Showing papers in "Multiple Sclerosis Journal in 2002"
TL;DR: Progress in HRQoL assessment in research or clinical monitoring is evolutionary and, arguably, comparable to the increasing use of MRI and immunological markers in quantifying MS severity.
Abstract: The goal of treatments for multiple sclerosis (MS) and other chronic neurological conditions that produce morbidity but have limited effect on mortality is to reduce disease impact on patients’ lives and to assure that interventions result in more good than harm. A measure of our success in reaching these goals can be made only with direct information from patients about how they experience the illness and the effects of treatments. Patient-derived data are increasingly accepted as an essential assessment domain in clinical research and treatment. Research shows that measures of patient perception and clinician-derived data are not redundant. ± 3 Observation of patient functioning in the clinic is not sufficient in itself since it has been determined that patient functioning in the artificial setting of the treatment center is not always duplicated at home. The approach to patient assessment that is considered relevant in monitoring the consequences of diseases and their treatments is known as `health-related quality of life’. Quality of life is one domain of health as defined by the World Health Organization (WHO). Health-related quality of life (HRQoL) is a discrete component of general quality of life. While general quality of life can be affected by many factors beyond the scope of health care including economic instability, civil unrest or poor environment, these have only an indirect relationship with HRQoL and are not included in its definition. While such factors as equal opportunity and social security are important to community health, these extend beyond the more immediate goal of treating the sick. This thinking led to the HRQoL definition: `Quality of life’ in clinical medicine represents the functional effect of an illness and its consequent therapy upon a patient, as perceived by the patient’. Although there is variation in terminology, this construct includes four broad domains: physical and occupational function, psychological function, social interaction and somatic sensation. Several operational characteristics of HRQoL assessment help to further define the construct. First and foremost, HRQoL is subjective. As Schipper and his colleagues explain `. . . in clinical medicine the ultimate observer of the experiment is not a dispassionate third party but a most intimately involved patient’. They note that since the goal of treatment is to minimize the manifest consequences of disease, HRQoL represents `the final common pathway of all the physiological, psychological and social inputs into the therapeutic process’. The second characteristic of HRQoL is that it is multifactorial. Having defined HRQoL as the integration of four domains, it is important to assure that patients’ daily experiences in each domain are explored in the questionnaire, albeit in a manner that is parsimonious and minimizes respondent burden. The third characteristic is self-administration: because HRQoL is subjective, there is concern that external administration would in some way influence patient report. The final characteristic is that HRQoL is time variable; it fluctuates. Progress in HRQoL assessment in research or clinical monitoring is evolutionary and, arguably, comparable to the increasing use of MRI and immunological markers in quantifying MS severity. Data derived from HRQoL measures are used for three general purposes. The first, most commonly used in research, is to classify or group patients by levels of disease severity. The second is to monitor for change in status that indicates a need for modifying the treatment plan or to predict the health of subjects at a future point in time. The third use is as an outcome variable in clinical research. HRQoL assessment is increasingly accepted as an outcome measure in MS research for disease-modifying treatments ± 11 and symptom management. ± 14 HRQoL assessment is less commonly used to monitor patient well-being as part of the usual process of care. This can be done routinely, in much the same way that upper and lower extremity monitoring is done using the NineHole Peg Test or Timed Twenty-five Foot Walk. However, challenges to using HRQoL monitoring in clinical practice are the limited availability of instruments proved to be sensitive to change in individual patients over time, easily interpreted by clinicians, accepted by patients as relevant, and that require limited time to complete. Quality of life researchers are actively engaged in improving the science of HRQoL interpretation at the individual level; it remains an emerging field. In this issue, Shawaryn describes a measure of illness intrusiveness that has good potential for use as an HRQoL screening instrument in the clinical setting. Her findings clearly demonstrate that the physical and cognitive aspects of MS affect HRQoL, each in different ways. Her findings hold for HRQoL as measured directly by the Multiple Sclerosis Quality of Life Inventory and indirectly, by the Illness Intrusiveness Rating Scale. This later measure has a number of benefits for clinical use including brevity, face validity, clinical relevance and patient acceptability. Even though there are not yet standard methods for determining when a change in this or other patient self-reported measures indicates a need to review or revise a patient’s treatment plan, these measures have an important use for physicians providing care to patients with MS and other chronic conditions. Routine use of such measures allows physicians to review, quickly and systematically, patient functioning and concerns and to help patients to become active participants in their care.
