Humm AM, Z'graggen WJ, Buhler R, Magistris MR, Rosler KM
J Neurol NeuroSurg Psychiatry 2005 Sep 20
Inselspital Bern, Department of Neurology, Switzerland
To compare the effects of IntraVenous MethylPrednisolone (IVMP) in patients with Relapsing/Remitting (RR-MS), Secondary/Progressive (SP-MS) and Primary/Progressive Multiple Sclerosis (PP-MS).
Clinical and NeuroPhysiological follow-up was performed in 24 RR-MS, 8 SP-MS and 9 PP-MS patients receiving 500 mg Solu-Medrol/d during 5 days for exacerbations involving the motor system.
We used Motor Evoked Potentials (MEPs) to measure Central Motor Conduction Time (CMCT) and applied the Triple Stimulation Technique (TST) to assess conduction deficits.
The TST allows an accurate quantification of the number of conducting Central Motor Neurons, expressed by the TST amplitude ratio.
There was a significant increase in TST amplitude ratio in RR-MS (p < 0.001) and SP-MS patients (p < 0.02) at day 5, paralleling an increase in muscle force.
TST amplitude ratio and muscle force remained stable at 2 months. In PP-MS, TST amplitude ratio and muscle force did not change. CMCT did not change significantly in any MS group.
In RR-MS and SP-MS patients, IVMP is followed by a prompt increase in conducting Central MotoNeurons paralleled by improvement in muscle force, which most likely reflects partial resolution of Central Conduction Block.
The lack of similar clinical and NeuroPhysiological changes in PP-MS patients corroborates previous clinical reports on limited IVMP efficacy in this patient group and points to PathoPhysiological differences underlying exacerbations in PP-MS.
Intrathecal Synthesis Of OligoClonal IgM Against Myelin Lipids Predicts An Aggressive Disease Course In MS
Villar LM, Sadaba MC, Roldan E, Masjuan J, Gonzalez-Porque P, Villarrubia N, Espino M, Garcia-Trujillo JA, Bootello A, Alvarez-Cermeno JC
J Clin Invest 2005 Jan;115(1):187-94
Hospital Ramon y Cajal, Departments of Immunology and Neurology, Madrid, Spain
OligoClonal IgM bands restricted to CerebroSpinal Fluid are an unfavorable prognostic marker in MS, the most common DeMyelinating Disease of the CNS.
We have attempted to identify the B-Cell subpopulation responsible for OligoClonal IgM secretion and the specificity of these bands. In addition, we explored the relationship between specificity and disease evolution.
Intrathecal B-Cell subpopulations present in 29 MS patients with OligoClonal IgM bands and 52 without them were analyzed.
A considerable increase in CD5+ B-Lymphocytes was found in patients with OligoClonal IgM bands.
These cells mostly secrete IgM AntiBodies recognizing nonproteic molecules. We also studied whether OligoClonal IgM bands present in CerebroSpinal Fluid of 53 MS patients were directed against Myelin Lipids.
This was the case in most patients, with PhosphatidylCholine being the most frequently recognized lipid. Disease course of 15 patients with OligoClonal IgM against Myelin lipids and 33 patients lacking them was followed.
Patients with Anti-Lipid IgM suffered a second relapse earlier, had more relapses, and showed increased disability compared with those without Anti-Lipid IgM.
The presence of Intrathecal Anti-Myelin Lipid IgM AntiBodies is therefore a very accurate predictor of aggressive evolution in MS.
Blood-Brain Barrier Alterations In Both Focal And Diffuse Abnormalities On Postmortem MRI In Multiple Sclerosis
Vos CM, Geurts JJ, Montagne L, van Haastert ES, Bo L, van der Valk P, Barkhof F, de Vries HE
NeuroBiol Dis 2005 Dec;20(3):953-960
VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands; VU University Medical Center, Department of Molecular Cell Biology and Immunology, PO Box 7057, 1007 MB Amsterdam, The Netherlands; VU University Medical Center, Graduate School NeuroSciences Amsterdam, Amsterdam, The Netherlands
Postmortem MRI-guided tissue sampling significantly enhances the yield of MS lesions in autopsy material, but so far it is unknown whether abnormalities concur with Blood-Brain Barrier
Here we sampled MS lesions with focal and diffuse abnormalities (Diffusely Abnormal White Matter; DAWM) on MRI; both were coupled to the presence of MS lesions upon NeuroPathological examination.
ExtraVascular distribution of fibrinogen, indicating BBB disturbance, was observed in so-called (p)reactive lesions that reflect discrete areas of Microglial activation without DeMyelination within an otherwise Normal-Appearing White Matter.
Leakage became more extensive in active DeMyelinating MS lesions to chronic inactive lesions. An enlargement of the PeriVascular (Virchow-Robin Space) containing infiltrated Leukocytes was associated with both DAWM and focal abnormalities on postmortem MRI.
This study shows for the first time that in MS Brain changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI.
Massive Apoptosis In Lymphoid Organs In Animal Models For Primary And Secondary/Progressive Multiple Sclerosis
Tsunoda I, Libbey JE, Kuang LQ, Terry EJ, Fujinami RS
Am J Pathol 2005 Dec;167(6):1631-46
University of Utah School of Medicine, Department of Neurology, 30 North 1900 East, 3R330 SOM, Salt Lake City, Utah 84132-2305
The mechanism(s) responsible for generating the different forms of Multiple Sclerosis, Primary/Progressive (PP) and Secondary/Progressive (SP) versus Relapsing/Remitting (RR), is not well understood.
