Neuroanatomical Determinants of Secondary Trigeminal Neuralgia: Application of 7T Ultra-High Field Multimodal Magnetic Resonance Imaging

Journal Pre-proof Neuroanatomical Determinants of Secondary Trigeminal Neuralgia: Application of 7T Ultra-High Field Multimodal MRI Annie E. Arrighi-Allisan, B.A., Bradley N. Delman, M.D., M.S., John W. Rutland, B.A., Amy Yao, M.D., Judy Alper, M.S., Kuang-Han Huang, Ph.D., Priti Balchandani, Ph.D., Raj K. Shrivastava, M.D. PII:

S1878-8750(19)32980-8

DOI:

https://doi.org/10.1016/j.wneu.2019.11.130

Reference:

WNEU 13799

To appear in:

World Neurosurgery

Received Date: 23 July 2019 Revised Date:

21 November 2019

Accepted Date: 22 November 2019

Please cite this article as: Arrighi-Allisan AE, Delman BN, Rutland JW, Yao A, Alper J, Huang K-H, Balchandani P, Shrivastava RK, Neuroanatomical Determinants of Secondary Trigeminal Neuralgia: Application of 7T Ultra-High Field Multimodal MRI World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.11.130. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Neuroanatomical Determinants of Secondary Trigeminal Neuralgia: Application of 7T Ultra-High Field Multimodal MRI Annie E. Arrighi-Allisan, B.A.a, Bradley N. Delman, M.D., M.S.b, John W. Rutland, B.A.a,c, Amy Yao, M.D.a, Judy Alper, M.S.c, Kuang-Han Huang, Ph.D.c, Priti Balchandani, Ph.D.c, Raj K. Shrivastava, M.D.d a

Department of Medical Education, Icahn School of Medicine at Mount Sinai, 1468 Madison

Avenue, New York, NY 10029 b

Department of Radiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue,

New York, NY 10029 c

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1468

Madison Avenue, New York, NY 10029 d

Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue,

New York, NY 10029

Corresponding Author: Annie Arrighi-Allisan 50 E 98th St., Apt 5A-4 New York, NY 10029 [email protected] Tel: 413-427-8202

Key Words: Trigeminal neuralgia, epidermoid, ultra-high field MRI, neurosurgery Running Head: Neuroanatomical Use of 7T: Secondary TN Disclosures: Financial support for salaries and MRI scans was provided by the National Institute of Health: National Cancer Institute, through grant NIH R01 CA202911-01A1. Funding was awarded to Dr. Bradley Delman, John Rutland, Judy Alper, Dr. Priti Balchandani, and Dr. Raj Shrivastava. Dr. Priti Balchandani is a named inventor on patents relating to MRI and RF pulse design. The patents have been licensed to GE Healthcare, Siemens AG, and Philips International. Dr. Balchandani receives royalty payments relating to these patents. The remaining authors report no conflicts of interest concerning the materials or methods used in this study or the findings specified in this paper.

Abstract Background: 7T MRI has demonstrated value in a variety of intracranial diseases, but its utility in trigeminal neuralgia has received limited attention. The authors of the present study applied ultra-high field multimodal MRI to two representative patients with secondary TN due to epidermoids in order to illustrate the possible clinical and surgical advantages of 7T over standard clinical strength imaging. Techniques included co-registration of multiple 7T sequences to optimize detection of potential concurrent neurovascular and neoplasm-derived compression. Methods: 7T MRI studies were performed on a whole body scanner. Two- and three-dimensional renderings of potential neurovascular conflict were created by co-registering time-of-flight (TOF) angiography and T2-TSE images in MATLAB and GE software. Detailed comparisons of various field strength images were provided by a collaborating neuroradiologist. Results: 7T clearly illustrated minute tumor-adjacent vasculature, while conventional, low-field imaging did not consistently provide adequate detail to distinguish CSF pulsatility from vessel. The tumor margins, while distinct from trigeminal nerve fibers at 7T, blended with those of surrounding structures at 3T. 2D and 3D co-registration of TOF angiography with T2-weighted MRI suggested that delicate, intervening vasculature may have contributed to these illustrative patients’ symptomatology. Conclusions: 7T provided superior visualization of vital landmarks and subtle nerve and vessel features. Co-registration of various advanced 7T modalities may help to resolve complex disease etiologies. Future studies should explore the extent to which this dual etiology may persist across tumor types, and utilize diffusion-based techniques to quantify what microstructural differences exist between patients with TN from varying etiologies.