954 citations
TL;DR: The association of fatigue and depression suggests that there might be either common underlying mechanisms or interdependence by a cause-and-effect relationship that requires further investigation.
Abstract: Objectives: Fatigue is one of the most common, yet poorly defined, disabling symptoms in patients with multiple sclerosis (MS). To delineate more clearly the frequency and type of fatigue, we first compared four widely used fatigue scales in consecutive MS patients. Secondly, to further clarify the nature of fatigue, we investigated its relation to physical disability, course of the disease, immunotherapy, and depression. Patients and Methods: Between February and September 2000, 151 consecutive MS patients entering our outpatient clinic (94 relapsing-remitting, 50 secondary progressive, and 7 primary progressive patients; mean age 29.0-7.3 years, mean disease duration 9.9-6.7 years, median EDSS 3.5) filled in a standardized questionnaire including four fatigue scales - Fatigue Severity Scale (FSS), MS-specific FSS (MFSS), Modified Fatigue Impact Scale (MFIS), and Visual Analogue Scale (VAS). Patients were included in the ‘MS-related fatigue group’ (MS-F) when they stated in the questionnaire that fatigue...
561 citations
TL;DR: Overall compliance to the training program was quite low, whereas incidence of symptom exacerbation by physical activity has been lower than expected (6%).
Abstract: Multiple sclerosis (MS) patients of an inpatient rehabilitation program have been randomly assigned to an exercise training (MS-ET) or nontraining group (MS-NI). Before and after 4 weeks of aerobic exercise training, a graded maximal exercise test with measurement of gas exchange and a lung function test was administered to all 26 patients fulfilling the inclusion criteria. Activity level, fatigue and health perception were measured by means of questionnaires. Twenty-six healthy persons served as control group and were matched in respect of age, gender and activity level. Training intervention consisted of 5x30 min sessions per week of bicycle exercise with individualised intensity. Compared with baseline, the MS training group demonstrated a significant rightward placement of the aerobic threshold (AT) (VO2+13%; work rate [WR])+11%), an improvement of health perception (vitality+46%; social interaction+36%), an increase of activity level (+17%) and a tendency to less fatigue. No changes were observed for the MS-NI group and the control groups. Maximal aerobic capacity and lung function were not changed by either training or nontraining in all four groups. Overall compliance to the training program was quite low (65%), whereas incidence of symptom exacerbation by physical activity has been lower than expected (6%).
521 citations
TL;DR: The studies in aggregate indicate that MSFC and MSFC change are clinically meaningful, and that MS FC has substantial advantages over alternative clinical outcome measures for MS clinical trials.
Abstract: With the advent and widespread use of partially effective disease modifying drug therapies for multiple sclerosis (MS), future clinical trials will undoubtedly test experimental interventions against standard therapy, or will test combinations of drugs against standard therapy. In either case, incremental progress in slowing disability progression in future MS clinical trials will require much larger sample sizes, more sensitive outcome measures, or a combination of the two. Because improved clinical outcome methods would likely accelerate progress in MS therapeutics, the National Multiple Sclerosis Society (NMSS) convened an international task force in 1994 to recommend improved clinical outcome measures. As the result of a two-year process of discussion and data analysis, the task force recommended the Multiple Sclerosis Functional Composite (MSFC) as a new clinical outcome measure for future MS trials. MSFC consists of timed tests of walking, arm function, and cognitive function, expressed as a single ...
