High-Resolution 3D Magnetic Resonance Imaging of the Sixth Cranial Nerve: Anatomic and Pathologic Considerations by Segment

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD High-Resolution 3D Magnetic Resonance Imaging of the Sixth Cranial Nerve: Anatomic and Pathologic Considerations by Segment Marinos Kontzialis, MD, Asim F. Choudhri, MD, Vivek R. Patel, MD, Prem S. Subramanian, MD, PhD, Masaru Ishii, MD, PhD, Gary L. Gallia, MD, PhD, Nafi Aygun, MD, Ari M. Blitz, MD Background: Weakness of the sixth cranial nerve is the most common cause of an ocular motor cranial nerve palsy. It is often difficult to identify a corresponding abnormality on neuroimaging to correlate with the clinical examination. Evidence Acquisition: High-resolution 3D skull base magnetic resonance imaging (MRI) allows for visualization of the sixth nerve along much of its course and may increase sensitivity for abnormalities in regions that previously were challenging to evaluate. In this review, the authors share their experience with high-resolution imaging of the sixth nerve. Results: For each segment, anatomic features visible on high-resolution imaging are described along with relevant pathologic entities. Conclusions: We present a segmental approach to highresolution 3D MRI for evaluation of the sixth nerve from the nuclear to the orbital segment. Journal of Neuro-Ophthalmology 2015;35:412-425 doi: 10.1097/WNO.0000000000000313 © 2015 by North American Neuro-Ophthalmology Society Division of Neuroradiology (MK, NA, AMB), Department of Radiology and Radiologic Science, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Radiology (AFC), University of Tennessee, Memphis, Tennessee; Department of Ophthalmology (VRP), University of Southern California, Los Angeles, California; Department of Ophthalmology (PSS), Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Otolaryngology-Head and Neck Surgery (MI), Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Neurosurgery (GLG), Johns Hopkins Medical Institutions, Baltimore, Maryland. Presented as an educational exhibit at ASHNR 2014, September 10-14 2014, Seattle, WA (second place educational exhibit award). A. M. Blitz received an honorarium for an educational talk on the cranial nerves from Siemens. The other authors report no conflicts of interest. Address correspondence to Ari M. Blitz, MD, Division of Neuroradiology, Department of Radiology and Radiologic Science, Johns Hopkins Medical Institutions, Phipps B-100, 600 North Wolfe Street, Baltimore, MD 21287; E-mail: [e-mail] 412 T he sixth cranial nerve also known as the abducens or abducent nerve (CN VI) is a purely motor nerve, which moves the eye into abduction. Weakness of CN VI is the most common cause of an ocular motor cranial nerve palsy (1), with an annual incidence of approximately 11.3/100,000 (2). The cranial nerves (CNs) may be divided into generic segments on neuroimaging (Fig. 1, abbreviated as CN #. segment) (3). This variation between segments in anatomic context poses particular imaging challenges, influences differential diagnosis, and has implications for surgery. Portions of each CN VI segment may be visualized using a high-resolution 3D magnetic resonance imaging (MRI) protocol, which includes isotropic 0.6-mm constructive interference in steady state (CISS) images before (Fig. 2A) and after (Fig. 2B-D) contrast (3). Isotropic acquisition allows for post hoc reconstruction in any plane. This approach facilitates evaluation of some segments that were previously not well visualized. This article is based on an institutional review board approved review of more than 885 skull base protocol MRIs performed at our institution from February 2010 to August 2014 (4). GENERAL CONSIDERATIONS Although the differential diagnosis of lesions affecting CN VI varies by segment, certain pathologic conditions do not have a known predilection for 1 anatomic segment. The most common cause of CN VI palsy is considered to be microvascular ischemic palsy, a self-limited condition where neuroimaging is not routinely recommended (1). However, a recent multicentered study showed that a structural lesion may be missed even in the most benign-appearing clinical setting (5). Additional pathologic entities may be visible on imaging, but do not have a clear predilection for particular CN segments. For this reason, such entities as metastasis, Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Anatomic segments of sixth cranial nerve (CN VI) (Reprinted with permission from [3]). CSF, cerebrospinal fluid. sarcoidosis, lymphoproliferative disorders, or vasculitides are not repeatedly included in the following segmental discussion. ROLE OF HIGH-RESOLUTION IMAGING IN SKULL BASE SURGERY Identification of the location of CN VI and its relationship to mass lesions is of