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Classification of disease subgroup and correlation with disease severity using magnetic resonance imaging whole-brain histograms: application to magnetization transfer ratios and multiple sclerosis.

This paper presents a new approach to characterize subtle diffuse changes in multiple sclerosis (MS) using histograms derived from magnetization transfer ratio (MTR) images. Two major parts dominate our histogram analysis; 1) Classification of MTR histograms into control and MS subgroups; 2) Correlation with current disability, as measured by the EDSS scale (a measure of disease severity). Two data reduction schemes are used to reduce the complexity of the analysis: linear discriminant analysis (LDA) and principal component analysis (PCA). LDA is better for the classification of MTR histograms as it takes into account the between-class variation. By using LDA, the space of MTR histograms is transformed to the optimal discriminant space for a nearest mean classifier. In contrast, PCA is useful for correlation with current disability as it takes into account the variation within each subgroup in its process. A multiple regression analysis is used to evaluate the multiple correlation of those principal components with the degree of disability in MS. This is the first application of such classification and correlation techniques to magnetic resonance imaging histogram data. Our MTR histogram analysis approach give improved classification success and improved correlation compared with methods that use traditional histogram features such as peak height and peak location.

Adult↗

Mediterranean and Amerindian MHC class II alleles are associated with multiple sclerosis in Mexicans.

OBJECTIVES: Human leukocyte antigen (HLA)-DRB1, DQA1, DQB1 allele typing was performed in Mexicans Mestizos with multiple sclerosis (MS) to define the HLA class II alleles associated with the disease in this population. METHODS: Patients (n = 51) diagnosed according to the Poser criteria and a group of 173 unrelated healthy subjects were studied. PCR-SSOP and PCR-SSP were used for genotyping. RESULTS: Fifty five percent of the patients were females. The mean age at disease onset was 27 years. A relapsing-remitting disease was the most frequent type of MS (67%). A significant association of DRB1*0403 (OR = 5.68) with MS was shown. DRB1*0802 was also involved in susceptibility (OR = 2.41). An excess of DRB1*0802 homozygotes was observed in patients (P = 0.005), this genotype being in genetic equilibrium in controls. CONCLUSIONS: Two novel class II associations are described in Mexicans with MS: DRB1*0403 and DRB1*0802. Both alleles share with DRB1*1501, valine-86 and negatively charged amino acids, in the DRB1-anchoring motif of pocket 4.

Adolescent↗

Longitudinal course of depression symptoms in multiple sclerosis.

BACKGROUND: Despite the high lifetime prevalence of depression in multiple sclerosis (MS), its longitudinal course is poorly understood. OBJECTIVE: To examine the longitudinal course of and reliable change in different depression symptom clusters in MS, and the longitudinal association of interferon beta treatment and coping with depression symptoms. METHODS: 53 MS patients were examined at two time points three years apart on the Beck Depression Inventory (BDI) and the Chicago Multiscale Depression Inventory (CMDI). RESULTS: Correlations from time 1 to time 2 for BDI, CMDI-total, CMDI-evaluative scale, and CMDI-vegetative scale were all highly significant, and reliable change indices reflected little change over time. In contrast, the correlation over time for the CMDI-mood scale was significantly lower (p<0.05) than the CMDI-evaluative and CMDI-vegetative scale correlations, and over 40% of patients showed reliable change. Patients who improved in their mood showed increased use of active coping, while patients who worsened showed decreased active coping strategies; the latter were also significantly more likely to have been taking interferon beta drugs at both time points than patients who did not change in their mood functioning. CONCLUSIONS: Mood symptoms of depression are significantly more variable over time than neurovegetative or negative evaluative symptoms in MS patients. Decreased use of active coping strategies may put patients at risk of increased depressed mood, whereas increased use of active coping may result in decreased depressed mood longitudinally. Interferon beta use may put patients at risk of increases in depressed mood.

Adaptation, Psychological↗

Magnetisation transfer ratio analysis of normal appearing white matter in patients with familial and sporadic multiple sclerosis.

