Spinal cord atrophy following the resection of multiple intraspinal arachnoid cysts: case report and literature review.

We report the first case of spinal cord atrophy developing 16 months after resection of multiple intraspinal arachnoid cysts. The patient presented with back pain and the cysts were successfully resected. Sixteen months later, her back pain recurred. Magnetic resonance imaging showed severe atrophy of the spinal cord.

Secondary spinal cord changes and spinal deformity following traumatic spinal cord injury.

Secondary spinal cord changes can follow spinal cord injuries (SCIs). This retrospective study was to uncover the chronic secondary changes that affect the spinal cord following severe injuries and to evaluate the influence of residual spinal deformity in the development of posttraumatic spinal cord changes. Fifty-eight patients (39 male, 19 female) with complete traumatic SCI and recent Magnetic resonance imaging (MRI) follow-up were reviewed retrospectively. A minimum of 2 years duration between trauma and MRI study was required (mean 2.9 years [2.1-4.7]). Two groups of patients were formed: with spinal deformity (and or spinal canal compromise) and without spinal deformity (and or spinal canal compromise). MRI of the injured spine demonstrated four major types of spinal cord changes; these are spinal cord atrophy, myelomalacia, syrinx, and focal cyst formation. The correlation of these changes to the presence of spinal deformity and or spinal canal compromise was also studied. Twenty-three patients (40%) of the studied population had more than 30° kyphosis and or 50% compromise of the spinal canal. Chronic spinal cord changes occurred in 25 patients (43%), 17 of these changes occurred in patients with spinal deformity and the remaining 8 occurred in patients without spinal deformity or canal compromise (p ≤ .05). The prevalence of spinal cord atrophy and focal cysts was significantly higher in patients with residual deformity and or spinal canal compromise (p ≤ .05). The authors recommend proper spinal cord decompression and fixation for patients with complete SCI to reduce the chance of secondary SCI.

Spinal cord atrophy as a measure of severity of myelopathy in adrenoleukodystrophy.

All men and most women with X-linked adrenoleukodystrophy (ALD) develop myelopathy in adulthood. As clinical trials with new potential disease-modifying therapies are emerging, sensitive outcome measures for quantifying myelopathy are needed. This prospective cohort study evaluated spinal cord size (cross-sectional area - CSA) and shape (eccentricity) as potential new quantitative outcome measures for myelopathy in ALD. Seventy-four baseline magnetic resonance imaging (MRI) scans, acquired in 42 male ALD patients and 32 age-matched healthy controls, and 26 follow-up scans of ALD patients were included in the study. We used routine T1 -weighted MRI sequences to measure mean CSA, eccentricity, right-left and anteroposterior diameters in the cervical spinal cord. We compared MRI measurements between groups and correlated CSA with clinical outcome measures of disease severity. Longitudinally, we compared MRI measurements between baseline and 1-year follow-up. CSA was significantly smaller in patients compared to controls on all measured spinal cord levels (P < .001). The difference was completely explained by the effect of the symptomatic subgroup. Furthermore, the spinal cord showed flattening (higher eccentricity and smaller anteroposterior diameters) in patients. CSA correlated strongly with all clinical measures of severity of myelopathy. There was no detectable change in CSA after 1-year follow-up. The cervical spinal cord in symptomatic ALD patients is smaller and flattened compared to controls, possibly due to atrophy of the dorsal columns. CSA is a reliable marker of disease severity and can be a valuable outcome measure in long-term follow-up studies in ALD. SYNOPSIS: A prospective cohort study in 42 adrenoleukodystrophy (ALD) patients and 32 controls demonstrated that the spinal cord cross-sectional area of patients is smaller compared to healthy controls and correlates with severity of myelopathy in patients, hence it could be valuable as a much needed surrogate outcome measure.

Spinal cord lesions and atrophy in NMOSD with AQP4-IgG and MOG-IgG associated autoimmunity.

BACKGROUND: Spinal cord (SC) affection is a hallmark symptom of neuromyelitis optica spectrum disorders (NMOSD). Patients with aquaporin-4 (AQP4-IgG+) or myelin oligodendrocyte glycoprotein (MOG-IgG+) antibody seropositivity show this overlapping clinical phenotype. OBJECTIVE: Quantitative comparison of SC lesions and atrophy in AQP4-IgG+ and MOG-IgG+ NMOSD. METHODS: AQP4-IgG+ (n = 38), MOG-IgG+ (n = 15) NMOSD patients and healthy controls (HC, n = 24) were analysed for SC lesion (prevalence, length, location), atrophy as mean upper cervical cord area (MUCCA), Expanded Disability Status Scale (EDSS), timed 25-foot walk speed (T25FWS) and 9-hole peg test (9HPT) measures. RESULTS: In total, 92% (35/38) of AQP4-IgG+ and 53% (8/15) of MOG-IgG+ patients had myelitis attacks (χ2 = 6.47, p = 0.011). 65.8%/26.7% of AQP4-/MOG-IgG+ patients had chronic SC lesions (χ2 = 5.16, p = 0.023), with similar proportions in cervical, upper thoracic and lower thoracic cord, and no length differences. MUCCA was decreased in AQP4-IgG+ (t = -2.27, p = 0.028), but not MOG-IgG+ patients (t = 0.58, p = 0.57) compared to HC. MUCCA associated with myelitis attacks (rho = -0.33, p = 0.016), EDSS (rho = -0.31, p = 0.030), pyramidal functional score (rho = -0.42, p = 0.003), T25FWS (r = 0.43, p = 0.010) and 9HPT Z-score (r = 0.32, p = 0.037), regardless of antibody status. CONCLUSION: AQP4-IgG+ patients had more myelitis attacks, SC lesions and SC atrophy was more pronounced than in MOG-IgG+ patients. MUCCA is associated with clinical myelitis attacks and disability in all NMOSD patients.

Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler's Murine Encephalomyelitis Virus Induced Demyelinating Disease.

BACKGROUND: Spinal cord (SC) lesions in Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. METHODS: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. RESULTS: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. CONCLUSION: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.

Gradient nonlinearity effects on upper cervical spinal cord area measurement from 3D T1 -weighted brain MRI acquisitions.

PURPOSE: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. METHODS: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. RESULTS: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%. CONCLUSIONS: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.

The effect of intramuscular interferon beta-1a on spinal cord volume in relapsing-remitting multiple sclerosis.

BACKGROUND: Spinal cord atrophy occurs early in multiple sclerosis (MS) and impacts disability. The therapeutic effect of interferon beta-1a (IFNß-1a) on spinal cord atrophy in patients with relapsing-remitting (RR) MS has not been explored. METHODS: We retrospectively identified 16 consecutive patients receiving weekly intramuscular IFNß-1a for 2 years [baseline age (mean ± SD) 47.7 ± 7.5 years, Expanded Disability Status Scale score median (range) 1.5 (0-2.5), timed 25-foot walk 4.6 ± 0.7 seconds; time on treatment 68.3 ± 59.9 months] and 11 sex- and age-matched normal controls (NC). The spinal cord was imaged at baseline, 1 and 2 years later with 3T MRI. C1-C5 spinal cord volume was measured by an active surface method, from which normalized spinal cord area (SCA) was calculated. RESULTS: SCA showed no change in the MS or NC group over 2 years [mean annualized difference (95 % CI) MS: -0.604 mm2 (-1.352, 0.144), p = 0.106; NC: -0.360 mm2 (-1.576, 0.855), p = 0.524]. Between group analysis indicated no differences in on-study SCA change [MS vs. NC; year 1 vs. baseline, mean annualized difference (95 % CI) 0.400 mm2 (-3.350, 2.549), p = 0.780; year 2 vs. year 1: -1.196 mm2 (-0.875, 3.266), p = 0.245; year 2 vs. baseline -0.243 mm2 (-1.120, 1.607), p = 0.712]. CONCLUSION: Established IFNß-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over 2 years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation.

A simplified approach to define cervical vertebral levels in spinal cord MRI studies.

BACKGROUND AND PURPOSE: Spinal cord (SC) cross-sectional areas (CSAs) assessed with MRI have proven to be extremely valuable imaging markers in several diseases. Among the challenges is the delineation of vertebral levels to determine level-dependent changes in cord atrophy. With this study, we aimed to (1) test the hypothesis that there is proportionality in the position of the first six intervertebral discs and the length of the upper portion of the SC and (2) show that a proportionality approach can simplify the CSA assessment across vertebrae offering good reliability. METHODS: Forty-six volunteers underwent standard T2-weighted and T1-weighted cervical SC MRI acquisitions. The distance between the obex and the intervertebral discs (from C2-C3 to T1-T2) was measured on the T2-weighted acquisitions of the entire cohort. In a test-retest experiment on 12 subjects, the % disc position values were used to define vertebral levels, and a comparison was performed with manual vertebrae assignment in terms of mean CSA and its coefficient of variation. RESULTS: The mean upper cord length for the cohort was 144.0 ± 13.1 mm. The discs' level % position in the upper cord was found to be fairly consistent, with standard deviations of 0.8%-1.7%. The mean vertebral CSA obtained with the proportionality method was substantially equivalent to the manual approach in terms of mean CSA values and test-retest reliability. CONCLUSIONS: With this study, we propose a proportionality method for the assignment of cervical SC vertebral levels that can simplify the processing of MRI datasets in the context of CSA measurements.

Brain and spinal cord atrophy in NMOSD and MOGAD: Current evidence and future perspectives.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe form of inflammation of the central nervous system (CNS) including acute myelitis, optic neuritis and brain syndrome. Currently, the classification of NMOSD relies on serologic testing, distinguishing between seropositive or seronegative anti-aquaporin-4 antibody (AQP4) status. However, the situation has recently grown more intricate with the identification of patients exhibiting the NMOSD phenotype and myelin oligodendrocyte glycoprotein antibodies (MOGAD). NMOSD is primarily recognized as a relapsing disorder; MOGAD can manifest with either a monophasic or relapsing course. Significant symptomatic inflammatory CNS injuries with stability in clinical findings outside the acute phase are reported in both diseases. Nevertheless, recent studies have proposed the existence of a subclinical pathological process, revealing longitudinal changes in brain and spinal cord atrophy. Within this context, we summarise key studies investigating brain and spinal cord measurements in adult NMOSD and MOGAD. We also explore their relationship with clinical aspects, highlight differences from multiple sclerosis (MS), and address future challenges. This exploration is crucial for determining the presence of chronic damage processes, enabling the customization of therapeutic interventions irrespective of the acute phase of the disease.

Serum neurofilament light chain predicts spinal cord atrophy in neuromyelitis optica spectrum disorder.

Levels of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorder (NMOSD). Here we investigated the association of sNfL and sGFAP levels with brain and spinal cord volumes in patients with NMOSD. Fifteen patients with NMOSD were enrolled in this prospective study. The median baseline level of sNfL was 42.2 (IQR, 16.1-72.6) pg/mL and decreased to 8.5 (IQR, 7.4-16.6) pg/mL at the end of the study. The reduction in sNfL was associated with a 7.5% loss of cervical spinal cord volume (CSCV) (p = 0.001). The levels of sGFAP reduced from 239.2 (IQR, 139.0-3393.3) pg/mL at baseline to 108.5 (IQR, 74.2-154.6) pg/mL. However, there was no strong correlation between sGFAP levels and CSCV changes during the follow-up period. Our data suggested that sNfL level is a useful biomarker for predicting spinal cord atrophy in patients with NMOSD.

Multiple sclerosis lesions and atrophy in the spinal cord: Distribution across vertebral levels and correlation with disability.

BACKGROUND: The vast majority of magnetic resonance imaging (MRI) studies on multiple sclerosis (MS) covered the spinal cord (SC), if at all, incompletely. OBJECTIVE: To assess SC involvement in MS, as detectable by whole SC MRI, with regard to distribution across vertebral levels and relation to clinical phenotypes and disability. METHODS: We investigated SC MRI with sagittal and axial coverage. Analyzed were brain and SC MRI scans of 17 healthy controls (HC) and of 370 patients with either clinically isolated syndrome (CIS, 27), relapsing remitting MS (RRMS, 303) or progressive MS (PMS, 40). Across vertebral levels, cross-sectional areas were semiautomatically segmented, and lesions manually delineated. RESULTS: The frequency of SC lesions was highest at the level C3-4. The volume of SC lesions increased from CIS to RRMS, and from RRMS to PMS whereas lesion distribution across SC levels did not differ. SC atrophy was demonstrated in RRMS and, to a higher degree, in PMS; apart from an accentuation at the level C3-4, it was evenly distributed across SC levels. SC lesions and atrophy volume were not correlated with each other and were independently associated with disability. CONCLUSION: SC lesions and atrophy already exist at the stage of RRMS in the whole SC with an accentuation in the cervical enlargement; SC lesions and atrophy are more pronounced in the stage of PMS. Both contribute to the clinical picture but are largely independent.

Relaxometry and brain myelin quantification with synthetic MRI in MS subtypes and their associations with spinal cord atrophy.

