Advanced MRI of the Optic Nerve

Most patients with idiopathic intracranial hypertension (IIH) are obese. Weight loss is felt to be an important factor in improving IIH. The mechanism by which weight loss leads to a reduction in elevated intracranial pressure is unclear. Evidence from prospective studies evaluating the role of weight loss in IIH is lacking. We performed a detailed review of the published literature regarding the association of IIH and obesity, including proposed pathogenetic mechanisms, and the effect of weight loss and weight-loss interventions in IIH. References were identified by searching PubMed with the terms idiopathic intracranial hypertension and weight loss. Additional citations were found in the identified references. Over 90% of IIH patients are obese or overweight. The risk of IIH increases as a function of body mass index (BMI) and weight gain over the preceding year. The risk of IIH-induced vision loss also increases with increasing BMI, especially with BMI >40 kg/m. Several mechanisms have been proposed linking obesity to the development of IIH but the pathophysiology remains unknown. Published studies and clinical observations strongly support weight loss as an effective treatment, although there are no prospective controlled trials. Weight loss in the range of 6%-10% often leads to IIH remission. Weight loss of ≥5% at 1 year is achieved in roughly 50%-70% of patients if they are enrolled in a high-intensity lifestyle modification program and in 20%-35% of patients if they direct their own weight loss. Weight is typically regained over 1-3 years but about a third of patients maintain ≥5% weight loss over the long term. Patients treated initially with lifestyle modification therapy show a modest persisting benefit over self-directed patients. Selected commercial weight loss programs also may improve long-term maintenance of weight loss. New antiobesity drugs significantly improve the proportion of obese patients who have ≥5% loss of weight at 1 year. Obesity is an important contributing factor for the development of IIH, although the pathophysiological mechanism linking obesity to IIH is unknown. The risk of developing IIH and associated visual loss increases with increasing BMI. Weight loss is an effective treatment for IIH. Long-term maintenance of initial weight loss is helped modestly by lifestyle modification programs and possibly by selected commercial weight loss programs. New antiobesity drugs may provide further options for IIH therapy in the future.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Advanced MRI of the Optic Nerve Michael J. Hoch, MD, Mary T. Bruno, BS, Timothy M. Shepherd, MD, PhD Background: Clinical orbital MRI protocols are routinely used to study the optic nerves and exclude compressive lesions, infarctions, or inflammation. However, the small caliber and divergent oblique orientations of the optic nerves make it challenging to characterize them well with conventional MRI, especially since adjacent air-filled bony structures distort the MRI signal and motion is a problem even in cooperative, healthy volunteers. Evidence Acquisition: Over the past 3 years we have experimented with multiple novel MRI approaches and sequences to better characterize the optic nerves. The perfect MRI protocol would be quantitative and sensitive to subtle optic nerve pathologic changes, provide high spatial resolution, be rapidly acquired, and resistant to motion degradation. Results: This review provides an update of recent MRI sequence innovations for the optic nerves being currently translated into clinical practice. Methods discussed include rapid MRI with compressed sensing or simultaneous multislice approaches, postprocessing techniques for quantitative T2 mapping or track density imaging, and multiple MRI sequences for measuring diffusion in the optic nerves. Conclusions: Recently-developed orbit-specific MRI coils, quantitative sequences, and rapid acquisition techniques can improve our future ability to study optic nerve pathologies noninvasively. As advanced MRI becomes more proficient at Department of Radiology and Imaging Sciences (MJH), Emory University, Atlanta, Georgia; Department of Radiology, Section of Neuroradiology (MTB, TMS), New York University Langone Medical Center, New York, New York; and Center for Advanced Imaging Innovation and Research (CAI2R) (TMS), New York, New York. Supported in part by the Center for Advanced Imaging Innovation and Research, an NIH NIBIB Biomedical Technology Resource Center (Grant P41EB017183). T. M. Shepherd speaks for Siemens Healthcare without accepting travel reimbursement or honorarium. T. M. Shepherd received research support from the National Institute of Aging (NIH 1K23 AG048622-01). The remaining authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Timothy M. Shepherd, MD, PhD, Department of Radiology, Section of Neuroradiology, New York University Langone Medical Center, 660 First Avenue, Room 226, New York, NY 10016; E-mail: [e-mail] Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 characterizing the optic nerves, its role in the clinical management of patients should increase. Journal of Neuro-Ophthalmology 2017;37:187-196 doi: 10.1097/WNO.0000000000000511 © 2017 by North American Neuro-Ophthalmology Society CLINICAL MOTIVATIONS FOR MRI IMAGING OF THE OPTIC NERVE T he optic nerve can be affected by numerous pathologies including primary neoplasms, metastases, inflammation, intracranial hypertension, and glaucoma. Although the retina and optic nerve head can be assessed with ophthalmoscopy and optical coherence tomography, large portions of the optic nerve are "hidden" from clinical examination by the globe and bones of the orbit and skull base. Computed tomography (CT) provides rapid acquisition in the emergency setting and excellent bone detail. MRI provides superior visualization of the orbital soft tissues and optic pathways without ionizing radiation (1,2). MRI better characterizes postchiasmatic portions of the visual pathways that also may be affected by different disorders. Clinical MRI of the Optic Nerve The optic nerve is not well characterized on conventional brain MRI because of its relatively small size and surrounding orbital fat. Optimized and targeted orbital sequences that include fat saturation ideally should be obtained before advanced MRI sequences described below are considered. A orbital MRI protocol is distinct from a routine brain MRI protocol-combining the 2 complete protocols may result in an excessively long examination for the patient and may not be reimbursed by insurance. The following is a brief synopsis of a typical orbital protocol, common optic nerve disease imaging findings, and when to clinically consider CT instead of MRI. 187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Routine Protocol Precontrast axial and coronal T1 (without fat saturation), axial T2, and coronal T2 images with fat suppression are common components of a clinical MRI orbit protocol. High signal from fat on precontrast T1 images without fat suppression helps to assess marrow in the bony orbit walls, evaluate the size of the extraocular muscles, and detect intraconal masses. After intravenous gadolinium injection, axial, and coronal T1 images with fat suppression are acquired. The orbital apex and optic canal are best evaluated on axial sequences. The optic nerve, chiasm and tracts are best assessed in the coronal plane. Postcontrast fatsuppression pulse sequences are an essential feature of the orbital protocol since the orbital portion of the optic nerve is surrounded by fat (3). Fat-suppression pulses are sensitive to magnetic field inhomogeneities and become suboptimal because of local geometric distortions in patients with dental or craniofacial hardware. A short tau inversion recovery (STIR) pulse sequence can be substituted to provide superior image quality (4). However, this longer sequence is prone to artifacts from eye motion and vessel pulsation. Common Disease Findings and Interpretation Because the optic nerve is a central nervous system structure, it is surrounded by all 3 meningeal layers, surrounded by cerebrospinal fluid (CSF), and its axons are myelinated by oligodendrocytes. The optic nerve, meninges, and CSF together constitute the radiologic optic nerve sheath complex (ONSC). The most common ONSC tumors are meningioma and optic pathway glioma (5). Both tumors demonstrate similar fusiform enlargement with enhancement. Meningiomas arise from arachnoid cells within the meninges so the centrally located optic nerve becomes compressed. Circumferential meningiomas have a typical "track-track" pattern of enhancement (6), whereas other meningiomas may have a more eccentric location. In contrast, gliomas expand the nerve centrifugally and there are often additional findings including nerve kinking, mucinous cyst formation, and skip lesions (7-9). MRI scans also can detect glioma spread to postchiasmatic structures (10). Optic nerve inflammation may mimic tumor on MRI in the acute setting with nerve expansion, edema, and enhancement. Typically, findings are most apparent in the orbital segment of the nerve, which will be swollen with increased T2 signal (11). Contrast enhancement is best seen with fatsuppression techniques in the coronal plane. Enhancement will be seen in greater than 90% of cases if the MRI is obtained within 3 weeks of symptom onset (12). Of note, MRI of the optic nerve for a patient with clinically-established MS presenting with new symptoms of optic neuritis is unnecessary since there are rarely alternative causes (13). CSF surrounding the optic nerve provides excellent contrast when evaluating the ONSC. Increased intracranial pressure in idiopathic intracranial hypertension can enlarge 188 the CSF space of the ONSC. This is best seen on fatsuppressed T2 images as vertical or horizontal buckling of the nerve. Papilledema appears as abnormal anterior convexity of the optic disc at the posterior globe on axial T2-weighted images (14). Alternatively, with intracranial hypotension there may be almost no CSF surrounding the optic nerve on MRI. Optic nerve atrophy from any cause will become obvious because of contrast between the nerve and surrounding CSF signal on T2 sequences. Reasons to Choose CT Over MRI Although MRI offers superior visualization of orbital soft tissues, the evaluation of structures with a low concentration of mobile protons (e.g., cortical bone) is limited. Hence, CT is recommended to evaluate orbital trauma or bony lesions (15,16). MRI also has longer scan times compared to CT that can lead to motion degradation in uncooperative, pediatric, elderly, or claustrophobic patients. CT also should be performed when MRI is not clinically feasible or contraindicated, including patients with implanted medical devices and in patients with CT-proven intraorbital ferromagnetic foreign bodies (e.g., from previous trauma or gunshot wound) (17). There are other causes of artifact for the orbital MRI such as cosmetic makeup and tattoos, dental braces, and asymmetric fat suppression. Some institutions now perform orbital MRI in patients with pacemakers when directly supervised by electrophysiology or cardiology. CHALLENGES TO MRI OF THE OPTIC NERVE There are several inherent challenges to imaging the optic nerve. The optic nerve is small in caliber varying between 1.5 and 4 mm in diameter and being most narrow in the optic canal (18). Especially for noise-limited MRI sequences like diffusion, there can be a stark trade-off between signalto-noise ratio (SNR) and sufficient spatial resolution to minimize partial volume effects with CSF and/or orbital fat. The adjacent air-filled paranasal sinuses and skull base create large magnetic field inhomogeneities that result in geometric distortions and signal drop-out that can mask optic nerve abnormalities. This problem is exaggerated at higher magnetic field strengths or in echoplanar techniques where long echo-train lengths are required to generate sufficient spatial resolution for the optic nerve. These magnetic field inhomogeneities also degrade fat saturation sequences. Artifacts from patient head motion or, more commonly, involuntary eye movements blur the optic nerve and confound quantitative approaches. The range of movement for the orbital optic nerve is highest, whereas the nerve is relatively tethered at the optic canal and there is minimal motion for its precanalicular portion (19). The orbital optic nerve has been documented to move a mean total distance of 11.8 mm over a mean area of 5.2 mm2 during a 3Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review minute diffusion acquisition in healthy volunteers asked to fixate on a stationary target placed on the inner surface of the MRI scanner bore (20). The relative position of the orbital nerve also can drift during the scan even in highlymotivated healthy subjects and conjugate gaze is not always maintained (especially if the eyes are "closed"). Asking the patient to fix their eyes on a single point for 5 minutes did not significantly reduce movement (21). Therefore, rapid MRI acquisitions to reduce motion degradation are a key emphasis of current research. Conversely, using real-time MRI to characterize motion of the optic nerve and other orbital structures has been relatively unexplored (22,23). Motion of the optic nerve at 3 different positions is demonstrated in the attached video using a coronal single-shot TABLE 1. Summary of advanced MRI sequences for characterizing the optic nerve with 1.5- or 3-T clinical MRI scanners MRI Sequence* Description Advantages Disadvantages Typical Resolution Acquisition Time, min 0.69 mm Poor fat saturation isotropic artifacts in the presence of metal 6.0 0.45 · 0.45 · Poor soft tissue 3-mm contrast and some blurring 0.7 Marginal spatial 3-mm resolution of optic isotropic (b nerves = 1500 s/mm2, 30 directions) Reduced SNR 1.5 · 1.5 · Reduced image