Introduction Trigeminal neuralgia (TN) is a chronic neuropathic disorder of the fifth cranial nerve characterized by extreme, paroxysmal, lancinating facial pain.1 The vast majority of cases are termed “classic” (primary) TN, and are believed to originate from trigeminal nerve compression by adjacent vascular structures.1,2 In distinction, secondary (or symptomatic) TN often stems from underlying tumors or broader diseases such as multiple sclerosis.1 Brain tumors causing secondary TN are typically found within the skull base and cisterns and likely produce symptoms through compression near the trigeminal nerve root entry zone (REZ). Intracranial tumors are identified as a possible etiology in up to 11% of patients who

present with facial pain.3-8 In such cases, the first line of treatment is often pharmacologic therapy with a neuropathic drug such as carbamazepine. Surgery is typically reserved for TN patients who remain or become refractory to conservative management.1 Additionally, gamma knife radiosurgery remains a viable, non-invasive alternative for those in whom surgery is contraindicated.9-13 In trigeminal neuralgia patients, accurate identification of the underlying etiology is essential to designing an effective treatment plan. Magnetic resonance imaging (MRI) is the most common imaging modality used to detect pathological neurological changes in TN patients; however, detection of small changes in the trigeminal REZ at clinical magnetic field strengths (1.5 or 3 Tesla) remains an arduous task.7,14,15 In fact, some small but critically positioned tumors may even escape preoperative detection by conventional MR scanning.16-18 Furthermore, in some cases, TN may be mediated by synergy between tumor and vessel, with the tumor displacing an adjacent vessel into the nerve’s trajectory.18-20 Identification of potential vascular compression is integral to the MRI assessment of TN. One critical sequence is time-of-flight (TOF) magnetic resonance angiography (MRA), which depicts flow-related enhancement for neurovascular imaging without intravascular contrast medium.21 Subsequent co-registration of TOF with other structural MR images allows for excellent visualization of intracranial vessels’ positions relative to the trigeminal nerve.19,22 This fusion technique may help to elucidate the degree to which a tumor or impinging vessel ultimately causes compression of the root entry zone. Increasing field strengths have been shown to confer diagnostic benefit in classic TN patients. For example, a study performed by Garcia et al. illustrated that 3D TOF MRA at 3T provides superior sensitivity and resolution to 1.5T when assessing trigeminal neuralgia patients for neurovascular compression.23 It stands to reason that the enhanced image quality afforded by imaging at 7T may further improve visualization of nerve integrity, adjacent vessels, or subtle lesions near the skull base that may be poorly defined at lower field strengths.24-27 The increased signal-to-noise ratio, improved contrast, and enhanced spatial resolution possible with ultra-high field 7T over conventional field strength scanning can be expected to improve visualization of the trigeminal nerve and surrounding structures.26 Despite the relevance of MR imaging to trigeminal neuralgia, 7T MRI has not yet been employed to examine patients with secondary TN. The present study employs multimodal 7T MRI as a preliminary investigation into the causative etiology in two patients presenting with TN

and concomitant epidermoid tumors. Furthermore, we compare this modality with standard clinical strength imaging to explore its diagnostic benefits and potential applications to secondary TN treatment.

Methods All 7T MRI studies were performed on a whole body scanner (Magnetom, Siemens Healthcare, Erlangen, Germany). An SC72CD gradient coil was used (Gmax = 70 mT/m, max slew rate = 200 T/m/s), with a single transmit and 32-channel receive head coil (Nova Medical, Wilmington, MA, USA). The imaging protocol included a T2-weighted turbo spin echo (T2-TSE) sequence: TE = 69 ms, TR = 6900 ms, flip angle = 150°, in-plane resolution = 0.4 x 0.4 mm2, slice thickness = 2 mm, slices = 40, time = 6:14 min. A time-of-flight (TOF) angiography sequence was additionally acquired: TE = 5.6 ms, TR = 18 ms, flip angle = 20°, in-plane resolution = 0.5 x 0.5 mm2, slice thickness = 0.7 mm, slices = 240, time = 10:13 min. A detailed comparison of 3T and 7T images was provided by our collaborating neuroradiologist (BD). The two-dimensional rendering of potential neurovascular conflict was created by co-registering TOF and T2-TSE images using Statistical Parametric Mapping 12 in MATLAB (r2017a, The MathWorks, Natick, MA). The three-dimension volume rendering was produced by superimposing TOF data, generated on General Electric Medical Systems AW Server 2.0 (Chicago, Illinois, USA), onto a coronal T2 image.

Results Figure 1 shows axial T2-weighted MR images of both illustrative patients at 7T. In both patients (a and b), the epidermoid is seen on T2 as hyperintense, but with the subtle, swirled internal texture of slightly lower signal. In the first patient (a), the tumor produces a moderate mass effect upon the anterolateral belly of the pons and pre-Gasserian nerve, resulting in both mild rightward deviation of the brainstem and widening of the ponto-trigeminal angle. Tumor (yellow arrowheads) displaces the left trigeminal nerve laterally in both instances, manifest by subtle widening of the ponto-trigeminal angle (white arrows in a and b) and, additionally, by displacement within Meckel’s cave in Patient 1 (green arrows in 1a). While the nerve maintains uniform caliber in 1a, cisternal mass effect in 1b illustrates remodeling of the nerve by flattening at the REZ, and compensatory broadening just anterior to the pontine emergence (green arrow).

Figure 2 compares the mass effect from the epidermoid within Meckel’s cave on T2weighted MRI at 7T, 3T, and 1.5T for the first illustrative patient. In the 7T preoperative image (2a), the left trigeminal nerve fibers are sharply marginated and are clearly displaced by the tumor laterally within Meckel’s cave. Note the juxtaposition against the normal contralateral (radiological right) side, where Meckel’s fibers remain wispy or “broom-like”. Small vessels are also well resolved at this field strength (blue arrow, for example). In the 3T preoperative image (2b), nerve fibers are precipitously less sharp and more difficult to resolve. In this image, it is unclear whether the pre-pontine low signal represents CSF pulsatility or vessel. In the 1.5T scan (2c), after cisternal decompression, there is more symmetric CSF pulsatility in the pre-pontine cisterns bilaterally (for example, vicinity of blue asterisk). As in the 3T preoperative scan, Meckel’s architecture is more poorly seen when compared with the 7T scan. In addition, small cisternal vessels are not resolved at this field strength. Figure 3 provides a similar comparison for the study’s second illustrative patient. At 7T, the left trigeminal nerve is visualized in its trajectory towards Meckel’s cave. A submillimeter vessel (blue arrowhead), likely venous given its CT angiography configuration (not shown), is closely apposed against the pons by mass effect from the epidermoid. In the 3T preoperative scan, the trigeminal nerve margins blend into the signal of the adjacent tumor. Surrounding vasculature is poorly resolved and nearly undetectable at this resolution. Figure 4 illustrates the diffusion-weighted imaging of Patient 2 at 7T and 3T. The tumor margins at 7T are sharper than at 3T, and show evidence of restricted diffusion with high signal intensity. In Figure 5, we qualitatively demonstrate potential evidence of neurovascular conflict in both patients through co-registration of TOF angiography with T2-weighted axial MRI. In 5a, the vessel likely closely abuts but does not pass directly through the nerve. Its apparent nerve penetration is likely due to discrepancies in slice thickness between the T2 and TOF images (2 vs. 0.7 mm, respectively). In 5b, the small vessel appears to approach, and potentially contact, the nerve. Co-registered 3-dimensional TOF and T2-TSE images for Patient 1 further illustrate this potential neurovascular conflict, likely potentiated by the adjacent mass (Figure 6).

Discussion The present study is the first to examine patients with tumor-associated TN using ultrahigh field, multimodal 7T MR imaging. Within this study, we demonstrated possible advantages of 7T for imaging secondary TN. First, ultra-high field images may enable more precise

presurgical planning and intraoperative navigation through better structural data, at higher signal and resolution, than conventional 1.5 and 3T images. In the patients included in the present study, 7T clearly illustrated delicate tumor-adjacent vasculature, while conventional, low-field imaging did not consistently provide adequate detail to distinguish CSF pulsatility from vessel. The tumor margins, while distinct from trigeminal nerve fibers at 7T, blended with those of surrounding structures at 3T (Figures 2-3). In addition, by co-registering 7T TOF angiography and T2-weighted images, we provided potential evidence of both vascular and tumor-derived compression (Figures 5-6). Though this technique is possible at lower field strengths, TOF at 7T may be more effective through its resolution of smaller vessels.26 The concept of tumor-mediated vascular compression in TN has been well documented;18-20,28 however, these descriptions largely result from intraoperative observations. Some delicate intervening vessels may go unnoticed if dissected with the tumor. Although the 7T images for these patients do not permit definitive attribution of TN to a combination of vessel and tumor, awareness of the potential for additional neurovascular conflict prior to surgery allows the surgeon to be cognizant of whether the patient might require both a resection and microvascular decompression.29,30

