George P. A. Rice

A neurologic rating scale (NRS) for use in multiple sclerosis

A neurologic rating scale (NRS) has been developed for clinical assessment of MS patients. The scale has been tested on 250 MS patients. Assignment of the NRS score is based on assessment of each component of the neurologic examination and accurately reflects overall neurologic function. Clinical exacerbations are evident as significant deviations from baseline scores. There was close interexaminer correlation, with the range of variability no greater than 2.6%. The NRS is a simple, reliable, and sensitive scale that can be used with other objective measurements of neurologic function, such as neurophysiologic studies, in the clinical assessment of MS patients.

Interferon β-1a in MS Results following development of neutralizing antibodies in PRISMS

Background: Debate continues concerning the relevance of neutralizing antibody (NAb) development on the efficacy of interferon (IFN) therapy in patients with multiple sclerosis (MS). The PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study of subcutaneous IFNβ-1a showed significant benefit on all efficacy outcomes with no significant impact from NAb development on relapses at 2 years. The 2-year extension permitted longer observation following NAb development. Methods: Exploratory post-hoc analyses of pharmacodynamic response and clinical and MRI outcomes were performed on data from 368 patients with relapsing MS treated with IFN from study start, based on NAb status. Results: Persistent NAbs, above 20 NU/mL, were present in 14% of the 44-μg three times weekly (TIW) and 24% of the 22-μg TIW group over 4 years. NAb development was associated with reduced pharmacodynamic marker induction at 1 year. Over the entire 4 years of study, relapse and disability measures were similar between NAb+ and NAb− patients. However, once NAbs developed, significant differences were noted between NAb+ and NAb− groups, particularly on MRI and relapse measures. The presence of binding antibodies alone did not affect outcome. Conclusion: Neutralizing antibody development in interferon-treated patients is correlated with reduced efficacy and is a potential cause for renewed disease activity.

Interferon β‐1a for early multiple sclerosis: CHAMPS trial subgroup analyses

The objective of this work was to assess the effect of interferon β‐1a (Avonex®) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High‐Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30μg interferon β‐1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem–cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon β‐1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem–cerebellar syndromes, and spinal cord syndromes.

Systemic alpha‐interferon therapy of multiple sclerosis

A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 × l06 IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.

Mollaret's meningitis associated with herpes simplex type 2 infection

We describe three patients with benign recurrent aseptic meningitis (Mollarets meningitis). For one of these cases, the episodes of meningitis were associated with herpetic outbreaks. Mollaret cells, which are a hallmark of Mollarets meningitis, were present in the CSF from two of the three patients. In all cases, herpes simplex virus type 2 DNA was present in the CSF during the acute illness as detected by polymerase chain reaction amplification, although viral cultures from CSF were all negative. Herpesviruses, notorious for frequent and sporadic recurrence, are ideal candidates for the cause of Mollarets meningitis.

Disease activity markers in multiple sclerosis Another look at suppressor cells defined by monoclonal antibodies OKT4, OKT5, and OKT8

Here we report our experience in profiling peripheral blood T-cell subsets with the monoclonal antibodies OKT4, OKT5 , and OKT8. Lymphocyte surface phenotype was measured by automated cytofluorometry. In a population survey, we were unable to detect differences between patients with multiple sclerosis (MS) and control subjects when we compared ratios of lymphocytes of helper cell phenotype (OKT4) to those with suppressor cell phenotype ( OKT5 and OKT8). No differences could be established between patients with stable disease, chronic progressive disease, or those with active disease. In a study of 10 patients followed through an exacerbation, we were also unable to define perturbations in these lymphocyte ratios that correlated with disease activity. Detailed analysis of the fluorescence histogram, which examines the entire spectrum of cell surface fluorescence intensity in a population of lymphocytes, was also not useful in predicting disease activity in these patients. The discrepancies between these data and other reports in the literature are discussed. We propose that these reagents are inadequate indices of disease activity, and that until other monoclonal reagents are developed and studied, the suppressor cell compartment is best assessed by assays of function.

Guidelines for physicians with patients on IFN beta-1b The use of an assay for neutralizing antibodies (NAB)

The production of neutralizing antibodies (NAB) may be associated with a reduction in clinical effectiveness of interferon beta 1b (IFN beta-1b). However, there are some NAB-positive patients who continue to do well, so the relationship between the clinical state and the NAB state is not constant. Approximately 90% of NAB-positive patients become so between six and 18 months of therapy. In the IFN beta-1b clinical trial, the data indicate that the relapse rate in NAB-positive patients after 18 months of high dose IFN beta-1b reverted to a level similar to placebo treated patients. NAB-negative patients on high dose IFN beta-1b continued to show progress, with a relapse rate of one half of both the NAB-positive patients and the placebo patients.nnIn order to help in clinical decision-making, a test for the detection …

Ibuprofen treatment versus gradual introduction of interferon β-1b in patients with MS

Article abstract Flu-like symptoms and injection site reactions are adverse effects of treatment with interferon β-1b in patients with MS. We compared gradual dose escalation, ibuprofen treatment, or their combination in an open-label study. The combination reduced the incidence of flu-like symptoms to rates comparable with the placebo group in the pivotal trial but increased the frequency of injection site reactions, albeit modestly and transiently.

Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.

Abstract—Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.

A genome-wide scan of male sexual orientation.

Genetic-epidemiological studies provide some evidence for a genetic component to male homosexuality.1 Mustanski et al.2 performed the first genome-wide linkage scan for male homosexuality using 403 microsatellite markers. The highest multipoint logarithm of the odds (LOD) score found by Mustanski et al.2 was 3.45 near the microsatellite D7S798 on chromosome 7q36 with approximately equivalent maternal and paternal contributions. As with all studies of complex traits, this result requires confirmation. Single-nucleotide polymorphism (SNP)based scans for linkage provide significantly greater genomic coverage and information content than do microsatellite assays;3 hence, we applied this technology to study a Canadian cohort of homosexual males. A total of 55 Canadian Caucasian families with two or more homosexual male siblings were studied, ascertained as previously described.4 DNA samples were normalized for concentration before labeling and hybridization to the Illumina HumanLinkage-12 BeadChip Infinium array (Illumina, San Diego, CA, USA), which comprises B6000 welldefined SNPs spread comparatively evenly across the human genome. The markers on the array exhibit low levels of linkage disequilibrium, and are thus suited for initial genome-wide screens. Genotype calls, generated using BeadStudio (Illumina), were obtained for 112 individuals. Pedigrees were verified using Pedstats,5 and data sets checked for unlikely genotypes; suspect sample SNP data points were removed from subsequent analyses. Nonparametric linkage analyses were carried out using MERLIN (http:// www.sph.umich.edu/csg/abecasis/Merlin/ index.html).6 The results of the genome-wide linkage scan are shown in Figure 1. A LOD score peak of 2.86 was obtained on chromosome 14 for SNP rs760335 (98.8 cM, position 93 884 697; genome build 36). The adjacent SNP loci are rs733559 (96.8 cM; 92 809 308, LOD1⁄42.08) and rs742893 (99.7 cM; 94 222 866, LOD1⁄41.74). Modeling of marker–marker linkage disequilibrium in the data set (r240.1) did not significantly alter the magnitude of LOD scores obtained (rs760335, maximum LOD1⁄42.47). However, when we analyzed 1000 simulated data sets of pedigree genotypes generated by MERLIN, a LOD score of X2.47 was obtained in 256 of the 1000 simulations, generating an empirical