204 citations
TL;DR: Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood).
Abstract: Cyclophosphamide is an alkylating agent used to treat malignancies and immune-mediated inflammatory non-malignant processes such as lupus nephritis and immune-mediated neuropathies. It has been studied as a treatment for multiple sclerosis (MS) for the past 30 years and is used by physicians in selected cases of progressive or worsening MS. Review of published reports suggests that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the central nervous system (CNS). There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Side effects include nausea, alopecia, infertility, bladder toxicity and risk of malignancy. The most commonly used regimens involve every 4- to 8-week outpatient i.v. pulse therapy given with or without corticosteroids and are usually well-tolerated by patients. Cyclophosphamide is currently used in patients whose disease is not controlled by beta-interferon or glatiramer acetate and those with rapidly worsening MS.
155 citations
TL;DR: The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS, and extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk.
Abstract: To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.
146 citations
TL;DR: Fifty-four subjects affected by clinically definite multiple sclerosis and with onset of the disease at 15 years of age or before were prospectively studied in five Italian MS centres, finding that disability after 8 years was highly predicted by disability in the first year.
Abstract: Fifty-four subjects (36 females and 18 males) affected by clinically definite multiple sclerosis (MS) and with onset of the disease at 15 years of age or before were prospectively studied in five Italian MS centres. Female/male ratio was 4.7 in subjects with age ≥12 years, suggesting a role of hormonal changes in triggering MS onset. The mean follow-up duration was 10.9-5.6 years. The functional systems more frequently involved at onset were the pyramidal and brainstem (both in 28% of cases). The onset was monosymptomatic in 31 subjects (57%). The course was relapsing-remitting in 39 subjects (72%) and relapsing-progressive in 15 (28%). Disability was assessed by the Expanded Disability Status Scale (EDSS): the mean score after 8 years of follow up was 3.5 (-2.5). The score was 6 in 24% of cases. Disability after 8 years was highly predicted by disability in the first year (p=0.008). There was a tendency to a worse prognosis in relation to the number o...
138 citations
TL;DR: It is shown that the neuroprotective agent riluzole seems to reduce the rate of cervical cord atrophy and the development of hypointense T1 brain lesions on magnetic resonance imaging.
Abstract: Progressive axonal loss is the most likely pathologic correlate of irreversible neurologic impairment in primary progressive multiple sclerosis In a run-in versus treatment trial, we show that the neuroprotective agent riluzole seems to reduce the rate of cervical cord atrophy and the development of hypointense T1 brain lesions on magnetic resonance imaging
133 citations
TL;DR: The use ofMRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics, and it was agreed that MRI does not represent a validated surrogate in any clinical form of MS.
Abstract: The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.
121 citations
TL;DR: Both the SEFCI and the NPSBMS identified significantly more patients with impairment than the RBANS, which was no more sensitive than the Mini-Mental State Exam (MMSE).
Abstract: To compare the sensitivities for detecting cognitive impairment in patients with multiple sclerosis (MS) and administration times of three brief batteries of neuropsychological tests, 64 patients with MS completed the Neuropsychological Screening Battery for Multiple Sclerosis (NPSBMS), the Screening Examination for Cognitive Impairment (SEFCI), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Failure on a particular test was defined as a score below the 5th percentile for healthy controls, and the number of patients who failed at least one or two tests (out of four) was determined for each battery. Both the SEFCI and the NPSBMS identified significantly more patients with impairment than the RBANS, which was no more sensitive than the Mini-Mental State Exam (MMSE). Results were similar at both the one- and two-failed-tests criteria, but there were no significant differences between the SEFCI and the NPSBMS at either failure criterion. Mean administration time was 22.6 min for the SEFCI compared to 31.7 min for the NPSBMS (p < 0.001). Eleven (17%) of the patients refused to attempt the Paced Auditory Serial Addition Test (PASAT), one component of the NPSBMS. For screening patents on a single occasion, the SEFCI is preferred because its administration time is shorter than the NPSBMS.