paramount importance in skull base surgery. Generally, surgeons are reticent to cross the trajectory of a functioning nerve to reach their target. The greatest degree of anatomic variation is in the location of CN VI.d, potentially placing CN VI within or outside the region of surgery for clival masses. The course of CN VI may be significantly altered by adjacent skull base masses, and whether the mass is separate from, abuts, displaces, or encases the cranial nerve is important in surgical planning. FIG. 2. A. Sagittal constructive interference in steady state (CISS) without contrast demonstrates CN VI.c from its origin in the region of the pontomedullary junction (white arrow) as it extends anteriorly toward the dorsal aspect of the clivus (white arrowhead). B. On postcontrast sagittal CISS, CN VI.c (black arrow) can be seen extending through a short CN VI.d (white arrowhead) segment into CN VI.e.I. C. Sagittal postcontrast CISS just lateral to the section seen in (B) demonstrates CN VI.e.II (black arrow) extending anteriorly into CN VI.f (white arrow). D. On axial postcontrast CISS, the left distal CN VI.e.I (white arrowheads) can been seen extending anteriorly into CN VI.e.II (black arrowheads). Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 3. A. Axial precontrast constructive interference in steady state through the facial colliculi, which can be identified as small convex protrusions in the ventral fourth ventricle (black arrowhead), serving as a landmark for the underlying CN VI.a (the approximate location of the left CN VI.a is demarcated by a circle and CN VI.b by an interrupted line). B. 3D reconstruction of the facial colliculi (white arrows). C. Cadaveric specimen photograph of the fourth ventricular floor depicts the convex facial colliculi (white arrows). NUCLEAR SEGMENT (CN VI.a) Anatomy The nucleus of CN VI (CN VI.a) is located in the dorsal pontine tegmentum. The parenchymal fascicular fibers of the facial nerve wrap around CN VI.a and create the facial colliculus, which can be identified as a small convexity protruding into the floor of the fourth ventricle (Fig. 3). Vascular Supply CN VI.a is supplied largely by branches of the anterior inferior cerebellar artery (AICA) known as the superior rami of the lateral medullary fossa. There is a lesser contribution to the medial aspect of CN VI.a, which is supplied by arteries of the foramen cecum, which in turn arise from the basilar artery (6). Clinical Presentation CN VI.a lesions present with an ipsilateral gaze palsy because of disruption of yoking of gaze by the projection from CN VI.a through the medial longitudinal fasciculus to the contralateral third nerve nucleus. Injury to the facial colliculus will produce ipsilateral horizontal gaze and facial palsy (Fig. 4). Pathologic Conditions A variety of conditions can affect CN VI.a and the adjacent CN VI.b including infarction, demyelination, hemorrhage, and tumor (7). Imaging Approach Conventional T1, T2, and diffusion-weighted imaging is generally used for evaluation of abnormalities of the FIG. 4. A. Axial fluid-attenuated inversion recovery image shows a pilocytic astrocytoma protruding into the fourth ventricle with mass effect on the facial colliculi (white arrows). B. Axial constructive interference in steady state demonstrates interval partial resection of the mass with minimal concavity along the dorsal pons and minimal residual tumor (white arrow). C. 3D reconstruction confirms concavity in the expected region of the facial colliculi (black arrows). The 3D reconstruction is presented from the dorsal perspective, with the right side of the patient on the right side of the image and vice versa. The patient awoke postoperatively with bilateral CN VI and CN VII palsies. 414 Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 5. Axial (A) and sagittal (B) T2 constructive interference in steady state images demonstrate a cavernous malformation (white arrowheads) in the region of the distal CN VI.b. The patient developed a right CN VI palsy because of intermittent hemorrhage within the mass. CN VI.b (black arrows) is seen in the cerebellopontine cistern. brainstem. Although CN VI.a is not directly visualized, the location of the nucleus can be inferred by identifying the facial colliculus (Fig. 3). CN VI.b can be inferred by identifying the facial colliculi posteriorly (Fig. 3) and its origin from CN VI.a anteriorly within the brainstem (Fig. 2A) the brainstem anteriorly (Fig. 2A). PARENCHYMAL FASCICULAR SEGMENT (CN VI.b) CISTERNAL SEGMENT (CN VI.c) Anatomy The parenchymal fascicular fibers of CN VI (CN VI.b) extend anteroinferiorly from CN VI.a and traverse the pons close to the medial lemniscus and the pyramidal tract. Anatomy The origin of CN VI.c is typically at the pontomedullary junction (Fig. 2A) (3). In 1 anatomical study, in approximately 20% of cases additional (1-3), rootlets arose from the inferior pons just rostral to the pontomedullary junction Vascular Supply The proximal portion of CN VI.b is supplied by the superior rami of the lateral medullary fossa, which arise from the AICA. The distal segment of CN VI.b is supplied by the anterolateral group of pontine perforating arteries arising from the basilar artery (6). Clinical Presentation A lesion to CN VI.b and more distal segments spares the internuclear motor neurons (discussed with the CN VI. a above) and results in lateral rectus paresis without horizontal gaze palsy. The ventral pontine syndrome of Raymond involves injury to CN VI.b and the corticospinal tract resulting in a contralateral hemiparesis. A more extensive lesion also ipsilateral facial paresis is known as Millard-Gubler syndrome (7). Pathologic Conditions A variety of conditions can affect CN VI.b, including infarction, demyelination, hemorrhage, and tumor (Fig. 5) (8). Imaging Approach As noted in CN VI.a (above), standard sequences are most commonly used for evaluation of brainstem. The location of Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 FIG. 6. Postcontrast sagittal oblique constructive interference in steady state image shows deformity of CN VI.c (black arrowheads) as an incidental finding. This is due to dolichoectasia and tortuosity of the distal basilar artery. Note visualization of the proximal petroclival interdural segment (CN VI.e.I, white arrows). No pathologic enhancement of CN VI was identified and extraocular movements were intact. B, distal basilar artery; M, medulla; P, pons. 415 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 7. CN VI.c schwannoma in a patient with neurofibromatosis Type 2. A. Axial precontrast constructive interference in steady state (CISS) image. The schwannomas (white arrow) are detected on precontrast axial CISS image. The normal left CN VI.c is seen (black arrow). Bilateral vestibular schwannomas are present (white arrowheads). B. Note that the proximal 3 mm of CN VI.c (black arrow) is spared by the tumor (white arrow) including the oligodendrocyte-myelinated component proximal to the transition zone. (9). CN VI.c extends superolaterally within the cerebellopontine cistern lateral to the anterior pontine membrane toward the dorsal aspect of the clivus (Fig. 2B) (10). The transition zone between the oligodendrocyte-myelinated central nervous system and the Schwann cell-myelinated peripheral nervous system averages 0.3 mm from the origin of CN VI.c (11). other CN palsies without an identifiable pattern of distribution in a diffuse process affecting the subarachnoid space. Pathologic Conditions CN VI.c receives arterial supply from branches of the vertebrobasilar system (12). The cisternal segment most frequently courses dorsal to the AICA (79%), although in some anatomic specimens (16%), CN VI.c can be found ventral to the AICA, with AICA occasionally (5%) dividing CN VI.c into 2 cisternal components (13). CN VI.c can be affected by neurovascular compression (dolichoectasia, aneurysm) similar to other neurovascular compression syndromes (15,16) although significant deformity may occur (Fig. 6), even in patients without clinical symptoms of CN VI dysfunction. CN VI.c schwannoma (Fig. 7) may arise in any segment distal to the transition zone (17). Subarachnoid processes including neoplastic, infectious, or inflammatory disease can affect the cisternal segment. Mass lesions protruding into the cerebellopontine cistern, for instance from the meninges (Fig. 8) or clivus, can also affect CN VI.c. Clinical Presentation Imaging Approach CN VI.c can be affected in isolation because of compression, as a false localizing sign in increased intracranial pressure (14), or may occur in combination with multiple CN VI.c is consistently identifiable on precontrast CISS because of the cisternographic effect (Fig. 2A, B) (3). Evaluation for pathologic enhancement is possible on the Vascular Supply FIG. 8. Relationship of meningioma (black arrowheads) within the cerebellopontine cistern to CN VI. Note that CN VI is not visible on precontrast constructive interference in steady state (CISS) image (A) at this level. On postcontrast CISS (B), increased signal within the mass on the basis of enhancement is evident. Enhancement allows visualization of the distal right CN VI.c (white arrow) before it pierces the inner layer of the dura (black arrow). In this individual, at this level, the left CN VI has pierced the inner layer of the dura (black arrows), and its proximal petroclival interdural segment (i.e., CN VI.e.I) (white arrowhead) is outlined by the petroclival venous confluence. 416 Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 9. Normal dural caves (white arrows) of CN VI in the axial plane (A) and (B). C. On precontrast axial constructive interference in steady state scan, there is prominent dilation of the right CN VI dural cave (black arrow) in a patient with idiopathic intracranial hypertension. The left dural cave is much less prominent and CN VI.d (white arrow) is seen. postcontrast CISS images when precontrast and postcontrast images are compared. DURAL CAVE SEGMENT (CN VI.d) ing CN VI.d (20). As CN VI pierces the inner layer of the dura, it changes course from a lateral direction in the cerebellopontine cistern to a more medial and cranial direction along the dorsum of the clivus, its first fixation point (21). Anatomy Clinical Presentation For the purposes of imaging, the dural cave of CN VI is defined by the presence of visible cerebrospinal fluid (CSF) around the nerve surrounded by the inner layer of dura (Fig. 9) (3). The CSF evagination, the posterior opening of which is termed the porus (18), communicates with the subarachnoid space, is short, and measures 1 mm or greater in 57% (18) to 86% (19) of cases. When 2 or more CN VI.c rootlets are present, there may be more than 1 correspond- CN VI.d is not in close proximity to other CNs. For this reason, an abnormality in the region of the dural cave is most likely to initially present with isolated CN VI palsy. Pathologic Conditions Dilation of the abducens dural cave can be observed in patients with idiopathic intracranial hypertension (IIH), and CN VI palsy is an example of a false localizing sign in FIG. 10. A. On precontrast constructive interference in steady state, the right CN VI.c (black arrow) is noted. A mass (white arrowheads) fills the left cerebellopontine cistern indenting the left ventral pons. The left CN VI.c is not visualized. B. After the administration of intravenous contrast, the left CN VI.e (white arrow) is seen in the petroclival venous confluence. As in the precontrast image, right CN VI.c (black arrow) has not yet pierced the dura at this level, reflecting slight physiologic asymmetry in the cranial-caudal location of CN VI.d. The relationship of the mass to the inner layer of dura (black arrowheads) is now clear, without evidence of extension of the presumed meningioma into the interdural space adjacent to CN VI.e (white arrow). The patient presented with left-sided facial pain and decreased facial sensation due to compression of the left CN V.c (not shown). Extraocular movements were intact postoperatively (Reprinted with permission from [3]). Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 417 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 11. A. Postcontrast coronal constructive interference in steady state image through the Dorello canals. CN VI.e segments (upward white arrows) are identified in cross section medial to the petrous apex and Meckel cave (downward white arrows). The nerves are surrounded by enhancing venous blood in the lateral aspect of the canals inferior to the sphenopetrosal ligament (white arrowheads). Note the intimate relationship between the CN VI.e, petrous apex, and Meckel cave, which accounts for the constellation of symptoms in Gradenigo syndrome. B. Oblique postcontrast reconstruction perpendicular to the long axis of the sphenopetrosal ligament (white arrowhead). Dorello canal is seen in cross section, CN VI.e (upward white arrows) (downward white arrows). C. Postcontrast oblique reconstruction demonstrates the distal cisternal segment of CN VI.e (upward black arrow), which pierces and mildly indents the inner layer of the dura (black arrowhead). The petroclival subsegment (upward white arrow) is outlined by the enhancing petroclival venous confluence. It extends inferior to a large sphenopetrosal ligament (downward white arrow) and continues as the cavernous subsegment (white arrowheads) to the superior orbital (leftmost arrowhead). D. Oblique postcontrast reconstruction in another patient demonstrates the entire CN VI.e. The petroclival segment (upward white arrow) and the cavernous segment (arrowheads) are seen. A small ligament (black arrowhead) is barely identified. IIH (Fig. 9C) (14). CN VI palsy is also the most common motor cranial neuropathy in intracranial hypotension (22). The dural cave segment is typically short, and masses in this region typically also affect the adjacent cisternal segment posteriorly or interdural segment anteriorly. A small meningioma, for instance, arising from the dural cave may lead to isolated CN VI palsy. FIG. 12. A 65-year-old man with CNV and CN VI palsies and history of metastatic adenocarcinoma. A. Axial precontrast constructive interference in steady state although the level of the Meckel caves and Dorello canal. Abnormal soft tissue is visualized in the right Dorello canal, the right petrous apex, and the