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Results for “Multiple Sclerosis, Chronic Progressive”

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PubMed2001

Apoptosis in neurones exposed to cerebrospinal fluid from patients with multiple sclerosis or acute polyradiculoneuropathy.

Primary cultures of murine cerebellar granule neurones were exposed to cerebrospinal fluid from patients with subtypes of multiple sclerosis or acute polyradiculoneuropathy (Guillain-Barré syndrome) for 2 days. Cells were then stained with Hoechst 33342 or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) to detect apoptotic bodies. The results were compared with control cultures exposed to cerebrospinal fluid from patients with no known neurological disease or deficit. There was no significant difference in the level of apoptosis induced between these controls and cultures not exposed to cerebrospinal fluid at all. Cultures exposed to cerebrospinal fluid samples from patients with relapsing-remitting multiple sclerosis did not have higher levels of apoptosis than cells exposed to controls, regardless of whether the sample was taken during relapse or remission. However, a significant increase in apoptosis was observed in cultures exposed to cerebrospinal fluid from patients with primary progressive multiple sclerosis, and apoptosis correlated with disease severity. This supports the existence of biochemical differences between subgroups of multiple sclerosis. A significant increase in apoptosis was also induced by cerebrospinal fluid samples from patients with acute polyradiculoneuropathy, suggesting the presence of neurotoxic factor(s) here also. The relevance to disease pathology is unclear.

Adult↗

PubMed2000

A conventional and magnetization transfer MRI study of the cervical cord in patients with MS.

OBJECTIVE: To evaluate the contribution made by cervical cord damage, assessed using a fast short-tau inversion recovery (fast-STIR) sequence and magnetization transfer ratio (MTR) histogram analysis to the clinical manifestations of MS. BACKGROUND: Previous studies have failed to show significant correlations between the number and extent of T2 spinal cord lesions and the clinical status of patients with MS. Fast-STIR is more sensitive than T2-weighted imaging for detecting cervical cord MS lesions. MTR histogram analysis provides estimates of the overall disease burden in the cervical cord with higher pathologic specificity to the more destructive aspects of MS than T2-weighted scans. METHODS: We obtained fast-STIR and magnetization transfer (MT) scans from 96 patients with MS (52 with relapsing-remitting [RRMS], 33 with secondary progressive [SPMS], and 11 with primary progressive [PPMS] MS) and 21 control subjects. Dual-echo scans of the brain were also obtained and lesion load measured. RESULTS: Eighty-one of the patients with MS had an abnormal cervical cord scan. Patients with SPMS had more cervical cord lesions and more images with visible cervical cord damage than did patients with RRMS or PPMS (p = 0.04). The entire cohort of patients with MS had lower average MTR of the cervical cord (p = 0.006) than control subjects. Compared to control subjects, patients with RRMS had similar cervical cord MTR histogram-derived measures, whereas those with PPMS had lower average MTR (p = 0.01) and peak height (p = 0.02). Patients with SPMS had lower histogram peak height than did those with RRMS (p = 0.03). The peak position and height of the cervical cord MTR histogram were independent predictors of the probability of having locomotor disability. We found no correlation between brain T2 lesion load and any of the cervical cord MTR histogram metrics. CONCLUSIONS: This study shows that the amount and severity of MS pathology in the cervical cord are greater in the progressive forms of the disease. An accurate assessment of cervical cord damage in MS gives information that can be used in part to explain the clinical manifestations of the disease.

Adult↗

PubMed2002

Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample.

OBJECTIVE: Previous research has shown high prevalence rates of depression in multiple sclerosis patients seen in specialty clinics. The relationships among depressive symptoms and severity, duration, and course of multiple sclerosis are controversial. METHOD: A survey was mailed to members of the Multiple Sclerosis Association of King County (Wash.). Of the 1,374 eligible participants, 739 returned the survey, a response rate of 53.8%. Data about demographic characteristics, employment, and duration and course of multiple sclerosis were collected. Severity of multiple sclerosis was determined by the Expanded Disability Status Scale, self-report version. Severity of depressive symptoms was evaluated with the Center for Epidemiologic Studies Depression Scale (CES-D Scale). Analysis of covariance was used to compare mean CES-D Scale scores across categories of multiple sclerosis, and logistic regression was used to identify variables associated with clinically significant depression. RESULTS: Clinically significant depressive symptoms (CES-D Scale score > or =16) were found in 41.8% of the subjects, and 29.1% of the subjects had moderate to severe depression (score > or =21). Subjects with advanced multiple sclerosis were much more likely to experience clinically significant depressive symptoms than subjects with minimal disease. Shorter duration of multiple sclerosis was associated with a greater likelihood of significant depressive symptoms, but the pattern of illness progression was not. CONCLUSIONS: In this large community sample, the severity of multiple sclerosis was more strongly associated with depressive symptoms than was pattern of illness. Clinicians should evaluate depression in patients with recent diagnoses of multiple sclerosis, major changes in functioning, or limited social support.