Clinical presentation Though classic and symptomatic TN may share overlapping clinical features, some enduring differences between the two have been noted throughout the literature. As seen in our study, these observations should be taken as a pattern, and not as a rule. Younger age of onset is often cited as a hallmark of tumor-elicited trigeminal neuralgia.18,30-32 Shulev et al. found the mean age of classic and symptomatic TN patients to be 61.4 and 51.2 years, respectively, although the symptomatic cohort exhibited a broad age range (28 to 78 years).18 Concordant with this age pattern, two recent patients with classic TN at the authors’ institution were ages 23 and 38, both younger than the first symptomatic patient presented here. Given the potential age overlap between classic and symptomatic TN populations, advanced high-field-strength imaging may improve detection of subtle lesions or intervening vessels disguised by a partially resected tumor. Unlike well-documented cases of symptomatic TN, in which neurological symptoms such as hemiparesis or hearing loss are present,20 the patients in the present study exhibited a more classic constellation of TN symptoms. Though symptoms may be nonspecific, these properties

are important reminders of the heterogeneous presentation of TN, regardless of underlying etiology.

Mechanisms and tumor attributes Vessels and lesions (for example, tumors or multiple sclerosis plaques) are considered to be the two predominant mechanical causes of TN. As the present study illustrates, ultra-high field neuroimaging may enhance visualization in patients whose underlying etiology potentially encompasses both tumor and vessel. The prevailing theory of TN is that chronic compression by either tumor or vessel leads to nerve compromise, first by degradation of the myelin sheath, and secondarily by attenuation of the underlying nerve structure. This demyelination is thought to enable ephaptic transmission, or cross-talk with normal adjacent nerve fibers, leading to highfrequency and uncontrolled electrical excitement.33 Despite this widely applicable hypothesis, tumor-evoked neuralgia patients often present with a wide range of symptoms and severities, and their outcomes are correspondingly varied as well. The unique histological features and pace of growth of epidermoids contribute to their distinctive clinical manifestation. Epidermoids are more commonly observed to encapsulate or infiltrate adjacent nerves, although they are capable of displacement as well, with or without vessel involvement. Importantly, keratin content in these tumors is hypothesized to chemically irritate their immediate surroundings.17,29,34-37 Epidermoids are slow-growing tumors that allow the surrounding tissue to accommodate more progressively than rapidly-growing lesions, therefore resulting in later and more gradual symptom onset.38 This insidious onset may induce a clinical presentation more typical of chronic vascular compression. As epidermoids characteristically adhere to adjacent vascular and neural structures, these tumors are more prone to subtotal resection and recurrence of both neoplasm and symptoms when compared to other intracranial tumor types.39 The clinical picture of TN is further complicated by patients who do not fall into one of the established categories of causes. Specifically, there remains a population of TN patients for whom there is no discernible compression, tumor, or intrinsic neural disease.40,41 Conversely, some patients may present with incidental findings of trigeminal nerve compression and no apparent symptoms,42 and some patients’ symptoms paradoxically appear contralateral to any discernable compression.19,43 These observations suggest that the causes of TN are varied, and that the underlying mechanisms of disease progression are perhaps more nuanced or complex

than the mere presence of an encroaching lesion or vessel.44 Anatomical determinants at more distant locations, such as displacement of the brainstem and/or trigeminal tracts, may also contribute to symptom manifestation.43 Although beyond the scope of this paper, diffusion MRI (dMRI) is an application of 7T MRI that allows for characterization of microstructural features between affected and unaffected nerves.15 Detailed quantification of nerve integrity in TN patients with different etiologies using dMRI may provide greater insight into both the shared and separate microstructural processes underlying these symptoms, and is an area of current investigation in our group.45

Limitations of 7T Despite 7T MRI’s promise in intracranial imaging, it is important to note its technical and physical limitations. B0 (magnetic field) increases proportionally with field strength, causing the operating radiofrequency (RF) wavelength to become roughly equivalent to the diameter of the human head. As a result, the strength of B1, or the radiofrequency field, drops precipitously in the outer regions of the head. This B1 inhomogeneity is more prominent in T2-TSE imaging due to the high flip angle.26 While the trigeminal REZ is centrally located and may be minimally affected by this signal dropout, other regions of interest may require alternative solutions, such as customized RF pulse sequences or parallel transmit coils.26 Though 7T MRI has yet to become ubiquitous, its presence at academic medical centers is growing rapidly. As of early 2019, at least 77 whole-body MRI systems of 7T or greater field strength have been installed around the world, and the number of installations continues to increase. The 7T Terra (Siemens Healthineers, Erlangen, Germany) system has become the first ultra-high field system to receive 510(k) clearance from the Food and Drug Administration (FDA) for clinical imaging. The FDA additionally categorized MRI up to 8.0 Tesla as not posing a significant health risk. MRI at ultra-high fields is entirely noninvasive and well tolerated by patients.26 In addition to providing anatomical information to guide surgical intervention, 7T multimodal imaging will enable greater use of minimally invasive surgical approaches.

Conclusions The present study explores the neuroanatomical and diagnostic benefits of 7T multimodal MRI to secondary TN patients with associated epidermoid tumors. Future studies should endeavor to directly compare symptoms, outcomes, and microstructural nerve characteristics of

patients with TN associated with diverse configurations. Vessel pulsatility, which has been posited as a prime determinant of classic trigeminal neuralgia, may produce a different symptomatology than an expansile tumor that compresses or infiltrates the trigeminal nerve. Differences in presentation may also be found between a lone compressive tumor and one that additionally contains a conflicting vessel. As adoption of ultra-high field MRI becomes more commonplace within clinical settings, applications of this imaging modality to TN and other intracranial conditions are expected to increase exponentially. More precise neuroanatomical mapping using modalities such as ultra-high field 7T may ultimately help to resolve complex intracranial disease etiologies.

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Figure Legends: Figure 1: T2-weighted appearance of cisternal epidermoids at 7T, including mass effect on the trigeminal nerves (CN V) in Patient 1 (a) and Patient 2 (b) at 7T. Medial epidermoid borders are demarcated by yellow arrowheads. Green arrows show laterally displaced trigeminal nerves, while white arrows indicate the ponto-trigeminal angle, which is slightly broadened in (a) and even more broadened in (b). Figure 2: Comparison of mass effect from epidermoid within Meckel’s cave on T2-weighted MRI at 7T, 3T, and 1.5T (Patient 1). White arrows indicate left trigeminal nerve fibers, and red asterisk marks epidermoid within Meckel’s cave (a and b). Green arrows show the right, unaffected, broom-like Meckel’s fibers (a), and blue arrows indicate small intracranial vessels (a and b). Blue asterisk (c) indicates increased symmetry of CSF pulsatility. Figure 3: Comparison of T2-weighted MRI at 7T and 3T (Patient 2). White arrows indicate trigeminal nerves (a and b), yellow arrowheads mark nerve-adjacent tumor, and blue arrowhead shows a submillimeter vessel visible at 7T, but not at 3T. Figure 4: Comparison of diffusion-weighted imaging (isotropic maps) for Patient 2 at 7T (a) and 3T (b). Lesion contour is much sharper and better defined at 7T. Figure 5: Intraoperative navigation for Patient 1. (a) Preoperative projected view of epidermoid tumor (yellow) and transverse and sigmoid sinuses (blue) through BrainLab Heads Up Display© (Munich, Germany). (b) Active removal of epidermoid tumor with visualization of total epidermoid mass and transverse and sigmoid sinuses (same color rules apply). Figure 6: Operative views for Patient 1. (a) Dissection and debulkment of epidermoid tumor (yellow asterisk) along arachnoid plane. (b) Trigeminal nerve (white arrow), now decompressed, following resection of epidermoid tumor. Figure 7: Co-registered TOF angiography with T2-weighted axial MRI for Patient 1 (a) and 2 (b). White arrows indicate trigeminal nerve (CN V), and blue arrows mark the point of potential neurovascular contact. Though this contact may be primary, its close apposition to the epidermoid suggests that the tumor potentiates this neurovascular contact. Figure 8: Co-registration of 3D TOF and coronal T2-TSE images for Patient 1 depicting the trigeminal nerve (white arrow), superior cerebellar artery (blue arrow), and mass effect from the epidermoid (pink arrowheads) on these structures.

Table 1: Clinical characteristics of two representative secondary TN patients Patient Age at surgical treatment Gender Relevant past medical history Symptoms

Symptom duration prior to surgery Tumor type Tumor location

Neurological exam (remainder) Prior treatment Surgical treatment

Resection Postoperative TN symptoms

Patient 1 49 Female None

Patient 2 27 Female Bilateral sinusitis, deviated septum, concha bullosa Left-sided severe facial pain Left intermittent facial pain, dizziness, vertigo, of maxillary (V2) and mandibular (V3) progressive feeling of “right distributions; intermittent eye fixation” left facial paresthesias 25 months 13 months Epidermoid Left cerebellopontine angle cistern and posterior Meckel’s cave Unremarkable

Epidermoid Left cerebellopontine angle

Carbamazepine (refractory 10 months prior to surgery) Left transtemporal skull base resection and partial sensory rhizotomy

None

Total Resolved at 14 months postoperatively

Unremarkable

Left transtemporal posterior fossa resection with secondary cranioplasty and fat graft Total Resolved at 15 months postoperatively