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Biomedical subjects

J S Wolinsky

Publications and source records attributed to J S Wolinsky.

At least 37 records · Page 2Linked to original sources
PubMed2001

Short-term brain volume change in relapsing-remitting multiple sclerosis: effect of glatiramer acetate and implications.

The assessment of brain volume change with serial MRI provides an objective measure of an important component of the pathology of multiple sclerosis. Glatiramer acetate (GA) has a beneficial effect on clinical and MRI measures of disease activity and burden in patients with relapsing-remitting (RR) multiple sclerosis. This study investigated the impact of GA treatment on the development of brain atrophy in RR multiple sclerosis patients. The study consisted of a 9-month, double-blind, placebo-controlled phase followed by a 9-month open-label phase. Patients were randomized to receive either 20 mg GA or placebo by daily subcutaneous injections and underwent brain MRI scans every month during the first phase, and every 3 months during the second phase of the study. Using a semi-automated segmentation technique based on local thresholding, brain volume was measured from seven contiguous periventricular slices from the scans obtained at baseline, the end of the double-blind phase and the end of the study. From the original trial cohort, image sets from 113 out of 119 patients randomized to GA, and 114 out of 120 randomized to placebo treatment were evaluated. Brain volume was significantly correlated with patients' disability at each time-point. No significant differences between placebo- and GA-treated patients were found for baseline brain volume and rate of brain volume change over the study, even though a possible late trend for treatment with GA to retard the loss of brain volume was observed. There was a significant, but modest, correlation between MRI activity during the double-blind phase, and brain volume change over the entire study among patients originally treated with placebo. The modest correlation between enhancement frequency and brain atrophy loss indicates that the suppression of inflammatory activity in RR multiple sclerosis patients is not fully and rapidly associated with a similar effect on the global neurodegenerative processes. This study also suggests that any effect of GA in preventing brain volume decrease is not evident early following institution of treatment.

Adult↗
PubMed2001

United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis Study Group and the MRI Analysis Center.

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2,433 +/- 59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

Adult↗
PubMed2001

Grey matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging.

Pathologically defined abnormalities in the cortical gray matter (GM) are well described in multiple sclerosis (MS) but are infrequently seen by conventional magnetic resonance imaging (MRI). We systematically evaluated 52 relapsing-remitting MS patients and 20 normal volunteers with high resolution MRI and short echo proton magnetic resonance spectroscopic imaging (MRSI). Individual tissue contributions to the spectroscopic voxels were estimated based on MRI that incorporated both CSF suppression and magnetization transfer, or double inversion images in which both CSF and GM were suppressed. Strong resonances in the 0.8 to 1.5 p.p.m. spectral region were observed in 13 MS patients. Image segmentation based on the MRI characteristics of tissues contributing to the spectroscopic voxels showed that these additional peaks originated mainly from GM. The presence of these additional peaks suggests that the normal appearance GM on MRI, is biochemically abnormal in a substantial proportion of relapsing-remitting MS patients.

Adult↗
PubMed2001

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group.

Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden.

Adult↗
PubMed2000

Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators.

OBJECTIVE: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of >/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score </= 5.0, or >/= 0.5 point for an enrollment EDSS score of >/= 5.5) not associated with an acute relapse. RESULTS: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). CONCLUSION: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Adjuvants, Immunologic↗
PubMed2000

Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators.

OBJECTIVE: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. BACKGROUND: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. METHODS: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. RESULTS: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as "black holes," and by a novel MRI composite disease measure. CONCLUSIONS: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Adjuvants, Immunologic↗
PubMed2000

The contribution of magnetic resonance imaging in the differential diagnosis of the damage of the cerebral hemispheres.

There are presently many magnetic resonance (MR) measures that can aid the assessment of damage to the brain. The conventional measures include T2 lesion volume, T1 enhanced lesion volume, and brain atrophy. Newer methodologies include magnetization transfer measures and proton spectroscopy. These methods have the potential for improving the specificity of MR with respect to the underlying pathology. MR spectroscopy offers the ability to quantitate the component of axonal loss in multiple sclerosis. MR techniques can be implemented to assess the effectiveness of treatment algorithms.

Blood-Brain Barrier↗
PubMed2000

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266

Adjuvants, Immunologic↗
PubMed2000

Combination therapy with glatiramer acetate (copolymer-1) and a type I interferon (IFN-alpha) does not improve experimental autoimmune encephalomyelitis.

We sought to determine whether combinations of glatiramer acetate and parenteral or ingested type I interferon were synergistic in experimental autoimmune encephalomyelitis. Glatiramer acetate, subcutaneous murine interferon-alpha, or ingested murine interferon-alpha individually improved clinical scores. In contrast, glatiramer acetate in conjunction with either subcutaneous or ingested interferon-alpha did not improve clinical scores compared with control. These data suggest that clinical trials designed to test a possible synergistic effect of glatiramer acetate and type I interferon in humans should be designed to detect possible adverse effects of this combination of immunomodulatory agents.

Animals↗
PubMed1999

The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis.

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.

Brain↗
PubMed1999

Ingested interferon alpha induces Mx mRNA.

We have demonstrated that ingested murine interferon alpha (IFN-alpha) suppressed clinical relapse in chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE), decreased inflammation and suppressed the adoptive transfer of EAE, and is a biological response modifier in patients with multiple sclerosis. We examined the relative levels of the Mx mRNA signal using semiquantitative reverse transcription-polymerase chain reaction analysis on splenocytes from mice and peripheral blood mononuclear cells from man after IFN-alpha ingestion. Both mice and man demonstrated inducible levels of Mx mRNA after ingesting IFN-alpha. Murine spleen T cells and CD8(+)T cells also demonstrated upregulation of Mx mRNA. Murine whole splenocytes demonstrated upregulation of Mx mRNA after IFN-alpha ingestion of 10 and 100 U, but not after 0, 1000, 5000 U. Ingested IFN-alpha acts via established pathways of type 1 IFN signalling.

Administration, Oral↗
PubMed1998

Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis.

Serial magnetic resonance (MR) studies that included proton MR spectroscopic imaging (MRSI), contrast-enhanced MR imaging (MRI), and lesion volumetric studies were performed on 25 multiple sclerosis (MS) patients with mild to modest clinical deficits. Each patient was scanned at varying intervals for up to 2 years, resulting in a total of 124 usable MR sessions. In these longitudinal studies, metabolic changes were observed on MRSI for some subjects before the appearance of lesions on MRI scanning. Regional changes in metabolite levels were observed to be dynamic and reversible in some patients. Transient changes in N-acetylaspartate (NAA) levels were sometimes found in acute plaques and indicate that a reduced NAA level does not necessarily imply axonal loss. An inverse correlation between the average NAA within the spectroscopic volume and the total lesion volume in the whole brain was observed. This negative correlation implies that NAA can serve as an objective marker of the disease burden. Strong lipid peaks in the absence of gadolinium enhancement and MRI-defined lesions were observed in 4 patients. This observation suggests that demyelination can occur independent of perivenous inflammatory changes and supports the presence of more than one pathophysiological process leading to demyelination in MS.

Adult↗
PubMed1998

Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis.

The change of brain lesion load, measured on T2-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collection, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.

Brain↗