102 citations
TL;DR: Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases, but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs).
Abstract: Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF) samples from patients with neurological diseases. Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases (INDs), but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs). MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity. A correlation between the CSF/serum albumin (QAlb) and CSF/serum MMP-9 (QMMP-9) was observed in IND and NIND but not in RR-MS patients, indicating that CSF MMP-9 levels in NIND and IND patients could be influenced by serum MMP-9 and blood-brain barrier (BBB) permeability properties. MS patients had higher values of QMMP-9:QAlb (MMP-9 index) than IND and NIND patients suggesting that in MS the increas...
TL;DR: The findings suggest that atrophy is a feature of focal demyelinating lesions, it may evolve over several years, and may have functional significance.
Abstract: To investigate optic neuritis as a model for atrophy in multiple sclerosis (MS) lesions we performed serial magnetic resonance imaging (MRI) on 10 patients with a history of optic neuritis using a fat saturated short-echo fast fluid-attenuated inversion recovery (sTE fFLAIR) sequence. The first study was performed a median of 19.5 months after the onset of optic neuritis and the second I year later. Using a computer-assisted contouring technique, a blinded observer calculated the mean area of the intra-orbital optic nerves. The mean area of affected optic nerves decreased over 1 year by 0.9 mm(2) from 11.1 to 10.2 mm(2) (p=0.01). Poor visual acuity and decreased visual-evoked potential (VEP) amplitude were associated with atrophy. These findings suggest that atrophy is a feature of focal demyelinating lesions, it may evolve over several years, and may have functional significance. Optic neuritis provides a model to study the effect of inflammatory demyelination through the ability to accurately measure visual function and to visualize and measure the optic nerves using magnetic resonance imaging.
TL;DR: Although rhIGF-1 did not alter the course of disease in this small cohort of MS patients, the drug was well tolerated and further studies using rhIGFs alone or in combination with other therapies may be of value because of the proposed mechanism of action of this growth factor on the oligodendrocyte and remyelination.
Abstract: The purpose of this open-label, crossover study was to determine the safety and efficacy of recombinant insulin-like growth factor-1 (rhIGF-1) using magnetic resonance imaging (MRI) and clinical me...
TL;DR: Perceptions of illness intrusiveness appear to be a central and essential measure of the impact of MS on HRQL, as illustrated by the broad and powerful network of relationships between illness intrusion and all aspects of HRQL.
Abstract: The relationship between the cognitive and physical aspects of multiple sclerosis (MS) and health-related quality of life (HRQL) was examined with particular focus on illness intrusiveness as a mediator of this relationship. Disease severity, cognitive functioning HRQL, depression, and illness intrusiveness were assessed in 90 patients with MS. Disease severity (Expanded Disability Status Scale [EDSS]) predicted physical aspects of HRQL (SF-36 Physical Component Summary [PCS], fatigue, and bladder control). Information-processing speed (Paced Auditory Serial Addition Test [PASAT]) predicted mental and emotional aspects of HRQL (SF-36 Mental Component Summary [MCS]). However, both the EDSS and the PASAT predicted depression. Illness intrusiveness was significantly correlated with all indicators of HRQL Illness intrusiveness also mediated the manner in which disease severity predicted: physical health, fatigue, and depression. Results underscore the need to assess MS and its impact more broadly rather than relying on traditional mobility-centered assessments. While in most cases physical indices of disease predict physical quality of life and cognitive assessments predict mental and emotional quality of life, the individuals perception of MS is also a major factor contributing to quality of life. MS dearly affects multiple aspects of life and activity, as illustrated by the broad and powerful network of relationships between illness intrusiveness and all aspects of HRQL Perceptions of illness intrusiveness appear to be a central and essential measure of the impact of MS on HRQL.
