Multiple Sclerosis: Simon JH

Simon JH, Li D, Traboulsee A, Coyle PK, Arnold DL, Barkhof F, Frank JA, Grossman R, Paty DW, Radue EW, Wolinsky JS. · Department of Radiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. · AJNR Am J Neuroradiol. · Pubmed #16484429 links to  free full text

This publication has no abstract.

Simon JH, Thompson AJ. · No affiliation provided · Neurology. · Pubmed #12963745 No free full text.

This publication has no abstract.

Simon JH, Kleinschmidt-DeMasters BK. · Imaging, Portland VA Medical Center, Mail Stop P2IMAG, 3710 SW Veterans Hospital Road, Portland, OR 97207, USA. · Neuroimaging Clin N Am. · Pubmed #19068410 No free full text.

Abstract: The classic multiple sclerosis variants including Devic's neuromyelitis optica (NMO), Balo's concentric Sclerosis, Schilder's disease, and Marburg MS are both interesting and instructive from a disease pathophysiology perspective. Although rare, the variants are important as they often arise in the differential diagnosis for severe, acute demyelinating disease, including MS and acute disseminated encephalomyelitis. In the case of NMO, an originally unsuspected and entirely new pathophysiology based on water channels has been described, only after the recent original description of the more specific diagnostic test for NMO based on serum immunoglobulin.

Simon JH. · Department of Radiology, University of Colorado Health Sciences Center, Campus Box A034, Denver, CO 80262, USA. · Mult Scler. · Pubmed #17262994 No free full text.

Abstract: Brain and spinal cord atrophy measures are becoming standard in multiple sclerosis (MS) clinical trials, yet we know little about the underlying mechanisms resulting in atrophy, or the factors accounting for variable rates of atrophy in individuals and across the MS phenotype. We do not understand, as yet, why apparently effective treatment does or does not affect atrophy. Some limitations of this measure may be accounted for by complex structural and temporal factors that become active at the initiation of injury, but are not immediately expressed. Additional limitations include differential effects related to the focal versus diffuse pathology in MS, and variable expression of the pathology underlying atrophy, depending on location in central nervous system (CNS) tissue.

Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, Miller DH, Montalban X, Simon JH, Polman C, Filippi M. · Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. · Lancet Neurol. · Pubmed #16987731 No free full text.

Abstract: Although the diagnosis of multiple sclerosis relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is also essential. The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteria for diagnosis of multiple sclerosis have not taken advantage of the potential of MRI to detect features "not suggestive" of multiple sclerosis. Recognition of such features in the work-up of patients suspected of having multiple sclerosis may reduce the likelihood of a false positive diagnosis of the disorder in some, while suggesting the correct alternative diagnosis in other patients. On the basis of this, a workshop of the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) was held to define a series of MRI red flags in the setting of clinically suspected multiple sclerosis that is derived from evidence-based findings and educated guesses. The presence of such red flags should alert clinicians to reconsider the differential diagnosis more extensively. In this review we will report on the conclusions of this international consensus, which should represent a first step beyond the concept of "no better explanation", and inform future diagnostic criteria for multiple sclerosis.

Simon JH. · Department of Radiology, University of Colorado Health Sciences Center, Denver, CO 80262, USA. · Radiol Clin North Am. · Pubmed #16297683 No free full text.

Abstract: In this article the basic features of the focal MR imaging lesions and the underlying pathology are reviewed. Next, the diffuse pathology in the normal-appearing white and gray matter as revealed by conventional and quantitative MR imaging techniques is discussed, including reference to how the focal and diffuse pathology may be in part linked through axonal-neuronal degeneration. The MR imaging criteria incorporated for the first time into formal clinical diagnostic criteria for multiple sclerosis are next discussed. Finally, a discussion is provided as to how MR imaging is used in monitoring subclinical disease either before or subsequent to initiation of treatment, in identifying aggressive subclinical disease, and treatment of nonresponders.

Filippi M, Falini A, Arnold DL, Fazekas F, Gonen O, Simon JH, Dousset V, Savoiardo M, Wolinsky JS, Anonymous00084. · Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. · J Magn Reson Imaging. · Pubmed #15906322 No free full text.