Activities of Daily Living↗

PubMed2003

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis.

OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.

Cost-Benefit Analysis↗

PubMed2002

T2 relaxation time histograms in multiple sclerosis.

An accurate measurement of the transverse relaxation time T(2), and the histogram of T(2) in the brain parenchyma can be accomplished in vivo using a multi-echo magnetic resonance imaging sequence. An estimate of the error in the T(2) measurement is derived using copper sulfate doped water phantoms. Correction factors are calculated and applied to the signal intensity of each voxel prior to the in vivo T(2) evaluation. These corrected T(2) are in good agreement with the theoretical values calculated from copper sulfate concentrations. This technique is then applied to calculate T(2) histograms of the brain. The population studied was composed of normal volunteers and multiple sclerosis patients. The corrected T(2) histogram method discriminates the normal control population from the MS population, and also discriminates between relapsing-remitting patients and primary progressive or secondary progressive patients. Moreover using this approach we are able to detect in MS patients a global shift of the T(2) of the white mater toward higher values. The results of this study showed that the method is easy to implement and may be used to characterize MS pathology.

Brain↗

PubMed2003

Coefficient D(av) is more sensitive than fractional anisotropy in monitoring progression of irreversible tissue damage in focal nonactive multiple sclerosis lesions.

BACKGROUND AND PURPOSE: Persistently hypointense lesions on T1-weighted MR images have been shown to correlate with the amount of axonal damage and clinical disability in multiple sclerosis (MS) patients. The purpose of this study was to investigate whether diffusion coefficient D(av) and fractional anisotropy (FA) are able to detect quantifiable differences among three groups of focal nonactive multiple sclerosis (MS) lesions that appear qualitatively different on T1-weighted images. METHODS: Conventional and diffusion tensor MR images of the brain were obtained in 18 patients with relapsing remitting (n = 10) or secondary progressive (n=8) MS and in 18 healthy volunteers. Focal nonactive MS lesions were classified as T1 isointense, T1 mildly hypointense, and T1 severely hypointense on unenhanced T1-weighted images. Differences among groups were assessed with one-way analysis of variance using the T1 lesion appearance as the grouping factor and either FA or coefficient D(av) as the dependent measure. RESULTS: FA was lowest and coefficient D(av) was highest in T1 severely hypointense lesions, and then, in ascending and descending order, respectively, T1 mildly hypointense lesions and T1 isointense lesions. A significant difference in the values of FA was detected only between T1 isointense lesions and T1 severely hypointense lesions (P <.01), whereas no difference was found between T1 mildly hypointense lesions and either one of these two groups. A significant difference was found in the values of coefficient D(av) among all investigated lesion groups. Coefficient D(av) was found to correlate inversely with the T1-weighted contrast ratio (r=-0.58, P <.0001), whereas FA and deltaFA (percentage of FA variation in the lesion, a relative FA measure that minimizes the effect of FA spatial dependence) were not. CONCLUSION: Coefficient D(av) is more sensitive than FA to variations in the degree of T1 hypointensity and, thus, in the amount of the permanent brain tissue damage in patients with MS.

Adolescent↗

PubMed2004

Clinicopathological study of a myelin oligodendrocyte glycoprotein-induced demyelinating disease in LEW.1AV1 rats.

Although multiple sclerosis is considered to be an autoimmune disease in the CNS, the immune responses that take place in the CNS and lymphoid organs remain to be elucidated. Here, we have successfully induced various subtypes of experimental autoimmune encephalitis (EAE) in LEW.1AV1 rats carrying RT1(av1) on the Lewis background genes by immunization with recombinant rat myelin oligodendrocyte glycoprotein (MOG) in various solutions with adjuvants. The purpose of the present study was to analyse in more detail the clinical and immunopathological features of MOG-induced EAE in LEW.1AV1 rats. Immunization with high doses of soluble MOG with pertussis toxin induced acute, frequently fatal EAE, whereas medium doses of partially aggregated MOG without pertussis toxin produced relapsing and remitting EAE. Secondary progressive EAE was induced in some rats by immunization with the immunization protocol having an intermediate nature between the above two. The optic nerve (approximately 60% of the immunized rats) and spinal cord (100%) were frequently involved and detectable both clinically and pathologically, while there was no lesion in the cerebrum. Histological examination revealed that, despite variety in the clinical subtypes, progression of the pathological processes was strikingly uniform, i.e. initial inflammation with minimal demyelination followed by predominant demyelination with minimal lymphocyte infiltration. These findings suggest that the lesion during the later stage is maintained by humoral factors. Taken together, this experimental system can serve as a model of neuromyelitis optica. Further analysis will provide useful information to elucidate the pathogenesis and to develop immunotherapy for neuromyelitis optica and multiple sclerosis.