TL;DR: There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value.
Abstract: Spasticity is a common disabling feature of multiple sderosis. A variety of drugs are in regular use as oral treatment induding badofen, dantrolene, tizanidine, and diazepam. Published evidence of effectiveness is limited. Most trials are of small size, of short duration, and have not reported on functional outcomes. Studies have been published which suggest that badofen, tizanidine, and diazepam are all effective in reducing dinical measures of spasticity, but there is little evidence that they lead to an improvement in patient function. There is no evidence to suggest any difference in effectiveness between them. The evidence that dantrolene has any effect on spasticity is of poor quality. Diazepam and dantrolene are associated with more side effects than baclofen and tizanidine. There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value. One randomized controlled trial of threonine does not support its effectiveness.
TL;DR: The QoL, assessed by the SF-36 scale, is correlated with disability in MS, and IFN-β1a treatment (Avonex®) has no negative effect on MS patient’sQoL.
Abstract: Background: Numerous data argue for initiating treatment with interferon-β(IFN-β) at an early stage in multiple sclerosis (MS). The consequences of its use may negatively influence the MS patient’s quality of life (QoL). Objective: To evaluate the QoL of MS patients before and after a one-year period of treatment with IFN-β1a (Avonex®). Patients and Methods: QoL was assessed using the SF-36 in 121 relapsing-remitting MS patients. We compared QoL before and after treatment and with data from a normal population. We also studied the possible influence of disease progression on the SF-36 scores. Results: One hundred six patients completed the study (87%). Compared to a normal population, patients were, at baseline, worse off for all QoL scales, varying from a minimum decrease of 0.73 SD in mental health, to a maximum decrease of 1.55 SD in general health. After treatment, we found no significant changes in any of the QoL scores, except for physical function, where we noted a slight but significant decrease (...
TL;DR: The relatively late occurrence of epileptic seizures indicates that the frequency of epileptogenesis, known to involve neuronal damage, increases in the later stages of MS.
Abstract: The occurrence of a first epileptic seizure, spinal or brainstem paroxysmal symptom and cranial neuralgia during 25 years after onset was studied in a population-based multiple sclerosis (MS) cohort of 255 patients. Epileptic seizures occurred in 20, paroxysmal symptoms in 11 and cranial (trigeminal, intermedius, retroauricular or occipital) neuralgia in 11 patients. The yearly incidence of epileptic seizures in MS was estimated to be 349(-153)/100,000, approximately seven times higher than in the general population. The yearly incidence of a first paroxysmal symptom in the present material was calculated to be 190 cases in 100,000 MS patients, and the yearly incidence of cranial neuralgia was 189 cases in 100,000 MS patients. The epileptic seizures were more frequent during the progressive course than in the relapsing-remitting (RR) course. The frequencies of paroxysmal symptoms and cranial neuralgia did not differ between these two disease courses. A coincidence of epileptic seizures and a decline in co...
TL;DR: Multiparametric MT measurements suggest both a reduction of macromolecular material and a focal increase of free water to occur several months before the appearance of an active lesion.
Abstract: Objective: Previous magnetization transfer (MT) studies in multiple sclerosis (MS) suggest a reduction of the MT ratio (MTR) precedes new lesion development. To gain further insight into pre-lesional tissue abnormalities, we investigated the time course of additional quantitative MT parameters. Methods: Serial magnetic resonance imaging (MRI), including a gadolinium-enhanced T1 scan and MT imaging by means of a FastPACE sequence, was performed on 12 patients (4 males, 8 females) with relapsing-remitting MS. Quantitative MT values including the magnetization exchange rate (kfor) and the native relaxation time (T1free) were analysed in the six months prior to the appearance of 44 enhancing lesions and in 88 control regions of persistently normal-appearing white matter (NAWM). Results: Appearance of new active lesions was preceded by a significant decrease of the MTR (F7,166=91.5; p <0.0001) and of kfor (F7,166=105.2; p <0.0001), and by an increase of T1free (F7,166=57.3; p <0.0001). The drop of kfor was the...