Abstract: On October 9-11, 2003, the third meeting of the White Matter Study Group of the International Society for Magnetic Resonance in Medicine was held in Venice, Italy. This article is the report of the meeting on how to use MRI in the diagnostic workup of multiple sclerosis (MS) and allied white matter disorders, and to define the nature and the extent of MS pathology in vivo. Both of these steps are central to the design of future treatment strategies aimed at limiting the functional consequences of the most disabling aspects of this disease.

Simon JH. · Department of Radiology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box A-034, Denver, CO 80262, USA. · Phys Med Rehabil Clin N Am. · Pubmed #15893678 No free full text.

Abstract: MRI provides multiple uses and applications in multiple sclerosis(MS). The basic features of the MRI-detected lesions, including the underlying pathology, are discussed. MRI allows assessment of the normal-appearing white and gray matter, and neuronal tract and functional system disturbances. An overview of the clinical significance of these MRI measures is included, as a basis for understanding their role as outcome measures in clinical trials. MRI recently assumed greater importance in its role in establishing an earlier diagnosis of MS after a first clinical event, and in monitoring subclinical disease before or subsequent to the formal diagnosis.The background to these applications and practical issues are discussed.

Simon JH. · Department of Radiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. · CNS Drugs. · Pubmed #11524021 No free full text.

Abstract: Magnetic resonance imaging (MRI) reveals that brain and spinal cord atrophy occur early in the course of multiple sclerosis (MS), far earlier than originally anticipated. This has important implications for the early treatment of patients with MS, as atrophy is thought to reflect destructive, irreversible pathology, and subclinical impairment if not overt disability. Several recent trials in MS have included atrophy as a secondary or exploratory measure of treatment efficacy. While measured cerebral volume or spinal cord area changes are small over 1 to 3 year intervals, they are sufficiently large that with current methodologies the atrophy measures should provide conclusive information as to the effectiveness of therapeutic interventions in halting progressive atrophy. Atrophy measures may also provide an important metric for the evaluation of disease in primary progressive MS, and in testing combined therapies and neuroprotective agents, where conventional MRI methodologies may be relatively weak.

Simon JH. · Sections of Neuroradiology and MRI, Department of Radiology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. · Neuroimaging Clin N Am. · Pubmed #11359723 No free full text.

Abstract: Until recently, atrophy of the brain and spinal chord was thought to occur late in the course of multiple sclerosis (MS) or as a result of rare, fulminant disease. Now atrophy is known to occur early and likely indicates destructive and irreversible pathologic change that may be subclinical. Central nervous system atrophy from MS now can be measured accurately over short time intervals. Atrophy may become an important prognostic indicator in MS and is being evaluated as a treatment outcome measure in population studies, and possibly in the future, in individuals.

Simon JH. · Department of Radiology/MRI, University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Campus Box A-034, Denver, CO, USA. · J Neurol Sci. · Pubmed #10606803 No free full text.

Abstract: Imaging considerations for the diagnosis and differential diagnosis of MS are based primarily on results of MR studies of the brain. Recent studies suggest that with current technology, MR imaging of the spinal cord can make important contributions, particularly in cases with equivocal or negative brain MRI studies. Spinal cord MRI may also assume an important role in early diagnosis.

Simon JH, McDonald WI. · Department of Radiology/MRI, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO, USA. · J Neurol Sci. · Pubmed #10606801 No free full text.

Abstract: The MR imaging-based assessment of the optic nerve in optic neuritis and multiple sclerosis provides information that is complementary to clinical and electrophysiological methods. The standard and more tissue destruction specific methods can be used in strategies to measure treatment efficacy and for understanding the mechanisms of relapse, recovery, and failure of recovery.

Fazekas F, Barkhof F, Filippi M, Grossman RI, Li DK, McDonald WI, McFarland HF, Paty DW, Simon JH, Wolinsky JS, Miller DH. · Department of Neurology and MRI Center, Karl-Franzens University, Graz, Austria. · Neurology. · Pubmed #10449103 No free full text.

Abstract: MRI is very sensitive in showing MS lesions throughout the CNS. Using MRI for diagnostic purposes, however useful, is a complex issue because of limited specificity of findings and a variety of options as to when, how, and which patients to examine. Comparability of data and a common view regarding the impact of MRI are needed. Following a review of the typical appearance and pattern of MS lesions including differential diagnostic considerations, we suggest economic MRI examination protocols for the brain and spine. Recommendations for referral to MRI consider the need to avoid misdiagnosis and the probability of detecting findings of diagnostic relevance. We also suggest MRI classes of evidence for MS to determine the diagnostic weight of findings and their incorporation into the clinical evaluation. These proposals should help to optimize and standardize the use of MRI in the diagnosis of MS.