Limited field-of-view in the Coronal 2.5-mm (b = distortions and phase-encode direction reduced 800 s/ improved spatial using 2D selective pulses FOV mm2, 10 resolution of optic diffusion nerve (ZOOMit) directions) 1.5 · 1.5 · Longer scan times Multishot, readout segmented Similar benefits to Coronal 2.5-mm (b = compared to echoplanar imaging with reduced FOV but multishot 800 s/ reduced FOV or short echo spacing with higher signal-todiffusion mm2, 10 conventional noise ratios (RESOLVE) diffusion MRI directions) Track density Super-resolution via Direct visualization of Offline processing 3-mm imaging postprocessing of high small white matter and quantification isotropic (b angular resolution DWI data pathways and errors from = 2500 with simultaneous multislice portions of cranial tractography s/mm2, 64 acquisition nerves biases directions) Coronal T2 mapping accounting for Sensitive to occult Additional 1.5 · 1.5 · multiecho intrinsic acquisition biases tissue pathology postprocessing 3-mm (10 spin echo and permits and vulnerable to serial echo images quantitative pulsation artifacts times) analysis 0.57-mm Subjective Fast, high-resolution 3D volumetric Compressed sensing isotropic impressions of 3D isotropic reconstructions using image T2 (SPACE) reduced image acquisition in sparsity with subquality Nyquist sampling 4.5‡ Axial radial VIBE Samples spokes through center of k-space Less motion degradation, obligatory fat saturation Rapid sampling of half k-space Fast and less sensitive to motion and snapshot image formation Coronal single-shot fast spin echo (HASTE) Axial diffusion- Contrast from white matter structure and cellular water tensor homeostasis imaging of head Sensitive to tissue pathology occult to conventional MRI sequences 2.2† 5.5† 4.5 5 2.5 *We have used vendor-neutral description of the MRI sequence, but also include Siemens Healthcare sequence names (in parentheses) since this affects the resolution, parameters, and scan times we typically obtain. "b-value" is a measure of diffusion-weighted strength. † Overall scan times for diffusion sequences will be influenced by the fat saturation approach used. ‡ With simultaneous multislice acquisitions using a slice acceleration factor of 2, scan time is reduced to 3 minutes. DWI, diffusion-weighted MRI; FOV, field of view; HASTE, half-Fourier acquisition single-shot turbo spin echo; s, seconds; SNR, signal-tonoise ratio. Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 189 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review fast spin echo sequence (see Supplemental Digital Content, Video, http://links.lww.com/WNO/A227). Optic nerve motion limits the utility of conventional postprocessing realignment techniques. Optic nerve orientation changes over its course and is consistently oblique to the standard axial, sagittal, and coronal planes of conventional MRI. The nerve is not simply a cylinder extending from globe to chiasm but is composed of 2 obliquely-oriented parts that taper and form a pivot at the orbital apex. The right and left optic nerves do not run parallel but rather diverge from each other anterolaterally toward their respective orbital apices. This limits MRI slice geometries to sample both optic nerves simultaneously. Most groups have focused on coronal orientations, but because of the small optic nerve size relative to 2D geometry slice thickness and diverging oblique orientations, there are still significant partial volume effects. Volumetric 3D isotropic MRI sequences minimize partial volume effects by facilitating multiplanar or curviplanar reformats. The optic nerve is better evaluated with 3D T1 and T2 sequences when compared with respective 2D sequences (24), However, volumetric 3D sequence acquisition times require 5-6 minutes. A further limitation is that volumetric T2 sequences are "CSF-weighted" such that pathological T2 signal intensity changes within the optic nerve can be hard to appreciate. The oblique optic nerve orientation also creates potential for artifactual hyperintensity in short echo time MRI sequences (e.g., proton density images) due to the magic angle effect, which is a complex phenomenon resulting from the quantum mechanics of spin interactions relative to their orientation to the main magnetic field (25,26). theoretically-doubled SNR compared with 1.5-T. However, it is not always so simple or straightforward-the MRI protocols must be adjusted because at 3-T more radiofrequency energy is deposited into the patient, T1 contrast decreases, T2 relaxation times shorten, whereas chemical shift and susceptibility artifacts may be increased. Several new research sequence innovations