posterior aspect of the right Meckel cave (white arrows). Notice the asymmetry of the Meckel caves (hatched arrows). The right Meckel cave is deformed, partially infiltrated, and anteriorly displaced. B. On the postcontrast scan, the left CN VI.e is visualized in the Dorello's canal between the dorsolateral clivus medially and the petrous apex laterally (white arrowhead). CN VI.e.II (black arrow) then extends anterior into the cavernous sinus between the left cavernous internal carotid artery and the left Meckel's cave. Abnormal enhancing tissue infiltrates the right Dorello canal, the right petrous apex, and the posterior right Meckel's cave in this patient with metastatic disease (white arrows). Both Meckel caves are visualized (hatched arrows). 418 Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review The location of the abducens porus (internal opening in dural cave) in the rostral-caudal direction is highly variable (13). From the perspective of neurosurgical planning, the most critical aspect of analysis of masses in this region is whether the CN VI.d is above, below, medial, lateral, or at the level of the mass (Fig. 10). High-resolution MRI is often critical in this regard. Imaging Approach noid ligament (Fig. 11). This ligament extends from the posterior clinoid process and the superolateral aspect of the clivus to the petrous tubercle (26). The Dorello canal is bordered by the petrosphenoidal ligament superiorly, the superior aspect of the clivus inferiorly, the dorsum sella medially, and the petrous apex laterally (Fig. 11) (26). The nerve is fixed to the surrounding dura matter as it traverses the Dorello canal, (26,27) the so-called second CN VI.d is well visualized on precontrast CISS. INTERDURAL SEGMENT (CN VI.e) Overview The interdural segment of CN VI (CN VI.e), the portion between the inner and outer layers of dura, extends from the dorsal aspect of the clivus to the superior orbital fissure (SOF) and is the longest interdural segment among the cranial nerves. It can be divided into the petroclival and cavernous subsegments. The term Dorello canal has been used interchangeably in the literature (23) to define the transition between the petroclival and cavernous subsegments or to describe the entire petroclival subsegment including the dural cave (4). We reserve the term Dorello canal for former definition, where CN VI.e typically passes under the petrosphenoidal (petroclinoid; Gruber) ligament (Figs. 2D, 11). For the purposes of nomenclature, we denote the petroclival subsegment of CN VI.e as CN VI.e.I and the cavernous subsegment of CN VI.e as CN VI.e.II. It should be noted that on anatomic studies, the arachnoid membrane and an accompanying dural sleeve surround CN VI past the petrosphenoidal ligament. However, on imaging, the distinction between CN VI.d and CN VI.e is made on the basis of the presence (CN VI.d) or absence (CN VI.e) of CSF visualized surrounding the nerve (Fig. 10). Visualization of CN VI.e.I and CN VI.e.II is based on venous enhancement which outlines the nonenhancing CN VI (Figs. 2B, C, 11) between the inner and outer layers of the dura. Identification of the unaffected cavernous CNs is necessary to document appropriate technique. Faint enhancement can obscure the nerve in the background of enhancing venous blood and is, in our experience, always pathologic. PETROCLIVAL INTERDURAL SEGMENT (CN VI.e.I) Anatomy Once CN VI pierces the inner layer of the dura at the cave, it ascends on the dorsal aspect of the clivus first within the inferior petrosal sinus (24) (Fig. 2B) for a variable length before entering what has been termed the petroclival venous confluence (25) to enter Dorello canal under the petrospheKontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 FIG. 13. A 53-year-old diabetic patient with osteomyelitis of the skull base developed a left CN VI palsy without facial pain or deafness. A. Precontrast axial constructive interference in steady state demonstrates left mastoid effusion. Meckel caves are within normal limits and symmetric (white arrows). B, C. Postcontrast axial CISS and T1 VIBE images demonstrate abnormal enhancement in the left petrous apex (upward white arrow) consistent with petrous apicitis. Abnormal enhancement is also visualized in the left Dorello canal and petroclival venous confluence (upward black arrows). The left CN VI.e.I is visualized in the left Dorello canal coursing through the abnormal enhancing inflammatory changes (white arrowhead). Notice that the Meckel caves are symmetric without evidence of abnormal enhancement (horizontal white arrows). 