OBJECTIVES: To assess differences in magnetisation transfer ratio (MTR) analysis of normal appearing white matter (NAWM) in patients with familial multiple sclerosis (MS) and those with sporadic MS. METHODS: 10 patients with familial MS, 10 patients with sporadic MS, and 10 healthy subjects were included in the study. Groups were matched according to the sex, age, disease duration, type of disease, EDSS, and MRI T1 and T2 lesion load. Magnetisation transfer imaging (MTI) with and without saturation pulse were performed. On the MTR map 16 different regions of interest of normal appearing white matter were analyzed. RESULTS: The mean MTR value of normal appearing white matter was significantly lower both in familial patients and those with sporadic MS compared with healthy subjects (33.8% v 46.4%; 38.6% v 46.4% respectively, p< 0.05). Additionally, patients with familial MS showed significantly lower mean MTR value than patients with sporadic MS (33.8% v 38.6%, p<0.05). There was also significant regional variation of MTR values between these two groups of patients. CONCLUSIONS: Lower and more widespread MTR abnormalities in patients with familial MS might indicate differences in the extent and nature of white matter pathology between familial and sporadic MS.

Adult↗

Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis.

Paroxysmal symptoms occur frequently in multiple sclerosis (MS). Usually they are treated with carbamazepine (CBZ) and phenytoin, although these medications are often interrupted due to adverse effects. We report 11 MS patients with trigeminal neuralgia (TN): 6 intolerant to a therapeutic dosage of CBZ, showing serious adverse effects and subsequently treated with a combination of low-dose CBZ and gabapentin (GBP) (group 1); 5 treated with lamotrigine (LMT), showing adverse effects and subsequently treated with GBP (group 2). Subjective pain level and impairment in performing daily activities were rated utilizing a 3-point scale at time 0 and at optimal dosage time (T1). GBP was initiated at 300 mg daily and titrated, until pain control was achieved without new adverse effects, to a maximum dose of 1,200 mg daily. CBZ or LMT were reduced to a level which no longer produced adverse effects, although resulting in a lack of efficacy in relieving pain. Pain control was obtained in all patients but 1, with no side effects. The plasma level analysis, performed in 5 patients, resulted in normal values. The mean dosages at T1 were: group 1 CBZ 400 mg and GBP 850 mg daily; group 2 LMT 150 mg and GBP 780 mg daily. Combining drugs with complementary modes of action may provide a rational pharmacological approach to the management of TN in MS.

Acetates↗

Cancer incidence in multiple sclerosis: a 35-year follow-up.

The risk of cancer among multiple sclerosis (MS) patients was evaluated emphasising cancers with a potentially infectious aetiology. Cancer incidence was estimated among incident MS patients in 1964-1993 (n = 1,597) in Finland. The cohort was followed up for cancer incidence through the Finnish Cancer Registry until 1999. A total of 85 cancer cases were diagnosed showing a standardised incidence ratio (SIR) of 1.0 (95% CI 0.8-1.2) for all cancers. The risk (SIR) of haematological tumours was 1.1 and that of central nervous system (CNS) tumours 1.3. The small excess risk of haematological malignancies is consistent with infectious aetiology, whereas the association between MS and CNS tumours may be due to misclassification.

Adult↗

Leukotropic herpesviruses in multiple sclerosis.

Detection frequency of human herpesvirus 6 (HHV-6) and Epstein Barr virus (EBV) DNA in multiple sclerosis (MS) patients and controls was investigated. DNA of peripheral blood mononuclear leukocytes (PBL) was isolated and amplified by polymerase chain reaction techniques. EBV DNA was detected in all patients and controls. HHV-6 DNA was detected in 7% of MS patients and in 14% of controls. Results are compared with other investigations of HHV-6 DNA in PBL, serum, CSF and brain of patients with MS. Results of the present study and other investigations do not show an association between HHV-6 in PBL and MS. Multiple Sclerosis (2000) 6, 66 - 68

DNA, Viral↗

Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients.