Immune-mediated demyelination and neurodegeneration are pathophysiological hallmarks of Multiple Sclerosis (MS) and main drivers of disease related disability. The principal method for evaluating qualitatively demyelinating events in the clinical context is contrast-weighted magnetic resonance imaging (MRI). Moreover, advanced MRI sequences provide reliable quantification of brain myelin offering new opportunities to study tissue pathology in vivo. Towards neurodegenerative aspects of the disease, spinal cord atrophy - besides brain atrophy - is a powerful and validated predictor of disease progression. The etiology of spinal cord volume loss is still a matter of research, as it remains unclear whether the impact of local lesion pathology or the interaction with supra- and infratentorial axonal degeneration and demyelination of the long descending and ascending fiber tracts are the determining factors. Quantitative synthetic MR using a multiecho acquisition of saturation recovery pulse sequence provides fast automatic brain tissue and myelin volumetry based on R1 and R2 relaxation rates and proton density quantification, making it a promising modality for application in the clinical routine. In this cross sectional study a total of 91 MS patients and 31 control subjects were included to investigate group differences of global and regional measures of brain myelin and relaxation rates, in different MS subtypes, using QRAPMASTER sequence and SyMRI postprocessing software. Furthermore, we examined associations between these quantitative brain parameters and spinal cord atrophy to draw conclusions about possible pathophysiological relationships. Intracranial myelin volume fraction of the global brain exhibited statistically significant differences between control subjects (10.4%) and MS patients (RRMS 9.4%, PMS 8.1%). In a LASSO regression analysis with total brain lesion load, intracranial myelin volume fraction and brain parenchymal fraction, the intracranial myelin volume fraction was the variable with the highest impact on spinal cord atrophy (standardized coefficient 4.52). Regional supratentorial MRI metrics showed altered average myelin volume fraction, R1, R2 and proton density in MS patients compared to controls most pronounced in PMS. Interestingly, quantitative MRI parameters in supratentorial regions showed strong associations with upper cord atrophy, suggesting an important role of brain diffuse demyelination on spinal cord pathology possibly in the context of global disease activity. R1, R2 or proton density of the thalamus, cerebellum and brainstem correlated with upper cervical cord atrophy, probably reflecting the direct functional connection between these brain structures and the spinal cord as well as the effects of retrograde and anterograde axonal degeneration. By using Synthetic MR-derived myelin volume fraction, we were able to effectively detect significant differences of myelination in relapsing and progressive MS subtypes. Total intracranial brain myelin volume fraction seemed to predict spinal cord volume loss better than brain atrophy or total lesion load. Furthermore, demyelination in highly myelinated supratentorial regions, as an indicator of diffuse disease activity, as well as alterations of relaxation parameters in adjacent infratentorial and midbrain areas were strongly associated with upper cervical cord atrophy.

Assessment of cervical spinal cord volume in pediatric-onset multiple sclerosis.

PURPOSE: Several studies of adult-onset multiple sclerosis (AOMS) patients have demonstrated that spinal cord volume loss is associated with disease progression and clinical disability. However, complementary studies of young patients with pediatric-onset multiple sclerosis (POMS) are lacking. Our retrospective study aimed to assess spinal cord volume in POMS patients compared with that in healthy controls. METHODS: Cervical spinal cord magnetic resonance images were evaluated for 20 POMS patients and 20 age- and sex-matched controls. Cross-sectional areas (CSAs) were measured at C2 and C7, along with the spinal cord average segmental area (CASA). The POMS group was further subdivided based on the presence or absence of spinal cord lesions, specifically C2 lesions. Pairwise area and volume comparisons were made across the different groups. RESULTS: No significant difference was found in CASA and CSA at C2 and C7 between POMS patients and comparative controls. However, CASA, CSA at C7, and estimated spinal cord volume were significantly lower in a small subset of POMS patients with C2 lesions (3 patients) than in controls (P = 0.001, 0.02, and 0.001, respectively). CONCLUSION: No significant difference was found in spinal cord areas and volumes between POMS patients and controls. This finding contrasts with spinal cord volume measurements in AOMS patients.

The course of cervical spinal cord atrophy rate and its relationship with NEDA in relapsing remitting multiple sclerosis.

This study aimed to compare the annualized segmental cervical spinal cord atrophy rate (ASCAR) in the early and late stages of relapsing remitting multiple sclerosis (RRMS), and to investigate the relationship between ASCAR and no evidence of disease activity (NEDA) in RRMS. Participants in this study included early stage MS (EMSg) patients, late stage MS (LMSg) patients, and healthy controls. All of the included participants (n = 175 subjects) were followed up for 14 months, and an MRI was performed on each participant at the beginning and at the end of the study. Cervical spinal cord average segmental area (CSCA) was measured by a semi-automated method, and ASCAR (mm2/year) was calculated. Data from the EMSg (n = 81 subjects) and LMSg (n = 94 subjects) patient groups were compared with each other and with the control group (n = 43 subjects). Examination of the initial CSCA values revealed that the baseline CSCA of the control group was larger than that of the EMSg (p < 0.001), and the baseline CSCA of the EMSg was larger than that of the LMSg (p < 0.001). The ASCAR of the control group, LMSg, and EMSg were 0.48, 0.93, and 1.81 mm2 (p < 0.001), respectively. Regression analysis revealed that disability increase was associated with ASCAR, while MRI activity and relapse presence were unrelated to ASCAR. In both patient groups, ASCAR was slower in those who fulfilled NEDA but this relationship was not significant. Cervical spinal cord atrophy progression over time occurs at a greater rate in the early stages of RRMS disease compared to the late stages. ASCAR was unrelated to MRI activity and relapse, which are clinical markers of acute inflammation.

A pipeline to quantify spinal cord atrophy with deep learning: Application to differentiation of MS and NMOSD patients.

PURPOSE: Quantitative measurement of various anatomical regions of the brain and spinal cord (SC) in MRI images are used as unique biomarkers to consider progress and effects of demyelinating diseases of the central nervous system. This paper presents a fully-automated image processing pipeline which quantifies the SC volume of MRI images. METHODS: In the proposed pipeline, after conducting some pre-processing tasks, a deep convolutional network is utilized to segment the spinal cord cross-sectional area (SCCSA) of each slice. After full segmentation, certain extra slices interpolate between each two adjacent slices using the shape-based interpolation method. Then, a 3D model of the SC is reconstructed, and, by counting the voxels of it, the SC volume is calculated. The performance of the proposed method for the SCCSA segmentation is evaluated on 140 MRI images. Subsequently, to demonstrate the application of the proposed pipeline, we study the differentiations of SC atrophy between 38 Multiple Sclerosis (MS) and 25 Neuromyelitis Optica Spectrum Disorder (NMOSD) patients. RESULTS: The experimental results of the SCCSA segmentation indicate that the proposed method, adapted by Mask R-CNN, presented the most satisfactory result with the average Dice coefficient of 0.96. For this method, statistical metrics including sensitivity, specificity, accuracy, and precision are 97.51%, 99.98%, 99.92%, and 98.04% respectively. Moreover, the t-test result (p-value = 0.00089) verified a significant difference between the SC atrophy of MS and NMOSD patients. CONCLUSION: The pipeline efficiently quantifies the SC volume of MRI images and can be utilized as an affordable computer-aided tool for diagnostic purposes.

A matter of atrophy: differential impact of brain and spine damage on disability worsening in multiple sclerosis.

As atrophy represents the most relevant driver of progression in multiple sclerosis (MS), we investigated the impact of different patterns of brain and spinal cord atrophy on disability worsening in MS. We acquired clinical and MRI data from 90 patients with relapsing-remitting MS and 24 healthy controls (HC). Clinical progression at follow-up (mean 3.7 years) was defined according to the Expanded Disability Status Scale-Plus. Brain and spinal cord volumes were computed on MRI brain scans. After normalizing each participants' brain and spine volume to the mean of the HC, z-score cut-offs were applied to separate pathologically atrophic from normal brain and spine volumes (accepting a 2.5% error probability). Accordingly, MS patients were classified into four groups (Group I: no brain or spinal cord atrophy N = 40, Group II: brain atrophy/no spinal cord atrophy N = 11, Group III: no brain atrophy/ spinal cord atrophy N = 32, Group IV: both brain and spinal cord atrophy N = 7). All patients' groups showed significantly lower brain volume than HC (p < 0.0001). Group III and IV showed lower spine volume than HC (p < 0.0001 for both). Higher brain lesion load was identified in Group II (p = 0.049) and Group IV (p = 0.023) vs Group I, and in Group IV (p = 0.048) vs Group III. Spinal cord atrophy (OR = 3.75, p = 0.018) and brain + spinal cord atrophy (OR = 5.71, p = 0.046) were significant predictors of disability progression. The presence of concomitant brain and spinal cord atrophy is the strongest correlate of progression over time. Isolated spinal cord atrophy exerts a similar effect, confirming the leading role of spinal cord atrophy in the determination of motor disability.

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.