Animals↗

PubMed2003

Current disease-modifying therapies in multiple sclerosis.

In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. Interferon beta has also been shown to be efficacious in secondary-progressive multiple sclerosis (SPMS) as well as in patients with isolated syndromes at risk to develop clinically definite multiple sclerosis (MS). Mitoxantrone is another disease-modifying drug that is available for SPMS and severe cases of RRMS. The clinical utility of disease-modifying agents in MS will be reviewed with respect to the anti-inflammatory, immunomodulatory, and immunosuppressive treatments that are currently available. Symptomatic therapies will not be considered.

Adjuvants, Immunologic↗

PubMed2003

Management of multiple sclerosis: current trials and future options.

PURPOSE OF THE REVIEW: The present review of multiple sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients. RECENT FINDINGS: A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS. Several short-term studies in relapsing/remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group). The findings of these trials remain open to interpretation and have generated considerable controversy, as expected. A phase 3 trial [the International MS Secondary Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta interferons (interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in secondary progressive MS. Two trials demonstrated apparent partial efficacy for the anthrecenedione mitoxantrone in active and progressive MS. Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral glatiramer acetate in relapsing/remitting MS, glatiramer acetate in primary progressive MS, and intravenous immunoglobulin in secondary progressive MS). SUMMARY: The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial inflammatory/demyelinating phase of the disease? What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?

Adjuvants, Immunologic↗

PubMed2003

Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging.

PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.

Cerebral Cortex↗

PubMed2000

Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern.

In order to investigate the associations between fatigue and depression, disability, and disease subtype, 207 individuals with clinically definite Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung Self-rating Depression Scale during a regular clinic appointment. Their current level of disability was established using the Expanded Disability Status Scale. Fatigue and depression were highly correlated (r=0.58), even when the depression measure was corrected for items overlapping with fatigue and other symptoms or consequences of MS (r=0.44). Fatigue and disability were also correlated (r=0.33). Multiple regression revealed that both depressed mood and disability were significant predictors of fatigue, together accounting for approximately 23% of the variance in patients' self-reported fatigue. The combined groups of primary progressive (n=45) and secondary progressive patients (n=25) appeared to have higher fatigue scores than relapsing-remitting patients (n=137). However, an analysis of covariance revealed that this apparent difference was in fact attributable almost exclusively to differences in disability among the three subtypes of MS. Other reports of differences in fatigue between subtypes of MS should be re-examined in light of this finding.

Adolescent↗

PubMedDate not supplied

A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.

Adolescent↗

PubMed2003

The development of clinical activity in relapsing-remitting MS is associated with a decrease of FasL mRNA and an increase of Fas mRNA in peripheral blood.

In this longitudinal study, we examined the expression of Fas, FasL, CCR3, CCR5 and CXCR3 mRNA in peripheral blood mononuclear cells (PBMCs) of secondary progressive (SP) and relapsing-remitting (RR) multiple sclerosis (MS) patients. In RR patients, FasL, CCR3 and CCR5 mRNA levels were increased prior to the exacerbations, but these decreased during clinical activity, while mRNA levels of Fas increased. SP patients have increased the levels of Fas and FasL mRNA; the latter was particularly increased during lesional activity. Our data support the hypothesis that changes in Fas and FasL mRNA related to clinical activity are due to the migration of inflammatory cells to the central nervous system (CNS).

Adult↗

PubMed2003

[Results of a multicenter study of Rebif-22 mcg administration in Russia].

The results of multicenter study of Rebif 22 micrograms in Russia have been reported. 167 multiple sclerosis patients have received Rebif 22 micrograms three times a week for 1 year. This study provides evidence for reduction of the relapse rate in patients with relapsing/remitting and secondary progressive multiple sclerosis. The tendency to the decrease of the severity of relapses, less need for steroid use and the decrease of EDSS score in patients with relapsing/remitting multiple sclerosis have been shown. In general Rebif 22 micrograms was tolerated well.

