Colleen Miller

Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire

Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Q uestionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. A nalyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. C ronbach’s a coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.

In vivo gene expression revealed by cDNA arrays: the pattern in relapsing–remitting multiple sclerosis patients compared with normal subjects

OBJECTIVES To use DNA arrays to identify differences in gene expression associated with relapsing-remitting (RR) MS. METHODS Total RNA was isolated from monocyte depleted peripheral blood mononuclear cells of 15 RR MS patients and 15 age- and sex-matched controls. The RNA was reverse transcribed to radiolabeled cDNA and the resultant cDNA was used to probe a DNA array containing over 4000 named human genes. The binding of radiolabeled cDNA to the probes on the array was measured by phosphorimager. RESULTS Of more than 4000 genes tested, only 34 were significantly different in RR-MS patients from controls. Of these, 25 were significantly increased and 9 significantly decreased in the RR MS patients. Twelve of these genes have inflammatory and/or immunological functions that could be relevant to the MS disease process. The potentially relevant genes that were elevated (15% to 28%) were P protein, LCK, cAMP responsive element modulator, IL-7 receptor, matrix metalloproteinase-19, M130 antigen, and peptidyl-prolyl isomerase. Those that were significantly decreased (15% to 35%) were SAS transmembrane 4 superfamily protein, STRL22 (C-C chemokine receptor 6), AFX protein, DNA fragmentation factor-45 and immunoglobulin gamma 3 (Gm marker). CONCLUSIONS The RR-MS disease effect was relatively restricted and most of the mRNAs tested were not different from the normal controls. However, there were significant differences identified in the expression of a subset of mRNAs, including 13 with inflammatory/immune functions that could be relevant to MS. The systematic use of DNA arrays can provide insight into the dynamic cellular pathways involved in MS pathogenesis and its phenotypic heterogeneity.

Risk of bone loss in men with multiple sclerosis

Context: O steoporosis and the increased fracture risk associated with osteoporosis become apparent in men appro ximately 10 years later than women. However, in recent studies, appro ximately 20% of healthy men in the age range 55-64 years were found to be osteopenic. Emerging data suggest a significantly increased prevalence of osteoporosis in men and women with multiple sclerosis (MS) compared to age-matched controls, but no specific clinical testing recommendations are available for men. Objective: To determine the proportion of male MS patients with osteoporosis and to identify the factors associated with the reduction in bone mass. Design: C onsecutive male MS patients seen at our MS clinic were screened with dual-X-ray absorptiometry (DEXA) scan for determining the bone mineral density (BMD). A ll patients had neurological Expanded Disability Status Scale (EDSS) evaluation. The results were compared to healthy age-matched male reference population using the Z score and to a cohort of women MS patients and women controls. C alcium, total testosterone, sex-hormone binding globulin (SHBG), 25-hydro xy-vitamin-D, and parathyroid hormone (PTH) were evaluated in male patients with decreased BMD. Relevant data on body mass index (BMI), medicatio n, alcohol consumption, smoking, and sexual dysfunction were recorded. Setting: Academic MS C entre. Patients and other participants: Forty consecutive male MS patients, age mean 51.2±8.7 years, and mean EDSS of 5.8±1.9 were evaluated with DEXA scan. O f these, 17.5% patients were relapsing - remitting (RR) MS, 57.5% were secondary progressive (SP) MS and 25% were primary progressive (PP) MS. Main outcome measure: Proportion of male MS patients with reduced BMD at the lumbar spine and femoral neck. Results: Thirty-two (80%) of our patients had a reduced bone mass of either lumbar spine or the femoral neck; of these 17 patients (42.5%) had osteopenia and 15 patients (37.5%) had osteoporosis. Twenty-o ne per cent (eight out of 38 patients) had vertebral, rib or extremities fractures. Multivariate linear regression analysis indicated that the EDSS (P B-0.0001) and BMI (P =0.0004) were the important factors associated with low BMD at the femoral neck and the EDSS was the important factor (P =0.0017) associated with low BMD at the lumbar spine. The same factors emerged as significantly associated with the corresponding Z scores, which are corrected for age and sex. No clear association between intravenous steroid therapy and BMD was evident in the multivariate analysis. Low levels of 25-hydroxy-vitamin-D were seen in 37.5% of patients. Conclusions: The proportion of male MS patients with reduced bone mass is high and disproportionate to their age and ambulation, consistent with an association between the MS disease process and patho logical bone loss. Increased awareness and bone density screening of male and female MS patients over 40 years of age is warranted.