Using Myelin Oligodendrocyte Glycoprotein (MOG <=>)(92-106), we have established animal models that mimic the different types of Multiple Sclerosis.
A.SW mice develop PP or SP-Experimental Allergic Encephalomyelitis (EAE) with large areas of DeMyelination and high titers of MOG AntiBody whereas SJL/J mice develop RR-EAE with PeriVascular T-Cells and mild DeMyelination.
In A.SW Progressive EAE, we found atrophy of the Thymus, Spleen, and Lymph Nodes with depletion of T and B-Cells and massive Apoptosis, as demonstrated by ImmunoHistoChemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis.
To test whether Lymphoid Apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic Thymocytes. Injection of Apoptotic Cells resulted in greater than 20% of mice developing SP-EAE with Ataxia.
SJL/J mice with SP-EAE had large areas of DeMyelination, high MOG AntiBody Titers and Atrophic Lymphoid organs. Spleen cells from mice with progressive EAE produced less Interferon-γ than those from RR-EAE when stimulated with mitogen.
We suggest that induction of Lymphoid Apoptosis alters the balance of Th1 versus Th2 Immune Responses and increases MOG <=> AntiBody production, leading to exacerbation of DeMyelination and subsequent disease progression.
Magnetization Transfer Histograms In Clinically Isolated Syndromes Suggestive Of Multiple Sclerosis
Fernando KT, Tozer DJ, Miszkiel KA, Gordon RM, Swanton JK, Dalton CM, Barker GJ, Plant GT, Thompson AJ, Miller DH
Brain 2005 Dec;128(Pt 12):2911-25
NMR Research Unit, Institute of Neurology, King's College, London, UK
In established Multiple Sclerosis, Magnetization Transfer Ratio (MTR) Histograms reveal abnormalities of Normal-Appearing White Matter (NAWM) and Gray Matter (NAGM).
The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with Clinically Isolated Syndromes suggestive of Multiple Sclerosis.
Magnetization Transfer Imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a Clinically Isolated Syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years).
SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, White Matter and Gray Matter were calculated.
Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed Multiple Sclerosis if this occurred sooner (n = 20).
Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects.
The MTR Histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the Histogram.
Mean NAWM and NAGM MTR were also reduced in the patients who developed Clinically Definite Multiple Sclerosis and Multiple Sclerosis according to the McDonald Criteria but not in the 24 patients with normal T2-weighted Brain Magnetic Resonance Imaging (MRI).
MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of Multiple Sclerosis.
A Longitudinal Study Of Cognition In Primary/Progressive Multiple Sclerosis
Camp SJ, Stevenson VL, Thompson AJ, Ingle GT, Miller DH, Borras C, Brochet B, Dousset V, Falautano M, Filippi M, Kalkers NF, Montalban X, Polman CH, Langdon DW
Brain 2005 Dec;128(Pt 12):2891-8
Institute of Neurology, Department of Clinical Neurology, London, UK
There are few longitudinal studies of Cognition in patients with Multiple Sclerosis, and the results of these studies remain inconclusive.
No serial NeuroPsychological data of an exclusively Primary/Progressive series are available.
Cross-sectional analyses have revealed significant correlations between Cognition and Magnetic Resonance Imaging (MRI) parameters in Primary/Progressive Multiple Sclerosis (PPMS).
This study investigated Cognitive and MRI change in 99 PPMS patients from five European centres for 2 years.
They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression.
The MRI parameters of T1 HypoIntensity load, T2 lesion load, and partial Brain volume were also calculated at each time point.
There were no significant differences between the mean Cognitive scores of the patients at year 0 and year 2.
However, one-third of the patients demonstrated absolute Cognitive decline on individual test scores.
Results indicated that initial Cognitive status on entry into the study was a good predictor of Cognitive ability at 2 years.
There was only a small number of significant correlations between changes in Cognition and changes on MRI, notably T1 hypointensity load with the two Attentional Tasks (r = -0.266, P = 0.017; r = -0.303, P = 0.012).
It is probable that multiple factors underlie this weak relation between the Cognitive and MRI measures.
AntiOxidants And PolyUnsaturated Fatty Acids In Multiple Sclerosis
van Meeteren ME, Teunissen CE, Dijkstra CD, van Tol EA
Eur J Clin Nutr 2005 Dec;59(12):1347-61
Numico Research BV, Department of Biomedical Research, Wageningen, The Netherlands
Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS). Oligodendrocyte damage and subsequent Axonal Demyelination is a hallmark of this disease.
Different pathomechanisms, for example, Immune-mediated inflammation, Oxidative Stress and ExcitoToxicity, are involved in the ImmunoPathology of MS. The risk of developing MS is associated with increased dietary intake of Saturated Fatty Acids.
PolyUnsaturated Fatty Acid (PUFA) and AntiOxidant deficiencies along with decreased cellular AntiOxidant defence mechanisms have been observed in MS patients.
Furthermore, AntiOxidant and PUFA treatment in Experimental Allergic Encephalomyelitis, an animal model of MS, decreased the clinical signs of disease.
Low-molecular-weight AntiOxidants may support cellular AntiOxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation.
PUFAs may not only exert ImmunoSuppressive actions through their incorporation in Immune Cells but also may affect cell function within the CNS.
Both dietary AntiOxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.