419 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 14. A 68-year-old patient with chondrosarcoma of the skull base and right CN VI palsy. A. Precontrast axial constructive interference in steady state shows a mass in the right petroclival region (white arrowheads), which erodes the periosteum of the dorsal clivus to infiltrate the petroclival confluence and the inner layer of the dura and extends into the cerebellopontine cistern, where it abuts CN VI.c (white arrow). The left CN VI.d is faintly seen (hatched arrow). The right dural cave is infiltrated and not identified. B. On the sagittal postcontrast oblique reconstruction, the proximal CN VI.c (black arrow) and the distal petroclival segment are seen (hatched arrow). The distal CN VI.c, CN VI.d, and the proximal CN VI.e.I are infiltrated and not identified. Notice the mass has violated the inner layer of the dura, extends into the cerebellopontine cistern, and abuts the pons. The CN III.c, III.d, and III.e are well visualized (white arrows). angulation of the sixth nerve, and the nerve extends laterally to reach the lateral wall of the cavernous portion of the internal carotid artery (ICA) (21). Usually, CN VI.e courses in the lateral aspect of Dorello canal. In variant cases when more than 1 CN VI.d is present, the multiple portions of CN VI.e.I may travel separately in the interdural space, with 1 portion extending above and the other below the petrosphenoidal ligament (20) before joining as CN VI.e.II. Vascular Supply The blood supply to CN VI.e.I is by the jugular branch of the ascending pharyngeal, the medial branch of the lateral clival artery, and meningohypophyseal trunk (28). Clinical Presentation Concomitant involvement of the trigeminal nerve (CN V) localizes the lesion to the petrous apex (Fig. 12). The classic clinical triad of Gradenigo syndrome, skull base osteomyelitis with involvement of Dorello canal and Meckel cave, includes diplopia, facial pain, and deafness (Fig. 13) (29). CN VI with hypoglossal nerve (CN XII) involvement localizes the lesion to the clivus (Godtfredsen syndrome) (30). Pathologic Conditions FIG. 15. Patient developed a left CN VI palsy due to inferior petrosal sinus thrombosis. A. Postcontrast axial constructive interference in steady state (CISS) through the pontomedullary junction demonstrates absent enhancement in the left inferior petrosal sinus and normal enhancement in the right inferior petrosal sinus (white arrow). Notice normal enhancement in the right sigmoid sinus (hatched arrow) and absent enhancement in the left sigmoid sinus (white arrowheads). The proximal CN VI.c is seen (black arrows). B. Postcontrast axial CISS through the upper medulla shows normal enhancement in the right sigmoid sinus (white arrow) and in the right inferior petrosal sinus (white arrow) proximal to the right jugular foramen. There is absent enhancement in the left inferior petrosal sinus and sigmoid sinus (hatched arrow) consistent with dural venous sinus thrombosis. 420 Skull base neoplasms which may impinge on CN VI.e.I include chondrosarcoma (Figs. 14, 15), chordoma, metastases, meningioma, and plasmacytoma/multiple myeloma (29). Approximately 75% of lesions producing Godtfredsen Syndrome are malignant, mainly metastases and nasopharyngeal cancer (30). Iatrogenic injury to CN VI.e.I can occur during catheter manipulation in the inferior petrosal sinus and the petroclival venous confluence (21). Inferior petrosal sinus thrombosis is an uncommon cause of CN VI palsy (Fig. 16). Imaging Approach CN VI.e.I is typically well visualized (Fig. 2B, D). Loss of visualization of the nerve in this region suggests pathologic Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 16. This patient had a history of right CN VI palsy for several days and was diagnosed with Tolosa-Hunt syndrome. Standard protocol magnetic resonance imaging was unremarkable. Postcontrast isotropic constructive interference in steady state. A. Axial image. The left CN VI.e (white arrows) is well visualized extending through Dorello's canal into the cavernous sinus. The right abducens nerve is not visualized in the cavernous region because of pathologic enhancement. B. In sagittal oblique reformatted views, CN VI.c (black arrow) and the proximal CN VI.e segment are seen with an abrupt transition to the region of pathologic enhancement (white arrow) (Reprinted with permission from [4]). enhancement because it can no longer be differentiated from surrounding venous blood (Fig. 16). CAVERNOUS INTERDURAL SEGMENT (CN VI.e.II) occasionally obscured on CISS imaging (3). CN VI.e.II receives sympathetic nerve fibers from the cavernous ICA, which then join CN V.1.e (interdural ophthalmic branch of the trigeminal nerve, V.1) and enters orbit. CN VI.e.II has the most medial entry and travels in the main venous compartment of the cavernous sinus, inferolateral to the cavernous ICA and medial to CN V.1.e (Fig. 17). Anatomy CN VI.e.II (Fig. 2C, D) courses medial to the superior aspect of Meckel cave and