Adjuvants, Immunologic↗

PubMed2003

A semiautomated measure of whole-brain atrophy in multiple sclerosis.

Brain atrophy is a proposed MRI marker of irreversible pathologic damage in multiple sclerosis (MS). The brain parenchymal fraction (BPF) is the ratio of brain parenchymal volume to the total volume within the surface contour. We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient). We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p<0.001). BPF correlated inversely with third ventricular width (r=-0.785, p<0.001), and total T1 hypointense lesion volume (r=-0.347, p=0.011), but not with total T2 hyperintense lesion volume (r=-0.213, p=0.13). BPF correlated negatively with expanded disability status scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01). Stepwise regression compared the relative abilities of MRI variables to predict clinical data. By regression of age, BPF, third ventricular width, T2 lesions, and T1 lesions, BPF was the best predictor of disability score (R(2)=0.204, p<0.001). Third ventricular width was the best predictor of disease duration (R(2)=0.316, p<0.001). None of the MRI variables differed between relapsing-remitting (RR) (n=60) and secondary progressive (SP) (n=18) disease course (p>0.05). The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%. We conclude that whole-brain atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.

Adult↗

PubMed2001

Blepharoclonus in multiple sclerosis.

OBJECTIVE: Keane described 2 patients with gaze-evoked blepharoclonus (BLC), a form of reflex BLC, and multiple sclerosis (MS). A search for common areas of demyelination and focal axonal atrophy (T1 black holes) of the central nervous system (CNS) in 11 patients with MS exhibiting eyelid closure BLC was conducted employing magnetic resonance imaging (MRI). Finding lesions in common CNS locations on these patients can help to elucidate the pathogenesis of this restricted movement disorder. MATERIALS AND METHODS: Eleven adult patients with relapsing-remitting, primary or secondary progressive MS were studied. MRI views were completed employing a 1.5-tesla scanner. Contrast Axial T1 imaging was obtained in 9 patients. RESULTS: TL blackholes were not identified. Ten patients had multiple, scattered periventricular (PV) areas of demyelination. Four patients exhibited brainstem lesions of diverse but inconsistent locations including midbrain, cerebellar peduncle, pons and medulla. In 2 of the patients the brainstem lesions were transient but BLC persisted after the lesions regressed. CONCLUSION: No common areas of CNS demyelination or focal axonal atrophy were identified on these patients with MS and BLC. The pathogenesis and clinical significance of BLC in MS remains to be elucidated.

Adult↗

PubMed2002

HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis.

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.

Adolescent↗

PubMed1999

Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease.

Nitric oxide (NO) has been implicated in the immunopathogenesis of MS as a potential mediator of neuronal loss. To investigate the role of.NO in the development of progressive disease we measured the NO metabolites (nitrate and nitrite) and neopterin, in the urine of 129 patients with demyelinating disease (DD): 23 with clinically isolated syndromes compatible with demyelination and in 46 relapsing remitting (RR) and 60 patients with progressive MS. Eighty-nine of these 129 patients underwent Gd-enhanced MRI. In addition 58 normal control subjects (NC), 19 AIDS and 35 rheumatoid arthritis (RA) patients were studied. Patients with DD, AIDS and RA had significantly elevated urinary nitrate plus nitrite (nit : creat. urine) and neopterin (neopt : creat.urine) to creatinine ratios compared to NC subjects. (Median[25th - 75th%] nit : creat.urine: NC=1183[962 - 1365] vs DD=1245[875 - 2403], AIDS=1686[1231 - 2531], and RA=1950[1214 - 2726] mumol/mol, P<0.001 and median[25th - 75th%] neopt : creat.urine: NC=99[76 - 151] vs DD=163[119 - 266], AIDS=972[653 - 1456], and RA=389[257 - 623] mu mol/mol, P<0.001). Patients with early DD and RR MS had significantly elevated nit : creat.urine compared to patients with progressive MS (nit : creat. urine: 1612[1020 - 2733] vs 1159[790 - 1641] mu mol/mol, P=0.006). The nit : creat.urine and neopt : creat.urine did not correlate with clinical relapse or MRI activity. Excretion of.NO metabolites is increased in patients with early or relapsing-remitting disease.NO appears to be a double-edged sword, mediating tissue damage and modulating complex immunological functions which may be protective in MS.

Acquired Immunodeficiency Syndrome↗