Myelin basic protein (MBP), a candidate autoantigen in multiple sclerosis (MS), exists in different isoforms and charge isomers generated by differential splicing of exons and by a combination of posttranslational modifications, respectively. These various isoforms and charge isomers of MBP vary in abundance and most likely serve different functions during myelinogenesis and remyelination. The least cationic among the charge isomers of MBP is citrullinated and is referred to as MBP-C8. MBP-C8 is relatively increased in the population of MBP isomers in more developmentally immature myelin and in MS brain tissue. In a previous study, we found that MBP-C8-reactive T cells could be detected in CD4+ T cell lines (TCL) generated with MBP from both MS patients and normal controls. Here, we examined the frequency and peptide specificity of MBP-C8-specific TCL generated with MBP-C8 in MS patients and controls. Ten subjects grouped in five sets, each an MS patient and a control, were studied. In all cases, the MS patient had either a higher overall number of MBP-C8-responding lines, responded with greater sensitivity to the MBP-C8 antigen or both. Few lines responded to the MBP-C8 peptides but, if they did, they appeared to be specific to the carboxyl-half of the MBP-C8 molecule. Given the large amounts of citrullinated MBP in MS brain tissue, a preferential T cell response to MBP-C8 may be involved in the induction and perpetuation of this disease. Multiple Sclerosis (2000) 6 220 - 225

Adult↗

Personality as a predictor of coping efforts in patients with multiple sclerosis.

The aim of the study was to explore personality traits as predictors of coping with disease-related distress in patients with multiple sclerosis (MS). All patients with clinically definite MS in a city with a population of approximately 100000 were asked to complete the NEO Personality Inventory and a multidimensional coping inventory (COPE). There was an 83% response rate yielding 49 patients for the study population and 49 controls, matched for age, gender and educational level to the MS-patients, were used as comparison. Only Neuroticism correlated significantly with emotion-focused coping in both groups. Extraversion and Openness to Experience were linked to task-oriented coping strategies in normal controls but not in the MS-group. Agreeableness was associated with avoidance-oriented coping strategies only in the MS-group. Thus, the relation of certain personality characteristics to the choice of strategies for coping with the disease-related distress appear to differ from coping with stressful problems in everyday life. As dispositional characteristics may interfere with adaptive coping responses, analysis of personality traits and coping strategies could contribute while attempting to relieve the consequences of chronic disease on everyday life.

Adaptation, Psychological↗

A double-blind pilot study of the effect of Prokarin on fatigue in multiple sclerosis.

UNLABELLED: In this 12-week study with 29 subjects, the effect of Prokarin (n=22), a proprietary blend of histamine and caffeine, was compared to placebo group (n=7) for the following outcomes: 1) fatigue as measured by the Modified Fatigue Impact Scale (MFIS); 2) lower limb function as measured by timed walk test; 3) upper limb function as measured by the pegboard test; 4) cognitive function as measured by the Paced Auditory Serial Additions Test (PASAT); 5) serum caffeine level; 6) change in brain chemistry as measured by quantitative magnetic resonance spectroscopy assay of N-acetyl aspartate (NAA); and 7) safety as measured by routine blood chemistry, TSH and urinalysis. Data were acquired at baseline, 4, 8 and 12 weeks. The Prokarin group MFIS mean was significantly different rom the mean of the placebo group at 12 weeks (df=24, t=2.08, P=<0.02), with respective means of 37.40, SD=15.18, for the Prokarin group and 53.2, SD=11.39 for the controls. For the secondary endpoints (PASAT, 25 foot timed walk, peg test, and magnetic resonance spectroscopy [MRS]), there were no significant differences between the Prokarin-treated group and the placebo group. However, there were significant improvements within the Prokarin group for each of these measures for the pre- versus posttreatment comparison at 12 weeks. Serum caffeine data indicated that caffeine exerted no independent effect on performance. No laboratory abnormalities were seen, and the treatment was well tolerated. CONCLUSION: There was a modest-size statistical effect of Prokarin on fatigue in multiple sderosis (MS) compared with the placebo group. A larger trial is warranted, based on this pilot study.