and technological advances described below have the potential for improved imaging the optic nerve (Table 1). RECENT INNOVATIONS FOR MRI OF THE OPTIC NERVE Half-Fourier Acquisition Single-shot Turbo Spin Echo Half-Fourier acquisition single-shot turbo spin echo (HASTE) imaging is a single-shot echo-planar fast spin echo sequence for high-resolution T2 images (31,32) specific to Siemens (but other MRI vendors provide similar Discussion of MRI innovations should begin with the use of high-field clinical scanners, that is, 3-Tesla which have High-Resolution Approaches Radial VIBE Traditional fat-suppressed postcontrast T1 turbo spin echo imaging is often motion-degraded because of respiration, vascular pulsation, and eye movements. The fat-suppressed T1-weighted 3D radial gradient-recalled echo-volumetric interpolated breath hold examination (Radial VIBE) samples the x and y planes of k-space in a radial spoke-wheel fashion (27,28). Note, "k-space" is a graphical representation of the data directly obtained during MRI scanning and represents an array of spatial frequencies present-the Fourier transformation of k-space creates the anatomical MRI images. Compared with conventional Cartesian sampling technique, radial sampling has reduced sensitivity to motion because of the varying sample directions and the oversampling of the center of the k-space (29). The radial-VIBE sequence has demonstrated superior image quality when evaluating the orbits compared with conventional postcontrast images (30) (Fig. 1). This sequence also lends itself to dynamic temporal resolution of contrast enhancement in the optic nerve or associated mass lesions (i.e., for potential future modeling characterization of perfusion and permeability). FIG. 1. Comparison of postcontrast images using standard T1 MRI with fat saturation (A) vs Radial-VIBE MRI (B) in the orbits of a 59-year-old man with a subtle left optic nerve sheath meningioma. The Radial-VIBE image (B) clearly shows classic "tramtrack" appearance of the tumor (arrow) not obvious on the conventional imaging (A). Note also the blurring of the lens and artifactual thickening of the extraoccular muscles in the standard images due to motion. 190 Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review versions). HASTE uses phase-conjugate symmetry to take advantage of "mirror-image" properties in k-space. Thus, just over half the data needs to be acquired while the remaining lines of k-space are estimated. HASTE images (,1 second) can virtually eliminate motion artifacts. HASTE 2D slices also are concatenated making it further resistant to motion degradation as only the portion of the study acquired during motion is imperfect. The precision of HASTE MRI exceeds ultrasonographic studies for determining optic nerve diameter (33) and HASTE measures of decreased caliber correlated with glaucoma severity (34). We routinely use orbital HASTE to supplement a diagnostic head MRI in patients with suspected clinically-isolated syndrome or MS (Fig. 2). The HASTE acquisition of 43 seconds gives us a relatively "free" look at the optic nerves. The acquisition can be acquired with or without fat saturation. Diffusion MRI Conventional Diffusion Diffusion-weighted MRI (DWI) characterizes how the random Brownian motion of water is altered in normal and pathologic nervous tissue environments (35). Reduced water diffusion has proven sensitive, but not specific, to many pathologies in the brain including ischemia, infection, and inflammation. There are reports demonstrating reduced diffusion for acute optic nerve ischemia (36,37) (Fig. 3) and acute optic neuritis (38,39). Diffusion also can increase the sensitivity for detecting highly-cellular malignancies that infiltrate the ONSC such as lymphoma or primitive neuroectodermal tumor. However, the typical axial DWI sequence for the brain is a poor choice for the orbits because of suboptimal resolution of the obliquely-oriented optic nerves and potential anisotropy effects. Diffusion Anisotropy Myelin creates a largely impermeable barrier to water diffusion orthogonal to the long axis of the axon. With insufficient angular resolution, routine diffusion trace MRI signal intensity can appear artificially increased (and called "pathologic") because one of the limited contributing diffusion MRI sequence gradients is oriented orthogonal to the long axis of the normal, healthy optic nerve. Diffusiontensor imaging (DTI) is the simplest mathematical extension of DWI to derive the principal orientations of water diffusion, quantify and eliminate these anisotropy artifacts, and generate tractography that correlates with specific white matter pathways (35). Fractional anisotropy is a scalar measure of the degree of diffusion coherence in one direction- values vary between 0 and 1, where CSF fractional anisotropy approaches "0" ,whereas for highly coherent white matter, like the corpus callosum, fractional anisotropy approaches "0.8-1." A useful benchmark for diffusion MRI quality then is the reported fractional anisotropy value for Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 FIG. 2. Comparison of coronal short tau inversion recovery (STIR) MRI obtained in 4 minutes (A) vs coronal half-Fourier acquisition single-shot turbo spin echo (HASTE) MRI obtained in 43 seconds (B) in a 25-year-old woman presenting with left optic neuropathy. The HASTE image provides a much more rapid characterization of left optic nerve volume loss, but T2 contrast in the affected optic nerve and overlying orbitofrontal brain is decreased by the rapid acquisition and longer echo time (144 milliseconds). Although rapid HASTE sequences also can be performed with fat saturation, they do not have the same dynamic range for optic nerve T2 contrast that can be obtained using STIR MRI sequences in cooperative patients that hold still. Coronal HASTE high-resolution images (C) can provide more precise, accurate measurements of optic nerve diameter, circumference and area (shown here in a different patient). the normal optic nerve-low values generally imply partial volume effects from orbital fat or motion degradation due to long scan times. This sensitivity to white matter structure and organization makes DTI and/or diffusion tractography useful surrogate markers for axon and myelin integrity. DTI parameters are altered for the optic nerves and radiations by glaucoma (40) and correlate with glaucoma severity (41). DTI values correlate well with visual dysfunction on visual evoked potentials in optic neuritis with MS (42). Unlike other clinical MRI sequences for the optic nerve, diffusion MRI provides a quantitative, objective marker of optic nerve pathology and seems sensitive to subtle microscopic 191 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 3. Two different examples of axial diffusion-weighted MRI in elderly male patients with cerebrovascular risk factors that both experienced sudden-onset vision loss in the left eye. Funduscopic examination with fluorescein angiography in both cases confirmed a left central retinal artery occlusion. MRI of the head was obtained to exclude other areas of ischemia. A. Diffusion-weighted MRI in the first patient demonstrates a long segment of hyperintensity (arrow) in the left retrobulbar optic nerve on diffusion trace with corresponding low ADC map (arrow) (B). C. The second patient's left optic nerve ischemia MRI findings were much more subtle on diffusion trace, (arrow) but there was a corresponding 27% reduction in the apparent diffusion coefficient (arrow) D. Diffusion anisotropy can artifactually increase perceived signal in normal optic nerves because routine diffusion acquisitions for head protocols use limited angular resolution, making confident detection of subtle abnormalities challenging without clinical suspicion or a dedicated orbit MRI protocol. tissue changes, such as early selective axonal loss, that are not easily recognized by radiologists, referring physicians and sometimes patients. Most clinical applications thus far have focused on DTI characterization of the optic nerves since the diffusion data required for this analytical model is feasible in patients. There are newer models of nervous tissue complexity (43) that may provide more specific measures of axon and myelin integrity, but these currently require long acquisitions that may not be practical in patients. Reduced Field-of-View or Multishot Methods DWI or DTI of the optic nerve remains challenging because you need high spatial resolution, yet, doubling spatial resolution reduces SNR by 87% and diffusion is already a "signal-starved" MRI sequence. It also is only clinically feasible to acquire DWI with echoplanar imaging where the relatively high spatial resolution needed requires a long echo train that becomes more vulnerable to magnetic susceptibility artifacts (e.g., from the adjacent sphenoid sinus). Reducing the field-of-view to exclude the unwanted tissues can reduce long echo-train lengths, but will lead to aliasing or wrap-around artifacts unless the MRI signal from the unwanted tissue volume is suppressed or never excited to 192 resonance in the first place (19). Using this technique, diffusion values correlated well with clinical and electrophysiological findings of optic neuritis (44). More recently, this method was used for DTI of the optic nerve in normal subjects and those with optic neuritis (21,45). Alternatively the echo-train length also can be reduced by segmenting it into separate components ("multi-shot") to reduce geometric image distortion (Fig. 4). This approach applied to DTI of the optic nerve provides a higher SNR (since overall phase-encode steps are not reduced) and improved resolution with fewer artifacts compared with single-shot techniques (46). The trade-off is increased scan time. Scan time may be reduced with parallel imaging, partial Fourier acquisitions and/or recently-developed simultaneous multislice (SMS) acquisitions (47). Other Directions Quantitative T2 A series of spin echo sequences with increasing echo time can characterize exponential MRI signal decay to estimate T2 values for nervous tissue. However the long scan times required are not clinically feasible (e.g., 30 minute scans). Multiecho fast spin echo pulse sequences, which acquire multiple measures of signal decay per 90° pulse, can reduce Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 4. Coronal T2 MRI shows normal aerated paranasal sinuses medial and inferior to the bony orbit (A) that result in geometric distortions when high-resolution coronal diffusion-weighted MRI of the optic nerves is attempted. Panel (B) demonstrates distortion in the coronal diffusion trace (top) and direction-encoded color (DEC) map (pixel intensity = fractional anisotropy, where red = left-right, green = anterior-posterior and blue = craniocaudal coherent orientations) such that it is difficult to even identify the bilateral optic nerves (arrows). C. A multishot echoplanar diffusion acquisition of the same patient generates almost distortion-free coronal diffusion trace and DEC map. This approach reduces the echo-train length to reduce geometric distortions at the expense of longer scan times. times for T2 mapping to 5-6 minutes but overestimate T2 values with wide variance (48). We have implemented an echo-modulation curve T2 mapping package that models both stimulated echoes and radiofrequency inhomogeneities to generate images independent of the scanner and parameter values and at clinically-feasible scan times (49). This method can be used to increase anatomical contrast and allow the accurate quantification of optic nerve T2 values. We have begun to implement this novel method in patients with optic neuritis and glaucoma, where subtle changes would not be seen on conventional imaging (Fig. 5). Like diffusion, T2 maps may detect optic nerve gliosis, demyelination, and axonal loss not visually-obvious on conventional MRI, but unlike diffusion there is ample SNR, the acquisition is fast, more resistant to susceptibility artifacts, and can be implemented even with older 1.5-T MRI scanners. compressed sensing reconstructions that take advantage of intrinsic image sparsity to undersample k-space potentially without meaningful compromise to image quality New MRI Acceleration Techniques A major limitation to MRI of the optic nerve is motion- patient cooperation and acquisition speed are the key factors to successful imaging. A recently-developed SMS approach can provide 2- to 4-fold acceleration of diffusion acquisitions without degrading image quality (47). This SMS method theoretically can be applied to any 2D acquisition such as turbo spin echo. We recently applied SMS diffusion acquisitions to generate 500-mm superresolution diffusion-based parameter maps of the in vivo human brainstem using Track Density Imaging (50,51) (Fig. 6). Compared with conventional 3-T MRI approaches, this approach provides direct visualization of optic tracts, oculomotor nuclear complex, and medial longitudinal fasciculus. Another promising method is Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 FIG. 5. Coronal reconstruction of a 3D volumetric scan (A) and echo-modulation curve (EMC) proton density map (B) of the orbital optic nerve in a 25-year-old woman with multiple sclerosis and remote history of right optic neuritis. The novel EMC mapping technique has potential to detect microstructural changes before they are clinically-apparent-here, there is a 20% increase in proton density in the right optic nerve (B, arrow) compared with controls that was not detected on conventional orbital MRI sequences (including short tau inversion recovery [STIR]). Note the dynamic range of the EMCderived color maps proton density was thresholded to render the abnormal optic nerve proton density more conspicuous. R, right; L, left. Color scale bar is relative proton density, no units. 193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 6. Oblique cropped axial reconstructed 500-mm isotropic super-resolution color-encoded track density images at the hypothalamus (A) and rostral midbrain (B) levels demonstrate the optic chiasm (A, short arrow), optic tracts (A, arrowheads), and oculomotor nerves (B, long arrows). Here, voxel intensity reflects the number of probabilistic tractography streamlines and color reflects coherent intravoxel streamline orientations (red = left-right, green = anterior-posterior and blue = craniocaudal). This new postprocessing technique shows great promise for future detailed study of the optic pathways, other cranial nerves, brainstem, and thalamic nuclei/connections involved in vision and eye movements. (52). With incoherent sampling and iterative nonlinear reconstructions, compressed sensing images can be generated with only 10%-20% k-space sampling and thus substantially reduced scan times while still providing images of sufficient diagnostic quality. This method has been combined with parallel imaging (53) and could serve as a rapid screening tool in the outpatient setting. New Coils for Better Visualization The sensitivity of surface coils falls off dramatically with increasing depth away from the patient. The move toward small multichannel surface coils often leads to dramatic improvements in SNR particularly for peripheral structures near the head surface. The disadvantage is nonuniformity of the image where the periphery is accentuated and signal from the center is attenuated. This can be corrected with postprocessing filters. The 32- and 64-channel coils now available commercially easily outperform coils that were state of the art a decade ago. We have explored the creation of new targeted orbit surface coils that do not overtly cover the eyes (Fig. 7). Specific, flexible multiple coil geometries targeted to the optic nerve and orbit can dramatically FIG. 7. A. An anatomic-specific, custom-built 10-channel transmit-receive coil for optic nerve and orbital MRI with the cover off and electronic components exposed. B. Normalized signal-to-noise ratios (SNR) for the same healthy volunteer with this coil (top) vs a manufacturer's 20-channel head and neck coil (bottom) where the SNR for the orbital optic nerve is increased up to 36% by the new coil. To achieve this SNR gain with the standard coil would require 85% longer scan time. 194 Hoch et al: J Neuro-Ophthalmol 2017; 37: 187-196 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review improve image quality (54,55). Coils can be designed for highly-specific indications and regions of the optic nerve if there is sufficient clinical justification. SUMMARY Characterization of the optic nerve is a common indication for MRI in routine clinical practice. Orbital MRI is often used to exclude compressive lesions, inflammation or optic nerve tumors. The small size and oblique orientation of the optic nerve, motion and distortion from nearby air-filled structures pose inherent challenges to imaging the optic nerve well. It should be emphasized that high-quality conventional MRI of the optic nerve should first be optimized and put into clinical use. There also are promising new approaches using high-resolution sequences and advanced quantitative techniques that may prove helpful in the near-future for clinical diagnosis and treatment in individual patients. Emerging MRI technologies that emphasize rapid acquisition should improve visualization of the optic nerve and facilitate accurate quantification of MRI properties that can detect visuallyoccult pathology. As advanced MRI becomes more adept at characterizing the optic nerve, its role in clinical management will increase. There remains a strong need for collaborative, multidisciplinary teams of radiologists, imaging scientists, neurologists, and ophthalmologists to further explore and develop MRI of the optic nerve to improve clinical management in patients. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: T. M. Shepherd, M. J. Hoch, and M. T. Bruno; b. Acquisition of data: T. M. Shepherd, M. J. Hoch, and M. T. Bruno; c. Analysis and interpretation of data: T. M. Shepherd, M. J. Hoch, and M. T. Bruno. Category 2: a. Drafting the manuscript: T. M. Shepherd, M. J. Hoch, and M. T. Bruno; b. Revising it for intellectual content: T. M. Shepherd, M. J. Hoch, and M. T. Bruno. Category 3: a. Final approval of the completed manuscript: T. M. Shepherd, M. J. Hoch, and M. T. Bruno. ACKNOWLEDGMENTS The authors thank Graham Wiggins, Noam Ben-Eliezer, Sohae Chung, Max Sale, and Jennifer Barger for their help with preliminary data used in this review. 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