., FSL, MRtrix3), but the development of homebrew pipelines is required to manage specific datasets or imaging analyses.
Moreover, the further critical point is that, although this technology represents crucial support for the surgeon, it could not replace their learning curve. For these reasons, this advanced surgery should be reserved for few or tertiary referral centers, highly specialized and dedicated specialists.
Finally, the future goal is to improve the reconstruction of extra-parenchymal white matter structures, as cranial nerves. Tractography of these structures is currently impaired by the small dimension of the cranial nerves and by the presence of susceptibility artifacts that dramatically reduced the MRI signal for the presence of air and bone55.
In conclusion, the synergistic collaboration between neurosurgeons and the neuroimaging team is crucial for clinical and research purposes, allowing planning with the highest accuracy the most effective surgical strategy for each patient and contributing to the advancement of personalized medicine in this field.
The authors have nothing to disclose.
We would like to thank the radiology technicians and nurses’staff of the Neuroradiology Area, IRCCS Istituto delle Scienze Neurologiche di Bologna, and their Coordinator Dr. Maria Grazia Crepaldi, for their collaboration.
BRAF V600E-specific clone VE1 | Ventana | ||
Dural Substitute | Biodesign, Cook Medical | ||
Endoscope | Karl Storz, 4mm in diameter, 18 cm in length, Hopkins II – Karl Storz Endoscopy | ||
Immunohistochemical staining instrument | Ventana Benchmark, Ventana Medical Systems | ||
MRI | 3T Magnetom Skyra, Siemens Health Care | ||
Neuronavigator | Stealth Station S8 Surgical Navigation System, MEDTRONIC |