Optical coherence tomography in multiple sclerosis: A 3-year prospective multicenter study

Prospective multicenter study; Multiple sclerosis; TomographyEstudi prospectiu multicèntric; Esclerosi múltiple; TomografiaEstudio multicéntrico prospectivo; Esclerosis múltiple; TomografíaObjective To evaluate changes over 3 years in the thickness of inner retinal layers including the peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (mGCIPL), in individuals with relapsing-remitting multiple sclerosis (RRMS) versus healthy controls; to determine whether optical coherence tomography (OCT) is sufficiently sensitive and reproducible to detect small degrees of neuroaxonal loss over time that correlate with changes in brain volume and disability progression as measured by the Expanded Disability Status Scale (EDSS). Methods Individuals with RRMS from 28 centers (n = 333) were matched with 64 healthy participants. OCT scans were performed on Heidelberg Spectralis machines (at baseline; 1 month; 6 months; 6-monthly thereafter). Results OCT measurements were highly reproducible between baseline and 1 month (intraclass correlation coefficient >0.98). Significant inner retinal layer thinning was observed in individuals with multiple sclerosis (MS) compared with controls regardless of previous MS-associated optic neuritis––group differences (95% CI) over 3 years: pRNFL: −1.86 (−2.54, −1.17) µm; mGCIPL: −2.03 (−2.78, −1.28) µm (both p 5 years (pRNFL: p < 0.05; mGCIPL: p < 0.01). Brain volume decreased by 1.3% in individuals with MS over 3 years compared to 0.5% in control subjects (effect size 0.76). mGCIPL atrophy correlated with brain atrophy (p < 0.0001). There was no correlation of OCT data with disability progression. Interpretation OCT has potential to estimate rates of neurodegeneration in the retina and brain. The effect size for OCT, smaller than for magnetic resonance imaging based on Heidelberg Spectralis data acquired in this study, was increased in early disease.The authors wish to thank Carolyn M. Ervin for her substantial contribution in the data analyses, as well as Mark Kirby, Aisling Towell, and Marie-Catherine Mousseau (Novartis Ireland Ltd.) for their writing support, funded by Novartis Pharma AG, Basel, Switzerland. FB is supported by the NIHR biomedical research center at UCLH

Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper

BACKGROUND AND OBJECTIVES: Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients. METHODS: Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty. RESULTS: The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs. CONCLUSION: The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of antispasticity agents and to produce evidence-based treatment algorithms

The ACROSS study : Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis

In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure. ACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure). Overall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified "high exposure." At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes. After 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group

Grey matter atrophy is associated with disability increase in natalizumab-treated patients

Background: Brain volume loss (BVL) is a key outcome in multiple sclerosis (MS) trials. Natalizumab is highly effective on inflammation with moderate impact on atrophy. Objective: To explore BVL in patients receiving natalizumab with an emphasis on grey matter (GM). Methods: We performed a retrospective post hoc analysis of BVL in 38 patients receiving natalizumab for 3 years using longitudinal voxel-based morphometry (VBM) and FreeSurfer. Results: Significant BVL was observed during first year: brain parenchymal fraction (BPF): −1.12% (p  right fronto-parietal cortex, right > left hippocampus and left caudate. FreeSurfer showed significant volume losses in subcortical GM, brainstem and cerebellum, and cortical thinning in the left insula. In the second year, only WMF decrease (−0.6%; p = 0.015) was observed with no VBM changes, although FreeSurfer detected significant volume loss in thalamus, hippocampus and cerebellum. Baseline gadolinium enhancement influenced WMF and BPF changes during the first year, but not GMF. Patients with confirmed Expanded Disability Status Scale (EDSS) worsening at 3 years had lower baseline GMF and left thalamus volume and greater BVL over follow-up. Conclusion: BVL develops mainly during the first year of natalizumab therapy. GM changes are independent of baseline inflammation and correlate with disability

The role of pontine lesion location in differentiating multiple sclerosis from vascular risk factor-related small vessel disease

Background: Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel disease (SVD) can be challenging. Objective and Methods: In order to determine whether or not pontine lesion location is a useful discriminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS cases with VRF. Results: MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS with VRF (0%, 0/43) (Exp(B) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p = 0.014) but there were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and non-MS with VRF patients (16.3%, 7/43) (Exp(B) = 0.89; 95% CI = (0.2, 3.94); p = 0.87). The presence of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that seen in MS without VRF (31.2%, 29/93, p = 0.99). Central lesions occurred in similar frequency in MS with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p = 0.15). Conclusion: Peripheral pons lesion location is a good discriminator of MS from vascular lesions

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer

BACKGROUND: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. AIM: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. METHOD: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1–C2; C2/3) on SC and brain images and the entire cervical cord (C1–C7) on SC images only. RESULTS: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1–C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all p ≤ 0.006 at the C1–C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. CONCLUSION: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches

Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge

Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-Established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practice: minimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses and MRI active lesions to detect treatment response in the real-world setting were also discussed. While most published studies on this topic involved patients treated with interferon-\u3b2, special attention was given to more recent studies providing evidence based on treatment with other and more efficacious oral and injectable drugs. Finally, the panel identified future directions to pursue in this research field

Association of Gray Matter Atrophy Patterns with Clinical Phenotype and Progression in Multiple Sclerosis

OBJECTIVES: Grey matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes. METHODS: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 MS patients (34 clinically isolated syndromes [CIS], 226 relapsing-remitting [RR], 95 secondary progressive [SP] and 43 primary progressive [PP] MS). Fifty-seven HC and 144 MS underwent 1-year follow-up. Baseline GM loss, atrophy progression and correlations with disability and 1-year clinical worsening were assessed. RESULTS: SBM identified 26 cerebellar, subcortical, sensory, motor and cognitive GM components. GM atrophy was found in MS vs HC in almost all components (p=range<0.001-0.04). Compared to HCs, CIS patients showed circumscribed subcortical, cerebellar, temporal and salience GM atrophy, while RRMS patients exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience and fronto-parietal GM atrophy was found in PPMS patients vs HCs, and SPMS vs RRMS. At 1-year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated (R2=0.65) with baseline lower normalized brain volume (beta=-0.13, p=0.001), greater sensorimotor GM atrophy (beta=-0.12, p=0.002) and longer disease duration (beta=0.09, p=0.04). Baseline normalized GM volume (odds ratio=0.98, p=0.008) and cerebellar GM atrophy (odds ratio=0.40, p=0.01) independently predicted clinical worsening (area-under-the-curve=0.83). CONCLUSION: GM atrophy differed across disease phenotypes and progressed at 1-year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening