Opticospinal multiple sclerosis: a pathogenetically distinct form?
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Humans↗
Biomedical subjects
C H Polman
Publications and source records attributed to C H Polman.
Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist.
Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence of MS several months after starting a cannabinoid receptor antagonist suggests that the cannabinoid system might indeed be relevant to disease pathogenesis in MS.
Appetite Depressants↗
Multiple Sclerosis Impact Scale (MSIS-29): relation to established measures of impairment and disability.
OBJECTIVE: To validate the newly developed Multiple Sclerosis Impact Scale (MSIS-29) in a large, well characterized, independent group of MS patients by investigating the relation between the MSIS-29 and the Guy's Neurological Disability Scale (GNDS), the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). METHODS: Two hundred MS patients were recruited at our outpatient department. At the same visit GNDS, EDSS, MSFC and MSIS-29 were assessed. Data obtained from GNDS, EDSS and MSFC assessment were compared to both physical and psychological impact scores of the MSIS-29. In addition the contribution of GNDS subcategories, EDSS functional systems and MSFC components to the physical and psychological impact scores of the MSIS-29 was studied. RESULTS: Median scores were 37.5 for the physical and 22.2 for the psychological impact score of the MSIS-29, 13.0 for GNDS and 4.0 for EDSS. Mean MSFC was 0.07. The physical impact score showed good correlations with both GNDS (0.79) and EDSS (0.68) and a moderate correlation with the MSFC (-0.53). The psychological impact score showed weak correlations with EDSS (0.22) and MSFC (-0.30) and a moderately strong correlation with the GNDS (0.58). In 50 (25%) patients, scores on physical and psychological impact scales diverted, i.e., a relative high score on one scale combined with a relative low score on the other scale. This was related to the clinical disease course. CONCLUSION: Our study supports the use of the MSIS-29 as a measure for the assessment of physical impact of MS on normal daily life. In addition, our data provides a deeper understanding of the factors that determine both physical and psychological disease impact. Discrepancies between the latter two aspects deserve further attention.
Adult↗
The patient's perception of a (reliable) change in the Multiple Sclerosis Functional Composite.
OBJECTIVE: To prospectively characterize the relation between two-year changes in functional impairment as measured by the Multiple Sclerosis Functional Composite (MSFC) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS). METHODS: One hundred and eighty-eight patients with multiple sclerosis (MS) were recruited at our outpatient clinic. Impairment and disability were assessed using the MSFC and GNDS at baseline and follow-up. Longitudinal correlations were studied between changes in MSFC and GNDS and their corresponding components. We also studied changes in GNDS in relation to what can be classified as a reliable change in MSFC; for example, 20% change in each MSFC component or a change of 0.5 in total MSFC score. In addition, we studied the change in total number of GNDS subcategories with a score of 3 or higher in relation to the predefined MSFC changes, these subcategories being indicative of the requirement for help by another person. RESULTS: Despite good cross-sectional correlations between MSFC and GNDS, no significant correlation was found between longitudinal changes in MSFC and GNDS. Analysing the change in GNDS in relation to the predefined MSFC changes shows that GNDS changes are nicely rank ordered when more stringent definitions of reliable change were applied. In addition, analysing the number of GNDS subcategories scored 3 or higher indicate that there is a profile of worsening on the MSFC being associated with increase in the amount of help required from others. CONCLUSION: Our longitudinal data suggest that a reliable change is associated with a likewise change in patient perceived disability, the smallest reliable change being identified by at least 20% change in each MSFC component.
Adult↗
[Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype.
BACKGROUND: Both multiple sclerosis (MS) susceptibility and MS clinical phenotype are in part genetically determined. [Alpha]B-crystallin is a candidate autoantigen in MS, and there are three polymorphisms in the promoter region of the encoding gene (CRYAB): at positions -C249G, -C650G, and -A652G. METHODS: These polymorphisms were studied in sporadic cases of MS, assessing disease susceptibility, clinical phenotype, and MRI appearance. RESULTS: The CRYAB polymorphisms influenced susceptibility as well as disease expression in MS. CONCLUSION: Carriers of the rare allele CRYAB-650*C had an increased likelihood of a noninflammatory, neurodegenerative phenotype characterized by a relatively rapid, primary progressive clinical disease course.
Adult↗
Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients.
The serum concentration of 24S-hydroxycholesterol reflecting brain cholesterol turnover may be a possible marker for neurodegeneration and demyelination in multiple sclerosis. Serum was analyzed for cholesterol precursors and oxysterols in multiple sclerosis patients of different clinical subtypes (n=20 each subtype) and in 37 healthy controls. Serum 24S-hydroxycholesterol levels were lower in primary progressive and in older relapsing remitting multiple sclerosis patients. Furthermore, serum levels of lathosterol were decreased in all clinical subtypes. The results are important given recent interest in statin treatment in multiple sclerosis, which will further decrease the cholesterol precursor and oxysterol levels. The decreased levels of brain specific and peripheral sterols indicate a role for cholesterol homeostasis in relation to the pathology of multiple sclerosis, at least in the primary progressive clinical subtype.
Adult↗
Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis.
Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1alpha and mGluR5) and group II (mGluR2/3) mGluRs was studied using immunohistochemistry in tissue from 12 multiple sclerosis cases and seven non-neurological controls. The expression patterns of both group I and II mGluRs in multiple sclerosis tissue differed significantly from those in control tissue. Strong mGluR1alpha immunoreactivity was observed in axons of the subcortical white matter, particularly in the centre of actively demyelinating lesions and in the borders of chronic active lesions. mGluR1alpha axonal immunopositivity was also found in normal appearing multiple sclerosis white matter, but axons in control white matter were generally negative. mGluR1alpha axonal labelling was associated with the presence of non-phosphorylated neurofilaments and beta-amyloid precursor protein, which are sensitive markers for axonal injury and disturbed axonal transport. Changes in mGluR immunoreactivity were also observed in glia. A diffuse increase in the expression of mGluR5 and mGluR2/3 was detected in reactive astrocytes in multiple sclerosis lesions. However, only a subpopulation of reactive astroglial cells expressed mGluR1alpha. In addition, labelling with antibodies to mGluR2/3 and, to a lesser extent labelling with antibodies to mGluR1alpha, was detected in a population of cells of the microglial/macrophage lineage that displayed a macrophage-like morphology. Our data suggest that mGluRs, like ionotropic glutamate receptors, play a role in the complex processes that are associated with the progressive brain damage in multiple sclerosis, including both glial activation and pathological changes in axons.
Adult↗
Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy.
OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.
Adult↗
Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.
Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.
Adjuvants, Immunologic↗
The INTERMED: a screening instrument to identify multiple sclerosis patients in need of multidisciplinary treatment.
OBJECTIVE: To analyse the value of the INTERMED, a screening instrument to assess case complexity, compared with the Expanded Disability Status Scale (EDSS) and the Guy's Neurological Disability Scale (GNDS) to identify multiple sclerosis (MS) patients in need of multidisciplinary treatment. METHODS: One hundred MS patients underwent INTERMED, EDSS, and GNDS examinations. Patient care needs were assessed by a multidisciplinary team and a goal oriented treatment plan was defined. Correlations between INTERMED, individual INTERMED domains, EDSS, GNDS sum score, and total number of proposed disciplines involved in the treatment plan were studied. RESULTS: Mean (SD) age was 40.6 (10.1) years. Median scores were 14.0 for the INTERMED, 4.0 for the EDSS, and 13.5 for the GNDS sum score. Moderate correlations were found between the INTERMED sum score and EDSS (r=0.59) and GNDS sum score (r=0.60). The number of disciplines as proposed by the multidisciplinary team showed the highest statistically significant correlation with the INTERMED sum score (r=0.41) compared with EDSS (r=0.32) and GNDS sum score (r=0.34). No significant or only weak correlations were found between the psychological domain of the INTERMED and EDSS or GNDS. CONCLUSION: The findings in this study show that there is an additional value of the INTERMED compared with the EDSS and GNDS in identifying MS patients in need of multidisciplinary treatment. The INTERMED domains show the area of the patient's vulnerability and care needs: especially the INTERMED's psychological and social domains may guide the clinician to deal with specific problems that complicate healthcare delivery.
Adult↗
One year changes in disability in multiple sclerosis: neurological examination compared with patient self report.
OBJECTIVE: To characterise prospectively the relation between one year changes in neurologist rating of neurological exam abnormalities as measured by the Expanded Disability Status Scale (EDSS) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS) in patients with multiple sclerosis. METHODS: Two hundred and fifty patients with MS were recruited at an outpatient clinic. Disability at baseline and one year follow-up was assessed using the EDSS and GNDS. Correlations between change in EDSS, GNDS-sum score, Functional Systems and GNDS subcategories were studied as well as the significance of changes in EDSS associated with changes in perceived disability. RESULTS: The correlation between one year changes in EDSS versus GNDS was substantially lower (0.19) than cross-sectional correlations between EDSS and GNDS either at baseline (0.62) or at follow-up (0.77). Notably, changes in functional system scores that are based on neurological examination are poorly or not at all correlated with changes in disability as perceived by the patient. Analysing the impact of a significant worsening in EDSS-score, a commonly applied outcome criterion in clinical trials, we found that this was associated with significant worsening, insignificant change, and significant improvement in the patients' perceived disability in 45%, 39% and 15% of patients, respectively. CONCLUSION: Patients' perception of change in disability differs not only quantitatively but also qualitatively from that of an examining physician. This seems to be due both to the fact that there are true differences in change as perceived by the patient and that measured by the physician and to the fact that changes in many dimensions of disability that are relevant to the patient have no measurable impact on the EDSS.