Administration, Cutaneous↗

Three screening batteries to detect cognitive impairment in multiple sclerosis.

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.

Adult↗

The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis.

The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.

Adult↗

Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis.

Beta-interferon (beta-IFN) has a proven treatment effect on relapsing-remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN combined with a low daily dose of prednisone (n = 33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis factor-alpha (TNFalpha) and intracellular adhesion molecule-1 (ICAM-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFalpha, interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS.

Adjuvants, Immunologic↗

Correlation of sexual dysfunction and brain magnetic resonance imaging in multiple sclerosis.

Sixty-two patients (40 women and 22 men) with multiple sclerosis (MS) were examined with 1.5 tesla magnetic resonance imaging (MRI) of the brain. Information on sexual and sphincteric disturbances has been collected, and data on disability, independence, cognitive performances and psychological functioning have been assessed. Calculations of T1- and T2-lesion load (LL) of total brain, frontal lobes and pons have been performed using a reproducible semiautomated technique. Whole brain, frontal and pontine atrophies were estimated using a normalized measure, the brain parenchymal fraction (BPF), obtained with a computerized interactive program. When comparing patients with and without sexual dysfunction (SD), there were no differences in total brain, frontal and pontine T1- and T2-LL, as well as in measures of whole brain and frontal atrophy. The only significant difference was in the pontine BPF (P = 0.026). In linear multiple regression analysis, SD was associated with depression (R = 0.56, P < 0.001) and, after adjusting for depression and anxiety, with bladder dysfunction (R = 0.43, P = 0.003) and pontine BPF (R = 0.56, P < 0.001). No association between SD and any of the measures of T1- and T2-LL was found. The findings showed a relationship between SD and pontine atrophy, confirmed the correlation of SD with bladder dysfunction and highlighted the role of psychological factors in determining SD.

Adult↗

Bone status in multiple sclerosis: beyond corticosteroids.

The aim of this study was to determine the possible factors affecting bone mineral density (BMD) in multiple sclerosis (MS). In this cross-sectional study, 65 clinically definite MS patients and 72 comparable controls were prospectively evaluated. To assess bone mineral metabolism in MS, the BMD of the lumbar spine and hip (femoral neck, trochanter and total) was measured by dual-energy X-ray absorptiometry, and serum vitamin D and parathyroid hormone levels and biochemical markers of bone turnover were also evaluated. MS patients had significantly lower BMD values than the control group at all measurement sites. There was a significant correlation between the disease duration and BMD values at the trochanter in women with MS. A correlation between femoral BMD values and functional status in women was also detected. There was no relationship between bone biochemical markers and BMD, except a negative correlation between bone alkaline phosphatase and trochanter BMD. Both disability and disease duration have an influence on BMD of the MS patients, whereas no significant correlation between glucocorticoid use and BMD was observed.

Adult↗

Multiple sclerosis pathology in the normal and abnormal appearing white matter of the corpus callosum by diffusion tensor imaging.

Lesions in the corpus callosum in multiple sclerosis (MS) include those that are hyperintense on T2-weighted images, which can be either focal (isolated) or connected, but there is evidence that the corpus callosum, similar to other white matter regions, contains normal appearing white matter (NAWM) which is abnormal based on quantitative MR methodologies. In this pilot study, diffusion tensor based measures were determined in corpus callosum from 10 patients with MS and 12 age and gender matched controls. T2-hyperintense lesions were carefully segmented out from normal appearing corpus callosum to minimize contamination of the NAWM fraction with these lesions. The orientationally averaged diffusion coefficient was increased and the fractional anisotropy reduced in the NAWM fraction of the MS patients. These results confirm prior studies which suggest that pathology in the NAWM occurs independent of focal MS lesions, and are not likely the result of sample contamination through or across slices. This injury to the NAWM may be the result of focal, microscopic T2-invisible lesions and/or secondary degeneration related to distant lesions whose related fibres cross the corpus callosum.

Adult↗