Multiple Sclerosis Journal

The autoimmune, cell-mediated condition experimental allergic encephalomyelitis (EAE) is the representative model for the inflammatory central nervous system disease MS. EAE has been extensively employed to determine the efficacy of pharmacological agents that may be of ultimate use in the treatment of MS. A wide variety of drugs has been examined for activity in EAE but, over the last decade, three groups of compounds have emerged with clear and reproducible ability to modify significantly the onset and progression of the disease. The immunosuppressants, the modulators of catecholamine activity and the antineoplastic agents have convincingly altered the course of EAE and, as a consequence, provided understanding of the mechanisms of disease expression and offered further insight into the pathogenesis of MS. The article stresses the usefulness of EAE as a model to identify prospective pharmacological treatments for MS and, in particular, considers those compounds subsequently assessed for their ability to interfere with the progression of the human disease.

Objectives: To determine the relationship between baseline CSF immunologic abnormalities and MS disease progression; To determine progression rates in an untreated, recently-diagnosed MS sample using several validated clinical measures.

Background: CSF immune abnormalities are common in MS but have not been linked to disease progression.

Design Methods: Thirty-six patients with definite (n=28), probable (n=2), or possible (n=6) MS were studied prospectively. Baseline CSF was analyzed for free kappa and lambda light chains, myelin basic protein, IgG synthesis rate, and IgG index. MS patients were entered into the study within 5 years of symptom onset and examined semiannually for as long as 53.4 months (median length offollow up 38.9 months). MS progression was defined as sustained worsening on the following clinical measurement instruments: the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI), the 9 Hole Peg Test (9HT) and the Box and Blocks test (BBT). Kaplan-Meier estimates of disease progression were calculated and the relationship between baseline CSF values and disease progression was determined using Cox proportional hazards regression models.

Results: By 36 months, 33% (95% Cl-10.3, 55.7) of patients had progressed on EDSS and 49.7% (95% Cl=27.7, 71.7) had progressed on at least one of the outcome measures. Patients with CSF free kappa chain levels in the upper quartile had a significantly higher risk of progression on EDSS (Hazard Ratio 3.78; p=0.04) and 9HT (Hazard Ratio 10.77, p=0.04).

Conclusions: In this study, CSF free kappa light chains predicted subsequent physical deterioration in prospectively evaluated MS patients. If this is confirmed by larger studies, then CSF free kappa light chains could serve as a target for intervention in therapeutic trials.

Traditional assessments of autonomic nervous system function have depended on invasive and complex procedures. Vagal power, which is the respiratory component of heart rate variability (HRV) is an alternative and non-invasive measure for indexing autonomic nervous control of the heart In the current study, 18 multiple sclerosis (MS) and 20 healthy subjects matched with respect to age, education and intelligence served as subjects. The MS group showed significantly lower vagal power during natural and paced breathing than healthy subjects. Importantly, heart rate did not differ between the two groups. If MS patients exhibit abnormalities in mechanisms mediating cardiac parasympathetic control, the impact on quality of life and vulnerability to adverse cardiac events need to be further evaluated. The results of this study may have implications with respect to the feasibility of using HRV as both a diagnostic and prognostic tool for evaluating parasympathetic nervous system dysfunction and in providing valuable information for developing more effective treatment and rehabilitation strategies.

An Uhthoff-like phenomenon was recently observed in a patient with clinically definite MS who experienced transient dysphonia brought on by exertion and relieved by cooling. The patient's dysphonia was felt to be related to intermittent temperature-dependent conduction block associated with a demyelinating plaque in the region of the left nucleus ambiguus. We have termed the patient's intermittent dysphonia ‘laryngeal Uhthoffs phenomenon'.

