H.J. Adèr

A New Rating Scale for Age-Related White Matter Changes Applicable to MRI and CT

Background and Purpose— MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Methods— Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using &kgr; statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Results— Interrater reliability was good for MRI (&kgr;=0.67) and moderate for CT (&kgr;=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. Conclusions— We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

Visual Rating of Age-Related White Matter Changes on Magnetic Resonance Imaging Scale Comparison, Interrater Agreement, and Correlations With Quantitative Measurements

Background and Purpose— To provide further insight into the MRI assessment of age-related white matter changes (ARWMCs) with visual rating scales, 3 raters with different levels of experience tested the interrater agreement and comparability of 3 widely used rating scales in a cross-sectional and follow-up setting. Furthermore, the correlation between visual ratings and quantitative volumetric measurement was assessed. Methods— Three raters from different sites using 3 established rating scales (Manolio, Fazekas and Schmidt, Scheltens) evaluated 74 baseline and follow-up scans from 5 European centers. One investigator also rated baseline scans in a set of 255 participants of the Austrian Stroke Prevention Study (ASPS) and measured the volume of ARWMCs. Results— The interrater agreement for the baseline investigation was fair to good for all scales (&kgr; values, 0.59 to 0.78). On the follow-up scans, all 3 raters depicted significant ARWMC progression; however, the direct interrater agreement for this task was poor (&kgr;, 0.19 to 0.39). Comparison of the interrater reliability between the 3 scales revealed a statistical significant difference between the scale of Manolio and that of Fazekas and Schmidt for the baseline investigation (z value, −2.9676;P =0.003), demonstrating better interrater agreement for the Fazekas and Schmidt scale. The rating results obtained with all 3 scales were highly correlated with each other (Spearman rank correlation, 0.712 to 0.806;P ≤0.01), and there was significant agreement between all 3 visual rating scales and the quantitative volumetric measurement of ARWMC (Kendall W, 0.37, 0.48, and 0.57;P <0.001). Conclusions— Our data demonstrate that the 3 rating scales studied reflect the actual volume of ARWMCs well. The 2 scales that provide more detailed information on ARWMCs seemed preferential compared with the 1 that yields more global information. The visual assessment of ARWMC progression remains problematic and may require modifications or extensions of existing rating scales.

Cost effectiveness of physiotherapy, manual therapy, and general practitioner care for neck pain: economic evaluation alongside a randomised controlled trial

Abstract Objective: To evaluate the cost effectiveness of physiotherapy, manual therapy, and care by a general practitioner for patients with neck pain. Design: Economic evaluation alongside a randomised controlled trial. Setting: Primary care. Participants: 183 patients with neck pain for at least two weeks recruited by 42 general practitioners and randomly allocated to manual therapy (n=60, spinal mobilisation), physiotherapy (n=59, mainly exercise), or general practitioner care (n=64, counselling, education, and drugs). Main outcome measures: Clinical outcomes were perceived recovery, intensity of pain, functional disability, and quality of life. Direct and indirect costs were measured by means of cost diaries that were kept by patients for one year. Differences in mean costs between groups, cost effectiveness, and cost utility ratios were evaluated by applying non-parametric bootstrapping techniques. Results: The manual therapy group showed a faster improvement than the physiotherapy group and the general practitioner care group up to 26 weeks, but differences were negligible by follow up at 52 weeks. The total costs of manual therapy (€447; £273;

Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.

402) were around one third of the costs of physiotherapy (€1297) and general practitioner care (€1379). These differences were significant: P<0.01 for manual therapy versus physiotherapy and manual therapy versus general practitioner care and P=0.55 for general practitioner care versus physiotherapy. The cost effectiveness ratios and the cost utility ratios showed that manual therapy was less costly and more effective than physiotherapy or general practitioner care. Conclusions: Manual therapy (spinal mobilisation) is more effective and less costly for treating neck pain than physiotherapy or care by a general practitioner. What is already known on this topic The cost of treating neck pain is considerable Many conservative interventions are available, such as prescription drugs, yet their cost effectiveness has not been evaluated No randomised trials of conservative treatment for neck pain have so far included an economic evaluation What this study adds Manual therapy is more effective and less costly than physiotherapy or care by a general practitioner for treating neck pain Patients undergoing manual therapy recovered more quickly than those undergoing the other interventions

Spinal cord abnormalities in recently diagnosed MS patients Added value of spinal MRI examination

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)‐12 (p40 and p35), tumor necrosis factor‐α, interferon‐γ, and IL‐10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing–remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL‐12p40 and decreased levels of IL‐10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL‐12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL‐12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL‐12p40 mRNA. In RR MS, IL‐10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL‐10 mRNA levels constitutively, suggesting that IL‐10 plays an important role in the control of disease progression. Ann Neurol 1999;45:695–703

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: Results of a randomized, double-blind, placebo-controlled MR-monitored phase II trial