TL;DR: The risk conferred by e4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles, and there were no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles.
Abstract: Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.
TL;DR: Compared with controls, MS patients demonstrated significantly higher concentrations of myo-inositol (Ins) in normal appearing white matter (NAWM) and lesions, which indicates diffuse involvement of the entire MS brain, which was not seen in the persisting CIS patients.
Abstract: Clinically isolated syndromes (CIS) are events suggestive for emerging multiple sclerosis (MS). A majority of patients develop MS within months or years whilst others remain clinically isolated. The goal of this study was to investigate whether biochemical metabolites detectable by 1H magnetic resonance spectroscopy (MRS) may serve to distinguish between these two groups. We investigated 41 patients 14 years after presentation with a CIS and 21 controls with combined quantitative short echo 1H MRS and magnetic resonance imaging (MRI) and assessed disability according to the Expanded Disability Status Scale (EDSS). At follow-up, 32 had developed MS, and 9 still had CIS. Compared with controls, MS patients demonstrated significantly higher concentrations of myo-inositol (Ins) in normal appearing white matter (NAWM) and lesions. Lesions also demonstrated a reduced N-acetyl-aspartate (NAA) level and an increase in choline-containing compounds (Cho). The NAWM Ins concentration was correlated with EDSS (r = 0.4...
TL;DR: Applications to multiple sclerosis are reviewed, which address the challenging notion that adaptive cerebral plasticity may have an important influence on the relationship between MS pathology and its clinical expression.
Abstract: Functional magnetic resonance imaging (fMRI) allows noninvasive localization of cerebral activation with relatively high spatial and temporal resolution. The considerable potential for the elucidation of the mechanisms of brain function has made it a useful tool to investigate the neural substrate of motor, sensory and cognitive functions. Understanding derived from these basic cognitive neuroscience investigations is beginning to be applied to clinically relevant problems. In this article, applications to multiple sclerosis (MS) are reviewed, which address the challenging notion that adaptive cerebral plasticity may have an important influence on the relationship between MS pathology and its clinical expression.
TL;DR: Findings obtained by the application of enzyme-linked immunospot (ELISPOT) assays to cytokine studies in MS are summarized and summarized.
Abstract: Multiple sclerosis (MS) is one of the leading causes of disability among young adults of Caucasian origin. One hundred and fifty years after the first description of the disease, the cause of MS remains unknown. Ironically, the few hypotheses concerning MS pathogenesis that are valid today were first proposed over a hundred years ago. However, equipped with the advanced technology of molecular biology and imaging systems, we are at present progressively uncovering dues to understanding the pathogenesis of the disease. It is dearly evident that aberrant immune responses occur in MS, and it is likely that the spectrum of cytokines produced decisively influences disease outcome. The detrimental consequences of IFN-gamma and the beneficial effects of IFN-beta treatment in MS support this hypothesis. However, there are still major gaps in our knowledge of the involvement of cytokines in MS. Numerous studies have addressed the question of cytokine levels in MS, often with conflicting results; elevated, normal and decreased levels of almost all cytokines have been reported. This scenario most probably reflects methodological dilemmas as well as the complex biology of cytokines. Here we focus on possible reasons for the discrepancies of results reported on cytokines in MS and summarize findings obtained in particular by the application of enzyme-linked immunospot (ELISPOT) assays to cytokine studies in MS.
TL;DR: Overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss and underline the importance of nonFocal pathology even in the early RR phase of the disease.
Abstract: Introduction: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which fact...
TL;DR: Cell transplantation will have considerable potential to achieve remyelination in situations where the endogenous repair process is failing due to concurrent death of oligodendrocytes and OPCs, but it is suggested that for this approach to be effective, it will be critical that the environment is permissive for remYelination.
