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Biomedical subjects

D E Goodkin

Publications and source records attributed to D E Goodkin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Drugs used to treat spasticity.

Spasticity is a common and disabling symptom for many patients with upper motor neuron dysfunction. It results from interruption of inhibitory descending spinal motor pathways, and although the pathophysiology of spasticity is poorly understood, the final common pathway is overactivity of the alpha motor neuron. Therapy for spasticity is symptomatic with the aim of increasing functional capacity and relieving discomfort. Any approach to treatment should be multidisciplinary, including physical therapy, and possibly surgery, as well as pharmacotherapy. It is important that treatment be tailored to the individual patient, and that both patient and care giver have realistic expectations. Pharmacotherapy is generally initiated at low dosages and then gradually increased in an attempt to avoid adverse effects. Optimal therapy is the lowest effective dosage. Baclofen, diazepam, tizanidine and dantrolene are currently approved for use in patients with spasticity. In addition, clonidine (usually as combination therapy), gabapentin and botulinum toxin have shown efficacy, however, more studies are required to confirm their place in therapy. Intrathecal baclofen, via a surgically implanted pump and reservoir, may provide relief in patients with refractory severe spasticity.

Baclofen↗
PubMed2000

Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group.

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon beta-1a (IFNbeta-1a, 30 microg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6-month intervals. The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNbeta-1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between-group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNbeta-1a group. These results support and extend previous observations of significant beneficial effects of IFNbeta-1a for relapsing MS.

Adolescent↗
PubMed1999

Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis.

OBJECTIVE: To 1) compare monthly serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-type 1 (TIMP-1) in patients with relapsing-remitting MS (RRMS) versus healthy controls and 2) determine the relationship among monthly serum levels of MMP-9 and TIMP-1 and MRI activity. BACKGROUND: Activated T-cells and macrophages secrete MMPs that may facilitate their migration across vascular subendothelial basement membranes into the CNS. The serum concentration of MMP-9 is reported to be higher in patients with RRMS than healthy controls. METHODS: Monthly evaluations including gadolinium-enhanced (Gd+) brain MRI and measures of serum MMP-9 and TIMP-1 were performed for up to 15 months in 24 patients with RRMS and for up to 4 months in 10 controls. RESULTS: Serum MMP-9 but not TIMP-1 levels are elevated in RRMS patients compared to healthy controls (p = 0.025, p = 0.61). In a univariate analysis, high MMP-9 and low TIMP-1 levels precede appearance of new Gd+ lesions (respectively; odds ratio = 3.3, p = 0.008; odds ratio = 2.2, p = 0.086). In a multivariate analysis, in comparison to months when MMP-9 is low and TIMP-1 high, MRI scans obtained the month following high MMP-9 and low TIMP-1 serum concentrations are more likely to report new Gd+ lesions (p = 0.0006, odds ratio = 21.5). CONCLUSION: An increase in the activity of matrix metalloproteinase-9 (MMP-9) relative to tissue inhibitor of MMP-type 1 (TIMP-1) may be related to formation of new MS lesions, suggesting that serum levels of MMP-9 and TIMP-1 may be surrogate markers of disease activity in relapsing-remitting MS.

Adolescent↗
PubMed1999

A pilot study of MRI activity before and during interferon beta-1a therapy.

We compared the number of new gadolinium-enhancing and T2-weighted lesions on six monthly MRI scans in eight patients with relapsing multiple sclerosis before and during treatment with weekly intramuscular interferon beta-1a (Avonex; 30 microg). MRI activity was modestly reduced during treatment (p = 0.016). The treatment effect was also significant after adjusting pretreatment lesion frequency for regression to the mean. Based on this pilot study, Avonex, as approved for treatment of relapsing forms of MS in the United States, reduces new MRI activity.

Adult↗
PubMed1999

A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

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.

Adjuvants, Immunologic↗
PubMed1999

Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

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.

Adjuvants, Immunologic↗
PubMed1999

Course of depression during the initiation of interferon beta-1a treatment for multiple sclerosis.

OBJECTIVE: To examine the hypothesis that increases in depression after initiation of treatment with interferon beta-1a for multiple sclerosis can be explained as representing a return to pretreatment levels of depression. DESIGN: Level of depression in patients with multiple sclerosis was assessed at 3 time points: 2 weeks before initiation of interferon beta-la treatment, at initiation of treatment, and at 2-month follow-up. SETTING: A health maintenance organization. PATIENTS: Fifty-six patients with confirmed relapsing forms of multiple sclerosis. MAIN OUTCOME MEASURE: The depression-dejection scale of the Profile of Mood States. RESULTS: Patients who scored high on the depression measure 2 weeks before the initiation of interferon beta-1a treatment showed significant reduction in depression at the initiation of treatment. However, depression returned nearly to initial levels within 2 months. CONCLUSIONS: These findings suggest that increases in depression after initiation of interferon beta-1a treatment are related to level of depression 2 weeks before initiation of treatment. Physicians should assess history of depression for all patients in whom interferon beta-1a treatment is initiated. Patients with a recent history of depression are at risk for increased depression within 2 months after starting interferon beta-1a treatment, even though they may not be depressed at the time of treatment initiation.

Adjuvants, Immunologic↗
PubMed1999

Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability.