Objective: The most recent diagnostic criteria for multiple sclerosis (MS) ascertain that findings from spinal cord MRI can be used to demonstrate dissemination in space. Because little is known about the prevalence and characteristics of cord lesions early in the disease, the authors studied the prevalence of spinal cord abnormalities in patients with early-stage MS and assessed their impact on diagnostic classification. Methods: The brains and spinal cords of 104 recently diagnosed patients with MS were examined. Median interval between first symptom and diagnosis was 18.4 months. The brain MRI protocol included before and after gadolinium axial T1-weighted conventional spin-echo sequences and dual-echo spin-echo images. For spinal cord MRI, sagittal cardiac-triggered dual-echo T2-weighted and sagittal T1-weighted spin-echo images were included. Clinical assessment for each patient included age, sex, clinical signs for spinal cord involvement, and Expanded Disability Status Scale. Results: Abnormal cord MRIs were found in 83% of patients, usually with only focal lesions. Diffuse cord abnormalities were found in 13% of patients, although in isolation they were found in only three patients. Focal cord lesions were often multiple (median number, 3.0), small (median, 0.8 vertebral segments), and primarily (56.4%) situated in the cervical spinal cord. In 68 of 104 patients (65.4%), two or more focal lesions were visible on spinal cord images. The criteria for dissemination in space, as defined in the McDonald criteria for the brain, were met in only 66.3% of the patients. This percentage increased to 84.6% when spinal cord MRI abnormalities were also included. Conclusion: Spinal cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.

Psychological distress two years after diagnosis of breast cancer: frequency and prediction

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p= 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months(p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

Are factor analytical techniques used appropriately in the validation of health status questionnaires? A systematic review on the quality of factor analysis of the SF-36

The present prospective study aimed at (1) investigating the frequency of high levels of psychological distress in women with early-stage breast cancer almost two years after diagnosis and (2) identifying characteristics associated with long-term distress. One hundred and seventy women participated on two occasions. Two months after surgery, patients completed questionnaires measuring psychosocial variables (e.g., stressful life-events, health complaints, sleep problems, social support, subjective distress, personality factors), demographic and biomedical variables (e.g., TNM status, type of surgery). At the second measurement, subjective distress was assessed for a second time by means of the Impact of Events Scale (IES). Almost two years after diagnosis, 16% of the women reported a high level of psychological distress as measured by the Intrusion scale (IES). Best predictors of a high level of distress were: intrusive thoughts about the disease, trait-anxiety, health complaints and problems with sleeping. No significant association was found between previous life-events, social support or biomedical variables and levels of distress.

Optimizing the association between disability and biological markers in MS.

Factor analysis is widely used to evaluate whether questionnaire items can be grouped into clusters representing different dimensions of the construct under study. This review focuses on the appropriate use of factor analysis. The Medical Outcomes Study Short Form-36 (SF-36) is used as an example. Articles were systematically searched and assessed according to a number of criteria for appropriate use and reporting. Twenty-eight studies were identified: exploratory factor analysis was performed in 22 studies, confirmatory factor analysis was performed in five studies and in one study both were performed. Substantial shortcomings were found in the reporting and justification of the methods applied. In 15 of the 23 studies in which exploratory factor analysis was performed, confirmatory factor analysis would have been more appropriate. Cross-validation was rarely performed. Presentation of the results and conclusions was often incomplete. Some of our results are specific for the SF-36, but the finding that both the application and the reporting of factor analysis leaves much room for improvement probably applies to other health status questionnaires as well. Optimal reporting and justification of methods is crucial for correct interpretation of the results and verification of the conclusions. Our list of criteria may be useful for journal editors, reviewers and researchers who have to assess publications in which factor analysis is applied.

Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients

Objective: Axonal damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain volume measurement on MRI can be used as an overall marker of tissue damage and axonal loss. The authors studied the relation of brain volume measurements with the MS Functional Composite (MSFC) in an attempt to improve the clinico-radiologic association. Methods: In 137 patients with MS (80 relapsing-remitting [RR], 36 secondary progressive [SP], and 21 primary progressive [PP]) and 12 healthy controls, a brain MRI scan was obtained. Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments. MRI analysis included determination of hypointense T1- and hyperintense T2-weighted lesion load, and two brain volume measurements: 1) the parenchymal fraction (PF): whole brain parenchyma/intracranial volume; and 2) the ventricular fraction (VF): ventricular volume/whole brain parenchyma. Results: The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01). For the patient population, moderate correlations were found between brain volume measurements and MSFC (0.36 for PF and -0.40 for VF). Patients with short disease duration showed a correlation of MSFC with both brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with brain volume measurements. Conclusion: Brain volume measurements are correlated with disability as assessed by the MSFC. Although in the early phase of the disease the amount of focal demyelination is important, the residual brain volume seems to be more relevant in determining disability in later phases of the disease.