Adult↗
Neutralising antibodies to interferon beta during the treatment of multiple sclerosis.
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Humans↗
Can the Expanded Disability Status Scale be assessed by telephone?
Information from patients who are unable to continue their visits to a study centre may be of major importance for the interpretation of results in multiple sclerosis (MS) clinical trials. To validate a questionnaire based on the Expanded Disability Status Scale (EDSS), patients in five different European centres were assessed independently by pairs of trained EDSS raters, first by telephone interview and a few days later by standardized neurological examination. Seventy women and 40 men with an average age of 43.7 years (range 19-74 years) were included in the study. Mean EDSS score at the last visit was 4.5 (0-9). EDSS assessment by telephone was highly correlated with the EDSS determined by physical examination (Pearson's correlation coefficient = 0.95). An intraclass correlation coefficient (ICC) of 94.8% was found for the total sample; 77.6% and 86%, respectively, for patients with EDSS < 4.5 (n = 46) and > 4.5 (n = 64). Kappa values for full agreement were 0.48; for variation by +0.5 steps and +1.0 steps, 0.79 and 0.90, respectively. Best agreement could be found in higher EDSS scores, where assessment by telephone interview might be needed most. The telephone questionnaire is a valid tool to assess EDSS score in cases where the patient is unable to continue visiting a study centre or in long-term follow-up of trial participants.
Adult↗
Axonal damage in the spinal cord of MS patients occurs largely independent of T2 MRI lesions.
OBJECTIVE: To determine the degree of axonal damage in relationship to signal abnormalities on T2-weighted high-resolution MRI in spinal cord tissue of patients with MS. METHODS: Spinal cord specimens of nine patients with MS and four controls were imaged at high resolution (4.7 T) in an axial plane and scored for lesions with increased signal intensity (SI). Histopathologic sections were cut and immunostained with NE14 (neurofilament marker) and Luxol fast blue (myelin stain). For each area, axonal density and diameter were quantified; axonal irregularity, NE14 axonal staining intensity, and myelin content were semiquantitatively scored. Included were 209 areas from MS cases and 109 areas from control cases distributed over lateral, posterior, and anterior columns. RESULTS: In control cases, no SI changes were found, average density of axons was 26,989/mm(2), average diameter was 1.1 micro m, and all scores for axonal irregularity, NE14 staining intensity, and myelin were normal. In MS cases, areas with increased SI were found, average axonal density was 11,807/mm(2) (p < 0.0001), and average axonal diameter 2.0 micro m (p = 0.001). Areas with high SI on MRI had lowest axonal density (average count: 10,504/mm(2); range: 3,433 to 26,325/mm(2)), largest diameter (average: 2.3 micro m; range: 1.0 to 4.0 micro m), and highest axonal irregularity and NE14 staining intensity compared to normal appearing cord tissue (NACT). However, NACT of MS cases also had lower axonal density (14,158/mm(2)) and higher average axonal diameter (1.6 micro m) than controls. CONCLUSIONS: Marked axonal loss occurs in MS spinal cords, largely independent of the degree of signal abnormality on T2-weighted MRI.
Adult↗
Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region.
BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
Adult↗
Quantitative functional measures in MS: what is a reliable change?
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Diagnostic Techniques, Neurological↗
Safety, tolerability, and efficacy of orally administered cannabinoids in MS.
The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.
Administration, Oral↗
Seasonal variation in immune measurements and MRI markers of disease activity in MS.
BACKGROUND: The exact mechanisms by which T cells contribute to MS progression are not known. Recently, the results of cross-sectional studies suggested seasonal variation of both interferon (IFN)-gamma production and the number of active MRI lesions in MS. OBJECTIVE: To investigate whether seasonal fluctuations of IFN-gamma and active MRI lesions could be confirmed and whether any correlations could be detected. METHODS: Data were analyzed from a group of 28 MS patients in whom detailed longitudinal monitoring of both immune function and MRI measurements had taken place. RESULTS: Significant seasonal variation was observed in T-cell activation as measured by the ability of T cells to secrete the pro-inflammatory cytokines tumor necrosis factor-alpha and IFN-gamma. Maximum values were found in samples obtained during autumn. Even though clear fluctuations were observed, no significant seasonal variation could be detected in the number of active MRI lesions. Fluctuations of in vitro IFN-gamma secretion correlated weakly with changes in active MRI lesions. CONCLUSIONS: The finding of seasonal variation of immune function in serially MRI-monitored MS patients suggests an environmental role in T-cell activation.
Adult↗