Neuropsychological counseling improves social behavior in cognitively-impaired multiple sclerosis patients

We studied the effectiveness of a newly-developed cognitive-behavioral intervention in 15 patients with marked cognitive impairment and behavior disorder. The design was a single-blind test of a neuropsychological intervention, with pre- and post-treatment assessments of personality and social behavior. MS patients underwent neurological examination and neuropsychological testing at baseline. The patients were then randomly assigned to neuropsychological counseling or standard, non-specific supportive psychotherapy. The active 12-week treatment emphasized enhancement of insight through education, social skills training, and behavior modification. All patients were re-examined within 2 weeks of the termination of treatment. Neuropsychological technicians were blind to treatment condition. Both groups showed evidence of cognitive impairment and personality/behavior disorder prior to treatment and were well matched on demographic, disability, and cognitive measures. Patients who underwent neuropsychological counseling showed significant positive response on measures of social behavior (e.g. excessive ego-centric speech) compared to those who underwent standard counseling. We conclude that these data support the use of non-pharmacological, neuropsychological counseling in patients with acquired, MS-associated behavior disorder.

Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica

Objective To determine whether neuromyelitis optica (NMO) immunoglobulin (IgG) antibody status in NMO/Devic’s disease patients followed prospectively is persistent or can change relative to the clinical status and/or response to therapy. Design A cross-sectional group of patients with NMO, relapsing extensive longitudinal transverse myelitis (RLETM) or optico-spinal multiple sclerosis (OSMS) were evaluated for the presence of NMO IgG antibodies. Repeated evaluation was made in all NMO/RLETM patients and in a subgroup of OSMS patients. Setting Baird Multiple Sclerosis Center, Buffalo, New York, an academic multiple sclerosis center. Results Out of a consecutive cohort of 38 patients evaluated for the presence of NMO IgG, 12 had NMO and 26 had OSMS. Five of the 12 NMO/RLETM patients were NMO IgG positive at the time of their initial evaluation. Four of these patients were repeatedly tested for NMO IgG: two of these became negative and two remained positive. One patient who was initially negative became positive during an acute event and again became negative during the stable disease phase following treatment. A positive test result was associated with active disease, whereas a negative NMO IgG result was consistently found in stable, long-term treated patients. None of the OSMS patients were positive for NMO IgG even during acute attacks. Conclusions NMO IgG antibodies are associated with active NMO/RLETM. A well-controlled stable disease usually under effective immunosuppressive therapy can transform the NMO IgG to a negative status. Repeated NMO IgG testing should be considered as a useful biological marker for monitoring NMO/RLETM disease and or response to therapy.

Flow Cytometric Analysis of In Vitro Proinflammatory Cytokine Secretion in Peripheral Blood from Multiple Sclerosis Patients

The cytokines, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-αrpar;, and interleukin-2 (IL-2) are important endogenous proinflammatory proteins and have been linked to disease activity in multiple sclerosis. In this study, we use flow cytometric methodology to compare the secretion of IFN-γ, IL-2, and TNF-α from peripheral blood-derived T cells of multiple sclerosis patients to the secretion in healthy controls. The percentages of IFN-γ, IL-2, and TNF-α secreting cells are not significantly different between multiple sclerosis patients and controls. However, the TNF-α secreting CDS cell percentage is correlated with the IFN-γ and IL-2 secreting CD3 cell percentages in multiple sclerosis patients. In the controls, only the TNF-α secreting CD3 cell percentage is correlated with IFN-γ. These findings show that correlated secretion of cytokines occurs in multiple sclerosis and suggest that concerted intercytokine interactions may play an important role in the disease.