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for MS consisting of the selective reminding, 10136 spatial recall, symbol digit modalities, paced auditory serial addition (PASAT) and word list generation tests is a sensitive measure of early cognitive impairment in MS patients. We administered it to 19 chronic stable MS patients every 60 days for 120 days to examine variability. The mean coefficient of variation for the tests ranged from 18% to 22%. A significant practice effect was seen in the PASAT results (P<0.05) using the Wilcoxon signed rank test These results suggest that cognitive fluctuations analogous to motor fluctuations may occur in MS patients and that the BRB-N may be useful in clinical trials of agents expected to alter cognitive function in MS patients if test-retest variability and practice effects are taken into account Further study is warranted.

We report the occurrence of clinically definite multiple sclerosis in an offspring of a couple with conjugal multiple sclerosis. Extensive investigation of all members of this family, which includes two additional asymptomatic children, eliminated the possibility of alternative neurological diagnoses. All family members were studied with magnetic resonance imaging (MRI), evoked potentials, and human leukocyte antigen (HLA) typing. An asymptomatic child had subtle white matter abnormalities on MRI, suggesting subclinical neurological involvement This study documents the third case of multiple sclerosis in the child of conjugal multiple sclerosis patients and provides the first report of MRI lesions in an asymptomatic offspring of the same parents. Neurodiagnostic and immunogenetic investigations of such rare family clusters may contribute to the elucidation of the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is associated with upregulation of both proinflammatory (interferonγ, IFNγ) and immunosuppressive (transforming growth factorβ, TGFβ) cytokines. To examine a possible relation between the MS-related HLA haplotype Dw2 and cytokine prof iles, we used in situ hybridization with labeled cDNA oligonucleotide probes to detect transcripts of the T helper type I (ThI) cell related IFNγ, the Th2 cell related interleukin-4 (IL-4) and of TGFβ in blood and cerebrospinal fluid (CSF) mononuclear cells from 62 patients with MS. Compared to patients with other neurological diseases and healthy controls, MS patients had elevated numbers of IFNγ, IL-4 and TGFβ mRNA expressing cells in blood and further augmented in CSF. Although several HLA-Dw2-positive individuals showed very high numbers of cells expressing these cytokines, no significant difference was found in comparison with Dw2-negative patients. However, expression of IL-4 and TGFβ mRNA was significantly increased in patients with shorter duration and minor disability and, for IL-4, in patients still in the relapsing-remitting phase compared to patients with secondary chronic progressive MS. Surprisingly, these changes which favour a beneficial, disease-downregulating effect of IL-4 and TGFβ in MS, were found to be confined to HLA-Dw2-positive patients. Our findings suggest that the HLA phenotype does not influence the overall level of immune reactivity in MS, but may distinguish subgroups characterized by particular cytokine expression patterns.

We have analyzed the distribution of tumor necrosis factor (TNF) a and-b microsatellite alleles in HLA-DQ and-DR typed Swedish patients with multiple sclerosis (MS) (n=l22) and ethnically matched control subjects (n=l78). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFal I was significantly associated with MS. This was also the case for the combination of TNFal I with TNFb4. However, TNFal I (alone or in combination with TNFb4) did not show any disease association independent of DQA 1*01021 DQBI*0602/DR2, whereas the previously reported strong association with HLA-DQAI*0102/DQBI*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFal I (and TNFb4) is most likely secondary to the increase of DQAI*0102/DQBl*0602/DR2 in MS patients. The proportion of TNFa6 positive individuals was lower among DR2-negative MS patients than among DR2-negative controls (p=0.08). Since the presence of the TNFab allele correlates with low TNFα production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNFα producers in response to exogenous stimuli.

We investigated two short tandem tetranudeotide (TGGA) repeat polymorphisms upstreams of the myelin basic protein (MBP) gene. The region was amplified by the polymerase chain reaction (PCR) and the two repeat systems were separated by cutting with the restriction enzyme NlaJM. The lengths of the DNA fragments were analyzed by vertical electrophoresis in Polyacrylamide gels followed by silver staining. We compared the DNA fragment frequencies of the two MBP regions in 34 patients suffering from multiple sderosis and in 78 suffering from monosymptomatk idiopathic optic neuritis to those in 200 healthy controls. We found no significant differences between the MBP fragment frequendes in either of the patient groups and in the control group.