Abstract: This review considers aspects of remyelination that require further clarification if successful strategies are to be devised to enhance remyelination in multiple sclerosis (MS). We speculate, based on our understanding of the rate with which oligodendrocyte progenitor cells (OPCs) repopulate OPC-depleted tissue in adult rats, that OPC depletion during the demyelination process could explain why remyelination fails in MS. We show that loss of OPCs in the context of large areas of demyelination would have serious consequences for remyelination as the rates of colonization of tissue by adult OPCs would lead to a situation where the cellular events associated with demyelination become uncoupled from the interaction of OPCs with demyelinated axons. Experimental studies indicate that transplanted neonatal OPCs would be able to repopulate large areas of demyelination with much greater efficiency than endogenous OPCs. This suggests that cell transplantation will have considerable potential to achieve remyelination in situations where the endogenous repair process is failing due to concurrent death of oligodendroytes and OPCs. However, we suggest that for this approach to be effective, it will be critical that the environment is permissive for remyelination.
TL;DR: The results indicate that neither the paracetamol nor the ibuprofen treatment regimen is better, and there was no significant difference in general satisfaction or incidence of additional symptoms.
Abstract: Interferon beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS) Adverse effects in the first weeks of treatment are common This open-label, multicenter, randomized, prospective study compared treatment of flu-like symptoms (FLS) with paracetamol versus ibuprofen administered 48 h within interferon injection The percentage of patients with FLS was comparable between both treatment groups and improved during the course of the study (baseline: paracetamol 92%, ibuprofen 90%; week 12: paracetamol 60%, ibuprofen 57%) More than 75% of patients receiving either paracetamol or ibuprofen reported no or only mild impairment of daily activities There was no significant difference in general satisfaction or incidence of additional symptoms (weakness, nausea, headache; paracetamol 846% patients, ibuprofen 860% patients) between the two groups A significant overall improvement from baseline to week 12 was observed for all parameters studied (paracetamol and ibuprofen groups were pooled) These results indicate that neither the paracetamol nor the ibuprofen treatment regimen is better
TL;DR: The BRBNT was slightly more sensitive in detecting impairment by the criterion of poor performance on one or more tests, and EDSS score was the only clinical variable independently associated with cognitive impairment on these batteries.
Abstract: Background: We compared two brief neuropsychological batteries devised to assess people with multiple sclerosis (MS) and used them to assess the relationship between cognitive impairment and clinical characteristics. Methods: We administered either the Brief Repeatable Battery of Neuropsychological Tests (BRBNT) or the Screening Examination for Cognitive Impairment (SEFCI) to 213 consecutive MS outpatients and 213 individually matched controls. Results: Administration times were longer for BRBNT than SEFCI, for MS and controls (p=0.001). People with MS had lower scores in all individual tests than controls (p<0.001, BRBNT and SEFCI). By the criterion of poor performance on one or more tests, the sensitivity of BRBNT was 41.9% and that of SEFCI 31.5%. The corresponding figures by poor performance on two or more tests were 16.2% for BRBNT and 18.5% for SEFCI. The Buschke Selective Reminding and Paced Auditory Serial Addition were the tests best discriminating between people with MS and controls for BRBNT, a...
TL;DR: The data support previous assumptions of a modulation of severity in MS by the CCR5D32 genotype, which may convey less inflammation and tissue destruction, and weak associations between candidate genes and disease variables cannot be excluded.
Abstract: As the understanding of the autoimmune inflammatory response in multiple sclerosis (MS) expands, polymorphic genes involved in this process become possible candidates that may determine the severity of disease Therefore, three candidate genes DRB1*1501, CCR5 and apolipoprotein E (APOE) were examined in a population-based patient sample (n = 70) to assess an association between disease progression measured by clinical disability and MRI parameters The total lesion area (TLA) on T2-weighted images was measured with a semi-automated threshold technique Patients with the CCR5delta32 allele showed a non-significant trend towards a smaller lesion burden (TLA/years duration), but were not associated to a milder EDSS/years duration Our data support previous assumptions of a modulation of severity in MS by the CCR5delta32 genotype, which may convey less inflammation and tissue destruction Carriers of the DRB1*1501 and APOE-epsilon4 allels did not reveal more severe disease progression, neither by the EDSS/years of duration nor by the TLA/years duration This study was performed on a population-based sample in a genetically homogeneous Danish population but, due to the limited number of patients examined, weak associations between candidate genes and disease variables cannot be excluded
TL;DR: A decrease of brain volume was found in relapsing-remitting MS patients treated with IFNβ-1a over 2 years and the only parameter that predicted brain volume decrease by 2 years of IFN β- 1a treatment was the mean volume of enhancing lesions over the 6-month pretreatment period.
Abstract: The aim of this study was to investigate changes of brain volume as measured by magnetic resonance imaging (MRI) in relapsing‐remitting multiple sclerosis (MS) patients under treatment with interferon beta-1a. Moreover, the relationship between brain volume changes and standard MR or clinical outcome variables was determined. After a 6-month pretreatment period, 52 patients with relapsing‐remitting MS were assigned to receive interferon beta-1a (Rebif-Serono) during a 24-month treatment period. MRI scans were performed monthly during the 6-month pretreatment period and for the first 9 months of the treatment period. A final MRI scan was also performed at the end of the 12- and 24-month treatment period. Over 24 months of IFN› -1a treatment, a significant decrease of hyperintense lesion volume was found (i18.0%; p<0.0001) compared to the last pretreatment scan, while T1 hypointense volume showed a slight nonsignificant increase (+2.2%), and brain volume showed a significant decrease (i2.2%; p<0.0001). The mean volume of enhancing lesions over the 6-month pretreatment period was significantly related to absolute (p=0.02; r=i0.32) and per cent change (p=0.03; r=i0.30) of brain volume during 24-month treatment period. No correlations between changes in brain volume and changes in T2 hyperintense volume or T1 hypointense volume were observed. Neither was there a relationship between brain volume and changes of Expanded Disability Status Scale (EDSS) or frequency in clinical relapses. Of the group in whom was detected a significant decrease of brain volume, 13 out of 26 (50%) had a sustained change in EDSS while in the group that did not have a significant decrease of brain volume, only 3 out of 26 (11.5%) had a sustained EDSS change (p=0.02). In this study a decrease of brain volume was found in relapsing‐remitting MS patients treated with IFN› -1a over 2 years. The only parameter that predicted brain volume decrease by 2 years of IFN› -1a treatment was the mean volume of enhancing lesions over the 6-month pretreatment period. Multiple Sclerosis (2002) 8, 119‐123
TL;DR: The data indicate that short courses of intravenous steroids have no major impact, whereas prolonged treatment with oral tapering does significantly affect brain volume, which is important for longitudinal studies and clinical trials in which brain volume is used as an outcome measure.
Abstract: Objective: Multiple sclerosis (MS) patients develop varying degrees of cerebral atrophy, which may already begin at disease onset The purpose of this study is to examine the effect of steroid treatment on cerebral volume in MS patients Methods: Thirty-five MS patients participating in a clinical trial of oral interferon beta, which included monthly MRI, were included in this study They suffered from an acute relapse and were treated with intravenous methylprednisolone (IV-MP); 13 of the patients were treated with oral prednisolone tapering after IV-MP The last MRI scan before and the first (and second for oral tapering patients) scan after IV-MP treatment were used for measuring parenchymal fraction (PF) and ventricular fraction (VF) Changes in PF and VF were analysed using Student’s t test Results: For the total population no significant changes in PF or VF were found However, the subgroup of patients receiving oral tapering after IV-MP showed changes, compatible with atrophy in both PF and VF, th
TL;DR: Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased, and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable.
Abstract: This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.