OBJECTIVE: To use the new consensus definitions of primary progressive multiple sclerosis (PPMS) and progressive relapsing multiple sclerosis (PRMS) to report the demographic, clinical, and natural history characteristics of multiple sclerosis (MS) that is progressive from the time of onset. DESIGN: Retrospective study by database/chart review and telephone interview. SETTING: Multiple sclerosis clinic at a university teaching hospital. PATIENTS: Eighty-three patients (prevalence, 6.9%) with PPMS and 12 patients (prevalence, 1.0%) with PRMS were studied. RESULTS: Fifty-nine percent of the patients with PPMS (n=49) and 67% of the patients with PRMS (n=8) were women. Mean +/- SD ages at the time of onset were 41.2 +/- 10.5 and 38.0 +/- 7.3 years, respectively; mean disease duration was 14.2 +/- 8.8 and 12.2 +/- 6.5 years, respectively. The initial symptoms involved leg weakness in 94% of the patients with PPMS (n = 78) and 100% of the patients with PRMS (n= 12). For the PPMS cohort, a syndrome consistent with isolated myelopathy was found in 36% of patients (n = 30) and arm weakness without leg weakness did not occur. Mean +/- SEM time of progression to a score of 6.0 on the Expanded Disability Status Scale was 10.2 +/- 1.0 years for patients with PPMS and 10.9 +/- 2.6 years for patients with PRMS. CONCLUSIONS: The clinical characteristics and disability progression of these MS subtypes were indistinguishable, with the exception of 1 or 2 relapses in patients with PRMS that occurred 8 months to 9 years after the onset of symptoms. We see little reason to consider PPMS and PRMS separate clinical entities; however, whether they can be better distinguished by radiological, histopathological, or immunological markers of disease activity remains unknown.

Adult↗
PubMed1999

Linkage analysis of candidate myelin genes in familial multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. A complex genetic etiology is thought to underlie susceptibility to this disease. The present study was designed to analyze whether differences in genes that encode myelin proteins influence susceptibility to MS. We performed linkage analysis of MS to markers in chromosomal regions that include the genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMGP), and myelin oligodendrocyte glycoprotein (MOG) in a well-characterized population of 65 multiplex MS families consisting of 399 total individuals, 169 affected with MS and 102 affected sibpairs. Physical mapping data permitted placement of MAG and PLP genes on the Genethon genetic map; all other genes were mapped on the Genethon genetic map by linkage analysis. For each gene, at least one marker within the gene and/or two tightly linked flanking markers were analyzed. Marker data analysis employed a combination of genetic trait model-dependent (parametric) and model-independent linkage methods. Results indicate that MAG, MBP, OMGP, and PLP genes do not have a significant genetic effect on susceptibility to MS in this population. As MOG resides within the MHC, a potential role of the MOG gene could not be excluded.

DNA Primers↗
PubMed1999

The psychosocial impact of multiple sclerosis: exploring the patient's perspective.

This study examined subjective patient experiences of the psychosocial consequences of multiple sclerosis (MS). Fifty patients were interviewed regarding the effects MS had on their lives and interpersonal relationships. These statements were collated and administered with a 5-point Likert scale to 94 MS patients. The responses were subjected to factor analysis. Three areas of subjective patient experience of the psychosocial consequences of MS emerged: demoralization, benefit-finding, and deteriorated relationships. Of particular interest was benefit-finding, which included a deepening of relationships, enhanced appreciation of life, and an increase in spiritual interests. Although benefit-finding was related to adaptive coping strategies such as positive reappraisal and seeking social support, it was unrelated to depression and was related to higher levels of anxiety and anger. These findings indicate that benefit-finding is a substantial and poorly understood part of the illness experience for MS patients.

Adaptation, Psychological↗
PubMed1999

Treatment adherence and patient retention in the first year of a Phase-III clinical trial for the treatment of multiple sclerosis.

The purpose of this study was to examine the relationship between patient management strategies employed by study personnel, and patient retention and adherence to treatment in the first year of a Phase III clinical trial of interferon beta-1b for treatment of secondary progressive multiple sclerosis (MS). Study staff from each of 35 sites were interviewed regarding patient management practices. Sites which were rated as more empathetic, as instilling a sense of purpose in the patient, and promoting less formal relationships with patients had high rates of adherence to treatment. In addressing specific patient concerns, attention to patients' emotional status and patients' expectations of trial participation were related to better adherence.

Data Interpretation, Statistical↗
PubMed1998

Glucocorticosteroid therapy for multiple sclerosis: a critical review.

Controversy remains as to the efficacy, route of administration and dose of glucocorticosteroid (GCS) in multiple sclerosis (MS) therapy. With the recent approval of new disease modifying treatments and increasing interest in cost-benefit assessments, it is timely to critically consider their role in MS therapeutics. In this paper we review our current understanding of the cellular and molecular mechanisms of action of GCS as they relate to the postulated pathophysiology of MS. We also critically review the use of glucocorticosteroid therapy to: (1) improve recovery from exacerbations of MS, (2) delay the onset of MS in patients who experience a first episode of monosymptomatic optic neuritis, and (3) delay the time to onset of sustained progression of disability in patients with clinically definite MS.

Adrenocorticotropic Hormone↗
PubMed1998

Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.

Brain↗
PubMed1998

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.

Alleles↗
PubMed1998

Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials. The Multiple Sclerosis Collaborative Research Group (MSCRG).

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physician-based composite of BBT, 9HPT, and TA was of comparable sensitivity (P = 0.013) in discriminating sustained treatment failure as the EDSS alone (P = 0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P = 0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

Clinical Trials as Topic↗
PubMed1998

Side effect profile and adherence to in the treatment of multiple sclerosis with interferon beta-1a.

This study examines the course of patient-reported side effects during the first 4 months of treatment for multiple sclerosis (MS) with interferon beta-1a (IFN beta-1a), and the relationship of those side effects to discontinuation of medication. Flu-like symptoms, muscle aches and chills decreased over the first 2 months of treatment but did not change over the second 2 months. Loss of feeling or numbness, tingling and depression increased over 4 months, however these side effects were generally mild. Loss of feeling or numbness and tingling at 2 month follow-up were significantly related to discontinuation of IFN beta-1a by 4 month follow-up.

Adolescent↗