Simon JH. · Department of Radiology, University of Colorado Health Sciences Center, Denver 80262, USA. · J Neuroimmunol. · Pubmed #10426356 No free full text.

Abstract: Based on observations from MR imaging studies, the natural history of the MS lesion appears to be progression from an acute enhancing lesion, corresponding to the early inflammatory stage, with evolution to a chronic T2 hyperintense lesion, which is the non-specific 'footprint' of the prior event. In addition to accumulation of these relatively non-specific lesions, we find in longitudinal evaluations that patients with only mild to modest disability are already developing significant cerebral atrophy. Atrophy, particularly that resulting from volume loss around the third ventricle, appears to be predicted by the presence of prior temporally and anatomically distant enhancing lesions. One can speculate that the initial enhancing-inflammatory lesion events in the brain, place into motion, at an early stage, the processes that ultimately lead to cerebral atrophy, and these processes may include early axonal injury.

Fisher E, Rudick RA, Simon JH, Cutter G, Baier M, Lee JC, Miller D, Weinstock-Guttman B, Mass MK, Dougherty DS, Simonian NA. · Whitaker Biomedical Imaging Laboratory, The Cleveland Clinic Foundation, OH 44195, USA. · Neurology. · Pubmed #12427893 No free full text.

Abstract: OBJECTIVE: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. METHODS: A follow-up study was conducted to reassess patients from a phase III trial of interferon beta-1a (IFNbeta-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. RESULTS: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. CONCLUSIONS: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN, Anonymous00071. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · Neurology. · Pubmed #12221157 No free full text.

Abstract: BACKGROUND: Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS. METHODS: A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). RESULTS: Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects. CONCLUSIONS: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

Beck RW, Chandler DL, Cole SR, Simon JH, Jacobs LD, Kinkel RP, Selhorst JB, Rose JW, Cooper JA, Rice G, Murray TJ, Sandrock AW. · CHAMPS Analysis Center, Jaeb Center for Health Research, Tampa, FL 33613, USA. · Ann Neurol. · Pubmed #11921054 No free full text.

Abstract: The objective of this work was to assess the effect of interferon beta-1a (Avonex) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30 microg interferon beta-1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem-cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon beta-1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem-cerebellar syndromes, and spinal cord syndromes.

Benedict RH, Bakshi R, Simon JH, Priore R, Miller C, Munschauer F. · Department of Neurology, State University of New York at Buffalo School of Medicine, Buffalo, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #11884654 links to  free full text

Abstract: The association between regional measures of cortical atrophy and neuropsychological (NP) dysfunction was studied in 35 multiple sclerosis (MS) patients. Patients underwent neurological examination, MRI, and NP testing. Blind quantitative MRI analysis yielded total T(2) lesion area (TLA) and third ventricle width (3VW). Cortical atrophy, rated by blind visual inspection, was more extensive in superior frontal and parietal cortices than in other regions. No MRI measures were correlated with depression scores. TLA and 3VW were significantly correlated with each NP test. Cortical atrophy measures for bilateral superior frontal cortex were retained in regression models predicting impairments in verbal learning, spatial learning, attention, and conceptual reasoning. The authors conclude that cerebral atrophy predicts NP impairment while accounting for the influence of TLA or 3VW. Regions of cortex most susceptible to atrophic and cognitive changes in MS are the right and left superior frontal lobes.

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Jak AJ, Kniker JE, Kooijmans MF, Lull JM, Sandrock AW, Simon JH, Simonian NA, Whitaker JN. · The Mellen Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. · Arch Neurol. · Pubmed #11405811 links to  free full text

Abstract: BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW. · Department of Neurology, State University of New York School of Medicine at Buffalo and Buffalo General Hospital, 14203, USA. · N Engl J Med. · Pubmed #11006365 links to  free full text

Abstract: BACKGROUND: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value. METHODS: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis. RESULTS: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months. CONCLUSIONS: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

Simon JH, Lull J, Jacobs LD, Rudick RA, Cookfair DL, Herndon RM, Richert JR, Salazar AM, Sheeder J, Miller D, McCabe K, Serra A, Campion MK, Fischer JS, Goodkin DE, Simonian N, Lajaunie M, Wende K, Martens-Davidson A, Kinkel RP, Munschauer FE. · Department of Radiology-MRI, University of Colorado Health Sciences Center, Denver, USA. · Neurology. · Pubmed #10908888 No free full text.

