Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. RESULTS: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. CONCLUSION: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT00525668.

Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies.

BACKGROUND: The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. METHODS: Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute's 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). RESULTS: All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. CONCLUSION: PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation.

Using perceptive computing in multiple sclerosis - the Short Maximum Speed Walk test.

BACKGROUND: We investigated the applicability and feasibility of perceptive computing assisted gait analysis in multiple sclerosis (MS) patients using Microsoft Kinect™. To detect the maximum walking speed and the degree of spatial sway, we established a computerized and observer-independent measure, which we named Short Maximum Speed Walk (SMSW), and compared it to established clinical measures of gait disability in MS, namely the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk (T25FW). METHODS: Cross-sectional study of 22 MS patients (age mean ± SD 43 ± 9 years, 13 female) and 22 age and gender matched healthy control subjects (HC) (age 37 ± 11 years, 13 female). The disability level of each MS patient was graded using the EDSS (median 3.0, range 0.0-6.0). All subjects then performed the SMSW and the Timed 25-Foot Walk (T25FW). The SMSW comprised five gait parameters, which together assessed average walking speed and gait stability in different dimensions (left/right, up/down and 3D deviation). RESULTS: SMSW average walking speed was slower in MS patients (1.6 ± 0.3 m/sec) than in HC (1.8 ± 0.4 m/sec) (p = 0.005) and correlated well with EDSS (Spearman's Rho 0.676, p < 0.001). Furthermore, SMSW revealed higher left/right deviation in MS patients compared to HC. SMSW showed high recognition quality and retest-reliability (covariance 0.13 m/sec, ICC 0.965, p < 0.001). There was a significant correlation between SMSW average walking speed and T25FW (Pearson's R = -0.447, p = 0.042). CONCLUSION: Our data suggest that ambulation tests using Microsoft Kinect™ are feasible, well tolerated and can detect clinical gait disturbances in patients with MS. The retest-reliability was on par with the T25FW.

Brain viscoelasticity alteration in chronic-progressive multiple sclerosis.

INTRODUCTION: Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS. METHODS: We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity µ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS. RESULTS: In chronic-progressive MS patients, µ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001). CONCLUSIONS: Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.

MRI pattern recognition in multiple sclerosis normal-appearing brain areas.

OBJECTIVE: Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing-remitting type) in lesioned areas, areas of normal-appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques. METHODS: A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information. RESULTS: Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10(-13)). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10(-7)). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10(-10)). INTERPRETATION: We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale.