A 73-Year-Old Woman With Confusion, Visual Field Disturbances, and Edematous White Matter Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.

We describe the case of a 73-year-old woman presenting with headaches, confusion, and vision disturbances. Brain MRI showed a large T2-hyperintense lesion in the right temporo-occipital region with vasogenic edema and leptomeningeal enhancement. A leptomeningeal biopsy was performed, which led to a definitive diagnosis.

Intrathecal methotrexate - Another tool for the treatment of refractory autoimmune encephalitis - Single institution cohort and literature review.

BACKGROUND: Autoimmune encephalitis (AIE) encompasses a range of inflammatory disorders manifesting with some combination of encephalopathy, seizures, behavioral changes, movement disorders, dysautonomia or other neurologic symptoms. Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is the most common AIE and is an autoantibody mediated disorder, often paraneoplastic. Untreated or undertreated AIE has a high degree of morbidity and mortality. Immunosuppressive treatment regimens including glucocorticoids, plasma exchange (PLEX), intravenous immunoglobulin (IVIG) and rituximab used alone or in combination for such patients. Patients' refractory to such treatments requires more aggressive and potentially toxic therapies. We report favorable outcomes in patients with refractory AIE who received intrathecal methotrexate (IT-MTX) as part of treatment. METHODS: Cases at our institution seen between 2010 and 2020 were reviewed. We identified 5 patients in our clinical practice whose clinical presentation was compatible with NMDARE. Three patients met criteria for definite NMDARE. An additional two patients met criteria for probable NMDARE in the acute setting but were ultimately seronegative autoimmune encephalitis. All patients received at least one dose of IT-MTX after failing conventional therapies. At the time of IT-MTX administration patients were catatonic, comatose, or severely encephalopathic despite initial treatments. RESULTS: All patients were treated with methylprednisolone; 3 received a course of IVIG, 4 underwent PLEX, and 4 received rituximab. At the time IT-MTX was given, three patients required mechanical ventilation and 1 had a pacemaker placed for autonomic failure. Two patients were under consideration for transition to palliative care. All patients improved and were at or near their premorbid baseline at last follow-up. All patients tolerated IT-MTX well. CONCLUSIONS: This retrospective review demonstrates the efficacy of intrathecal methotrexate in the treatment of severe AIE who had failed other immunosuppressive regimens.

Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment.

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.

Sarcoidosis and the Nervous System.

PURPOSE OF REVIEW: This article provides an overview and update on the neurologic manifestations of sarcoidosis. RECENT FINDINGS: The 2018 Neurosarcoidosis Consortium diagnostic criteria emphasize that biopsy is key for diagnosis and determines the level of diagnostic certainty. Thus, definite neurosarcoidosis requires nervous system biopsy and probable neurosarcoidosis requires biopsy from extraneural tissue. Without biopsy, possible neurosarcoidosis can be diagnosed if the clinical, imaging, and laboratory picture is compatible and other causes are ruled out. Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious when other treatments are inadequate. SUMMARY: Sarcoidosis is a multisystem noninfectious granulomatous disorder that is immune mediated, reflecting the response to an as-yet unidentified antigen or antigens. Neurosarcoidosis refers to neurologic involvement due to sarcoidosis that clinically manifests in 5% of cases of sarcoidosis, with asymptomatic involvement in as many as another one in five patients with sarcoidosis. Sarcoid granulomas can occur in any anatomic substrate in the nervous system, causing protean manifestations that have earned neurosarcoidosis the sobriquet the great mimic. Nevertheless, central nervous system sarcoidosis occurs in well-defined presentations that can be classified as cranial neuropathies, meningeal disease, brain parenchymal (including pituitary-hypothalamic) disease, and spinal cord disease. In addition, the peripheral nervous system is affected in the form of peripheral neuropathy and myopathy. Glucocorticoids are the cornerstone of treatment, especially in the acute stage, whereas steroid-sparing agents such as methotrexate, mycophenolate mofetil, and azathioprine are used for prolonged therapy to minimize steroid toxicity. Anti-tumor necrosis factor agents may help in refractory cases.

7T quantitative magnetization transfer (qMT) of cortical gray matter in multiple sclerosis correlates with cognitive impairment.