Abstract: BACKGROUND: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. OBJECTIVE: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. METHODS: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon beta-1a (IFNbeta-1a)-treated patients with mild to moderate disability relapsing-remitting MS. RESULTS: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNbeta-1a-treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. CONCLUSION: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Simonian N, Lajaunie M, Miller DE, Wende K, Martens-Davidson A, Kinkel RP, Munschauer FE, Brownscheidle CM. · Department of Radiology-MRI, University of Colorado Health Sciences Center, Denver 80262, USA. · Neurology. · Pubmed #10408550 No free full text.

Abstract: OBJECTIVE: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon beta-1a (Avonex). METHODS: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. RESULTS: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. CONCLUSION: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Rudick RA, Cookfair DL, Simonian NA, Ransohoff RM, Richert JR, Jacobs LD, Herndon RM, Salazar AM, Fischer JS, Granger CV, Goodkin DE, Simon JH, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munchsauer FE, O'Reilly K, Priore RL, Whitham RH. · Mellen Center For Multiple Sclerosis Treatment and Research, Department of Neurology, The Cleveland Clinic Foundation, OH 44106, USA. · J Neuroimmunol. · Pubmed #10378864 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Du YP, Chu R, Hwang D, Brown MS, Kleinschmidt-DeMasters BK, Singel D, Simon JH. · Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado 80010, USA. · Magn Reson Med. · Pubmed #17969125 No free full text.

Abstract: Quantitative mapping of the myelin water content can provide significant insight into the pathophysiology of several white matter diseases, such as multiple sclerosis and leukoencephalopathies, and can potentially become a useful clinical tool for early diagnosis of these diseases. In this study, multicompartment analysis of T(2)(*) decay (MCAT(2)(*)) was used for the quantitative mapping of myelin water fraction (MWF). T(2)(*) decay of each voxel at multiple slice locations was acquired in fixed human brains using a multigradient-echo (MGRE) pulse sequence with alternating readout gradient polarities. Compared to prior techniques using Carr-Purcell-Meiboom-Gill (CPMG) acquisition, the MGRE acquisition approach has: 1) a very short first echo time ( approximately 2 ms) and echo-spacing ( approximately 1 ms), which allows for the acquisition of multiple sampling points during the fast decay of the myelin water signal; 2) a low RF duty cycle, which is especially important for achieving acceptable specific absorption rate (SAR) levels at high field strengths. Multicompartment analysis was then applied to the T(2)(*) decay in each pixel using a 3-pool model of white matter to detect the signal arising from the myelin water, myelinated axonal water, and mixed water compartments.

Simon JH, Zhang S, Laidlaw DH, Miller DE, Brown M, Corboy J, Bennett J. · Department of Radiology, University of Colorado, Denver, Colorado 80252, USA. · J Magn Reson Imaging. · Pubmed #17024655 No free full text.

Abstract: PURPOSE: Focal inflammatory/demyelinating lesions are thought to be the source of Wallerian degeneration or other injury to local, transiting fiber tracts in the brain or spinal cord in multiple sclerosis (MS). A methodology is established to isolate connections between focal demyelinating lesions and intersecting fibers to permit explicit analyses of the pathology of secondary fiber injury distant from the focal lesion. MATERIALS AND METHODS: A strategy is described and feasibility demonstrated in three patients with a clinically isolated syndrome and positive MRI (at high risk for MS). The strategy utilizes streamtube diffusion tractography to identify neuronal fibers that intersect a focal lesion and pass through a region of interest, in this case the corpus callosum, where distal (to focal lesion) interrogation can be accomplished. RESULTS: A sizeable fraction of the normal appearing white matter (NAWM) in the early stages of disease can be defined in the corpus callosum, which is distinctive in that this tissue connects to distant demyelinating lesions. CONCLUSION: The new class of tissue called fibers-at-risk for degeneration (FAR) can be identified and interrogated by a variety of quantitative MRI methodologies to better understand neuronal degeneration in MS.