lateral to the proximal cavernous ICA, where it is fixed by connective tissue (21) and can be Vascular Supply Blood supply to CN VI.e.II is derived from the inferolateral trunk of the cavernous ICA (28). FIG. 17. A. Postcontrast axial constructive interference in steady state (CISS) through the cavernous sinuses demonstrates bilateral CN VI.e.II (arrowheads) lateral to the internal carotid arteries and medial to the Meckel caves. The lateral aspect of the right Gruber ligament (upward white arrow) is seen. Bilateral superior orbital fissure and the right CN VI.f (horizontal white arrow) are seen. B. Postcontrast coronal CISS through the pituitary gland demonstrates bilateral CN VI.e (white arrows). All the cranial nerves are visualized in the cavernous sinuses bilaterally. Note that the visualization of the cranial nerves in the cavernous sinuses is based on venous enhancement and can be seen only after contrast administration. Abnormal hypointense signal within the clivus in both planes represents fibrous dysplasia. Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 421 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Facial pain or sensory loss in the distribution of the maxillary division of the trigeminal nerve (CNV.2) associated with CN VI palsy is a presentation of nasopharyngeal carcinoma, sometimes referred to as pseudo-Gradenigo syndrome (35,36). Pathologic Conditions FIG. 18. A. Postcontrast coronal constructive interference in steady state demonstrates that all the cranial nerves are well depicted in the normal right cavernous sinus outlined by enhancing venous blood. The abducens nerve is located within the substance of the cavernous sinus surrounded by venous blood, inferolateral to the right internal carotid artery (ICA) (hatched arrow), and medial to CN VI.e. The remained of the CNs is arranged along the lateral wall of the sinus. The mass in the left cavernous sinus enhances avidly (arrowheads) and is a recurrent meningioma. It displaces the left ICA (black arrow) and left cavernous sinus nerves inferolaterally, and the individual nerves cannot be identified. The mass also extends extracranially through an expanded left foramen ovale. III, third nerve; IV, fourth nerve; V1, ophthalmic nerve; V2, maxillary nerve; V3, mandibular nerve; VI, sixth nerve. Cavernous sinus syndrome is most commonly due to neoplasm (e.g., pituitary adenoma, nasopharyngeal carcinoma, metastases, lymphoma, and meningioma) (Fig. 18) (35,37). Other common causes include carotid artery aneurysm (38) and CCF (cavernous sinus thrombosis is an uncommon cause) (7). Embolization of a CCF or intracavernous ICA aneurysm can produce CN VI palsy, presumably because of direct compressive effect or nerve ischemia. Lymphoproliferative and infiltrative disorders (IgG4related disease, sarcoidosis), inflammation/Tolosa-Hunt syndrome (Figs. 16, 20), and trauma are all important diagnostic considerations (7,39). Infectious causes of cavernous sinus syndrome have declined because of antibiotics, but remain a life-threatening condition, particularly for patients vulnerable to fungal disease (36,40). Accurate diagnosis and management may require biopsy. Precise localization of relevant neurovascular structures is essential to reduce procedure-associated morbidity. Clinical Presentation CN VI palsy with Horner syndrome localizes the lesion to the proximal cavernous sinus (Parkinson syndrome) (31). Involvement of CNs which course through the cavernous sinus increases the likelihood of localization to the cavernous sinus (32). Despite the most medial location of CN VI.e.II in the cavernous sinus, the third nerve is more commonly affected by pituitary tumor (33). CN VI palsy with episcleral venous congestion and elevated intraocular pressure ± proptosis are classical features of carotid cavernous fistula (CCF) (34). Imaging Approach CN VI.e.II is best visualized with postcontrast imaging including postcontrast CISS (Fig. 2C, D). Inside the cavernous sinus, one can consistently identify the interdural segments of CNs III, IV, V.1, and V.2, which are arranged along the lateral fibrous sinus wall (Fig. 19). Thin linear structures are rarely seen on postcontrast CISS from the undersurface of the cavernous ICA to CN VI.e.II and may represent sympathetic plexus fibers. FORAMINAL SEGMENT (CN VI.f) Anatomy The SOF is located between the greater and lesser wings of the sphenoid bone and lies inferolaterally to the optic strut. The SOF extends superolaterally to inferomedially in the coronal plane and CN VI.f lies in the inferomedial compartment (41). Vascular Supply FIG. 19. This patient developed an isolated left CN VI palsy. Postcontrast coronal constructive interference in steady state through the anterior cavernous sinus and superior orbital fissure demonstrates the normal hypointense right CN VI (white arrow). The left CN VI enhances and is obscured (white arrowhead). The presumptive clinical diagnosis was microvascular ischemic palsy. 