Cognitive impairment (CI) is a major manifestation of multiple sclerosis (MS) and is responsible for extensively hindering patient quality of life. Cortical gray matter (cGM) damage is a significant contributor to CI, but is poorly characterized by conventional MRI let alone with quantitative MRI, such as quantitative magnetization transfer (qMT). Here we employed high-resolution qMT at 7T via the selective inversion recovery (SIR) method, which provides tissue-specific indices of tissue macromolecular content, such as the pool size ratio (PSR) and the rate of MT exchange (kmf). These indices could represent expected demyelination that occurs in the presence of gray matter damage. We utilized selective inversion recovery (SIR) qMT which provides a low SAR estimate of macromolecular-bulk water interactions using a tailored, B1 and B0 robust inversion recovery (IR) sequence acquired at multiple inversion times (TI) at 7T and fit to a two-pool model of magnetization exchange. Using this sequence, we evaluated qMT indices across relapsing-remitting multiple sclerosis patients (N = 19) and healthy volunteers (N = 37) and derived related associations with neuropsychological measures of cognitive impairment. We found a significant reduction in kmf in cGM of MS patients (15.5%, p = 0.002), unique association with EDSS (ρ = -0.922, p = 0.0001), and strong correlation with cognitive performance (ρ = -0.602, p = 0.0082). Together these findings indicate that the rate of MT exchange (kmf) may be a significant biomarker of cGM damage relating to CI in MS.

Multiple sclerosis and sarcoidosis: A case for coexistence.

BACKGROUND: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS. METHODS: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS. RESULTS: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS. CONCLUSIONS: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T1- and T2-weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM. OBJECTIVE: To study cortical GM pathology related to CI in MS using glutamate-sensitive chemical exchange saturation transfer (GluCEST) MRI at 7.0 Tesla (7T). METHODS: A total of 20 patients with relapsing-remitting MS and 20 healthy controls underwent cognitive testing, anatomical imaging, and GluCEST imaging. Glutamate-sensitive image contrast was quantified for cortical GM, compared between cohorts, and correlated with clinical measures of CI. RESULTS AND CONCLUSION: Glutamate-sensitive contrast was significantly increased in the prefrontal cortex of MS patients with accumulated disability (p < 0.05). In addition, glutamate-sensitive contrast in the prefrontal cortex was significantly correlated with symbol digit modality test (rS = -0.814) and choice reaction time (rS = 0.772) scores in patients (p < 0.05), suggesting that GluCEST MRI may have utility as a marker for GM pathology and CI.

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. METHODS: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. RESULTS: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). CONCLUSIONS: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Multiple sclerosis lesions affect intrinsic functional connectivity of the spinal cord.

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

Selective Inversion Recovery Quantitative Magnetization Transfer Brain MRI at 7T: Clinical and Postmortem Validation in Multiple Sclerosis.

BACKGROUND AND PURPOSE: An imaging biomarker of myelin integrity is an unmet need in multiple sclerosis (MS). Selective inversion recovery (SIR) quantitative magnetization transfer imaging (qMT) provides assays of myelin content in the human brain. We previously translated the SIR method to 7T and incorporated a rapid turbo field echo (TFE) readout for whole-brain imaging within clinically acceptable scan times. We herein provide histological validation and test in vivo feasibility and applicability of the SIR-TFE protocol in MS. METHODS: Clinical (T1 - and T2 -weighted) and SIR-TFE MRI scans were performed at 7T in a postmortem MS brain and MRI data were acquired in 10 MS patients and 14 heathy volunteers in vivo. The following parameters were estimated from SIR data: the macromolecular-to-free water pool-size-ratio (PSR), the spin-lattice relaxation rate of water (R1f ), and the MT exchange rate (kmf ). Differences in SIR parameters across tissue types, eg, white matter lesions (WM-Ls) and normal appearing WM (NAWM) in patients, and normal white matter (NWM) in heathy volunteers were evaluated. Associations between SIR parameters and disability scores were assessed. RESULTS: For postmortem scans, correspondence was observed between WM-Ls and NAWM from histology and PSR/R1f values. In vivo differences were detected for PSR, R1f , and kmf between WM-Ls and NWM (P ≤ .041). Associations were seen between WM-Ls/ NAWM PSR and disability scores (r ≤ -.671, P ≤ .048). CONCLUSIONS: SIR-qMT at 7T provides sensitive, quantitative measures of myelin integrity for clinical and research applications.

Untangling the R2* contrast in multiple sclerosis: A combined MRI-histology study at 7.0 Tesla.

T2*-weighted multi-echo gradient-echo magnetic resonance imaging and its reciprocal R2* are used in brain imaging due to their sensitivity to iron content. In patients with multiple sclerosis who display pathological alterations in iron and myelin contents, the use of R2* may offer a unique way to untangle mechanisms of disease. Coronal slices from 8 brains of deceased multiple sclerosis patients were imaged using a whole-body 7.0 Tesla MRI scanner. The scanning protocol included three-dimensional (3D) T2*-w multi-echo gradient-echo and 2D T2-w turbo spin echo (TSE) sequences. Histopathological analyses of myelin and iron content were done using Luxol fast blue and proteolipid myelin staining and 3,3'-diaminobenzidine tetrahydrochloride enhanced Turnbull blue staining. Quantification of R2*, myelin and iron intensity were obtained. Variations in R2* were found to be affected differently by myelin and iron content in different regions of multiple sclerosis brains. The data shall inform clinical investigators in addressing the role of T2*/R2* variations as a biomarker of tissue integrity in brains of MS patients, in vivo.

Amide proton transfer CEST of the cervical spinal cord in multiple sclerosis patients at 3T.

PURPOSE: The ability to evaluate pathological changes in the spinal cord in multiple sclerosis (MS) is limited because T1 - and T2 -w MRI imaging are not sensitive to biochemical changes in vivo. Amide proton transfer (APT) chemical exchange saturation transfer (CEST) can indirectly detect amide protons associated with proteins and peptides, potentially providing more pathological specificity. Here, we implement APT CEST in the cervical spinal cord of healthy and MS cohorts at 3T. METHODS: APT CEST of the cervical spinal cord was obtained in a cohort of 10 controls and 10 MS patients using a novel respiratory correction methodology. APT was quantified using two methods: 1) APTw , based off the conventional magnetization transfer ratio asymmetry, and 2) ΔAPT, a spatial characterization of APT changes in MS patients relative to the controls. RESULTS: Respiratory correction yielded highly reproducible z-spectra in white matter (intraclass correlation coefficient = 0.82). APTw signals in normal-appearing white matter (NAWM) of MS patients were significantly different from healthy controls (P = 0.04), whereas ΔAPT of MS patients highlighted large APT differences in NAWM. CONCLUSION: Respiration correction in the spinal cord is necessary to accurately quantify APT CEST, which can provide unique biochemical information regarding disease processes within the spinal cord. Magn Reson Med 79:806-814, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series.

OBJECTIVE: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-α. METHODS: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. RESULTS: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. CONCLUSIONS: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

Quantitative characterization of optic nerve atrophy in patients with multiple sclerosis.

BACKGROUND: Optic neuritis (ON) is one of the most common presentations of multiple sclerosis (MS). Magnetic resonance imaging (MRI) of the optic nerves is challenging because of retrobulbar motion, orbital fat and susceptibility artifacts from maxillary sinuses; therefore, axonal loss is investigated with the surrogate measure of a single heuristically defined point along the nerve as opposed to volumetric investigation. OBJECTIVE: The objective of this paper is to derive optic nerve volumetrics along the entire nerve length in patients with MS and healthy controls in vivo using high-resolution, clinically viable MRI. METHODS: An advanced, isotropic T2-weighted turbo spin echo MRI was applied to 29 MS patients with (14 patients ON+) or without (15 patients ON-) history of ON and 42 healthy volunteers. An automated tool was used to estimate and compare whole optic nerve and surrounding cerebrospinal fluid radii along the length of the nerve. RESULTS AND CONCLUSION: Only ON+ MS patients had a significantly reduced optic nerve radius compared to healthy controls in the central segment of the optic nerve. Using clinically available MRI methods, we show and quantify ON volume loss for the first time in MS patients.

Evaluating single-point quantitative magnetization transfer in the cervical spinal cord: Application to multiple sclerosis.

Spinal cord (SC) damage is linked to clinical deficits in patients with multiple sclerosis (MS), however, conventional MRI methods are not specific to the underlying macromolecular tissue changes that may precede overt lesion detection. Single-point quantitative magnetization transfer (qMT) is a method that can provide high-resolution indices sensitive to underlying macromolecular composition in a clinically feasible scan time by reducing the number of MT-weighted acquisitions and utilizing a two-pool model constrained by empirically determined constants. As the single-point qMT method relies on a priori constraints, it has not been employed extensively in patients, where these constraints may vary, and thus, the biases inherent in this model have not been evaluated in a patient cohort. We, therefore, addressed the potential biases in the single point qMT model by acquiring qMT measurements in the cervical SC in patient and control cohorts and evaluated the differences between the control and patient-derived qMT constraints (kmf, T2fR1f, and T2m) for the single point model. We determined that the macromolecular to free pool size ratio (PSR) differences between the control and patient-derived constraints are not significant (p > 0.149 in all cases). Additionally, the derived PSR for each cohort was compared, and we reported that the white matter PSR in healthy volunteers is significantly different from lesions (p < 0.005) and normal appearing white matter (p < 0.02) in all cases. The single point qMT method is thus a valuable method to quantitatively estimate white matter pathology in MS in a clinically feasible scan time.

Chemical exchange saturation transfer of the cervical spinal cord at 7 T.

High-magnetic-field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1 - and T2 *-weighted images were acquired for lesion localization and the transmitted B1 (+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Δω = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright © 2016 John Wiley & Sons, Ltd.