422 The blood supply to CN VI.f is derived from the anteromedial branch of the inferolateral trunk of the cavernous ICA (12,28). Clinical Presentation The SOF connects the cavernous sinus and intracranial cavity with the orbit and can be involved by pathology Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 20. Tolosa-Hunt syndrome. A, B. Precontrast and postcontrast axial constructive interference in steady state (CISS) through the superior orbital fissure reveals asymmetric fullness and enhancement in the left cavernous sinus (white arrowheads) extending and expanding the left superior orbital fissure (between white arrows). C, D. Precontrast and postcontrast coronal CISS shows the normal right superior orbital fissure (horizontal white arrow). There is effacement of the normal fat planes and expansion by enhancing tissue with the left superior orbital fissure (white arrowhead). The optic nerves (downward white arrows) are identified medial to the anterior clinoid processes. originating in either compartment (Fig. 19). Clinically, the presentation resembles cavernous sinus syndrome with CN V involvement limited to the ophthalmic division (CN V.1), and possible exophthalmos. Proptosis may also be present and is more often seen with SOF pathology than cavernous sinus disease and may be helpful localizing the pathologic process (7). Pathologic Conditions Trauma, neoplasms, infection, and inflammation can affect CN VI.f. Common inflammatory conditions are Tolosa- Hunt syndrome (Fig. 20), orbital pseudotumor, sarcoidosis, and Wegener granulomatosis (42). Bone disorders associated with osseous hypertrophy and expansion, such as fibrous dysplasia, Paget disease, and osteopetrosis, can involve the SOF and lead to ophthalmoplegia (43). Imaging Approach CN VI.f is visualized with high-resolution postcontrast imaging. Lesions of sufficient size may alter the surrounding bone and become visible on CT. ORBITAL (EXTRAFORAMINAL) SEGMENT (CN VI.g) Anatomy CN VI crosses the SOF and the annulus of Zinn medial to the lateral rectus muscle origin, inferior to the nasociliary nerve, and lateral to the inferior division of the CN III.g (41) CN VI.g extends laterally along the medial aspect of the lateral rectus muscle and inserts at the junction between its posterior third and anterior two-thirds (Fig. 21). Clinical Presentation Ophthalmoplegia, ptosis, and decreased corneal sensation may be encountered on examination (39). The term orbital apex syndrome is applied with optic nerve involvement (42). Mass effect in the orbit results in proptosis and swelling of the eyelids and chemosis, aiding localization. Pathologic Conditions FIG. 21. Postcontrast coronal constructive interference in steady state although the proximal orbits demonstrates the CN VI.g. as round hypointensities (white arrows) coursing on the medial surface of the proximal lateral rectus muscles. Kontzialis et al: J Neuro-Ophthalmol 2015; 35: 412-425 Inflammatory, infectious, neoplastic, and iatrogenic/traumatic causes can affect the orbital apex (42). Head and neck tumors (including perineural spread), nerve sheath tumors, 423 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review meningioma, metastatic disease, and hematologic malignancies are included in the differential diagnosis (42). Imaging Approach CN VI.f is frequently, although not consistently, visualized coursing along the medial aspect of the lateral rectus muscle to the point of innervation and may be seen on highresolution 3D MRI because of the contrast with adjacent orbital fat. Despite use of a fixation spot placed in MRI gantry, orbital motion artifacts limit the application of highresolution MRI for CN VI.f in certain individuals. CONCLUSION Recognition of the segmental anatomy of the cranial nerves allows for a regimented approach to imaging evaluation and lends itself to categorization of pathologic entities. Knowledge of the varying patterns of clinical presentation of patients with CN VI dysfunction may dictate the imaging protocol used and should direct attention to the segment most likely to be affected. Many patients presenting with CN VI palsy have not received a diagnosis guided by imaging abnormalities in the past. Future studies are necessary to determine how many patients may benefit from a segmental approach to highresolution 3D MRI of CN VI palsy. REFERENCES 1. Chi SL, Bhatti MT. The diagnostic dilemma of neuro-imaging in acute isolated sixth nerve palsy. Curr Opin Ophthalmol. 2009;20:423-429. 2. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology. 2004;111:369-375. 3. 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