Rapid disease course in African Americans with multiple sclerosis.

OBJECTIVE: To investigate utility of a Multiple Sclerosis Severity Scale (MSSS)-based classification system for comparing African American (AA) and white American (WA) multiple sclerosis (MS) subpopulations in the New York State Multiple Sclerosis Consortium (NYSMSC) database. MSSS is a frequency-rank algorithm relating MS disability to disease duration in a large, untreated reference population. Design/ METHODS: Distributions of patients in 6 MSSS-based severity grades were calculated for AA and WA registrants. RESULTS: There were 419 AA and 5,809 WA patients in the NYSMSC, who had EDSS recorded during years 1-30 since symptom onset. Median EDSS was not different in AA and WA (3.5 vs 3.0, p = 0.60), whereas median MSSS in AA was higher than in WA (6.0 vs 4.8, p = 0.001). AA patients were overrepresented in the 2 most severe grades (41.5% vs 29.3% for WA) and underrepresented in the 2 lowest grades (23.4% vs 35.4%; p < 0.001). In multivariable analysis (ordered logistic and median regression), MSSS for AA remained significantly higher than in WA after adjusting for age, gender, disease duration, disease type distribution, and treatment with disease-modifying therapies. CONCLUSIONS: The 6-tiered MSSS grading system is a powerful tool for comparing rate of disease progression in subpopulations of interest. MSSS-based analysis demonstrates that African ancestry is a risk factor for a more rapidly disabling disease course.

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

Use of intravenous gamma globulins in neuroimmunologic diseases.

Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.

The role of X-chromosome inactivation in female predisposition to autoimmunity.

We propose that the phenomenon of X-chromosome inactivation in females may constitute a risk factor for loss of T-cell tolerance; specifically that skewed X-chromosome inactivation in the thymus may lead to inadequate thymic deletion. Using a DNA methylation assay, we have examined the X-chromosome inactivation patterns in peripheral blood from normal females (n = 30), female patients with a variety of autoimmune diseases (n = 167). No differences between patients and controls were observed. However, locally skewed X-chromosome inactivation may exist in the thymus, and therefore the underlying hypothesis remains to be disproved.

Are quantitative functional measures more sensitive to worsening MS than traditional measures?

The authors used data collected prospectively during a multicenter trial in 133 patients with secondary progressive MS to assess the relative sensitivity of quantitative functional tests and traditional measures, including the Expanded Disability Status Scale (EDSS) and Ambulation Index. Quantitative functional measures worsened in 69% of patients during an average of 6 months of observation, whereas the Clinical Global Impression of Change worsened in 33% and the EDSS worsened in 25% of patients. These changes should be interpreted in the context of the test-retest reliability for each measure.

A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium.

We have obtained a current profile of multiple sclerosis York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.

Oligoclonality of CD8+ T cells in multiple sclerosis.

We have shown earlier that CD8+ T cell oligoclonality occurs frequently in normal individuals and general exhibits a very diverse repertoire. In order to investigate the role of CD8+ T cells in MS, we analysed CD8 oligoclonality in 125 patients with MS in varying stages of disease. A multiplex PCR assay for CDR3 length variation was employed to detect oligoclonality in 25 TCRBV segments/families. CD8 clonal dominance was found to be frequent in MS. Comparison of the CD8 T cell repertoire in MS with that in normal controls revealed an increased frequency of oligoclonality involving the TCRBV9, -18 and -23 families. Sequence analysis of the TCRs from these clonally dominant CD8+ cells revealed a high degree of diversity overall. However, we observed one instance of identical TCRBV18 sequences in CD8 cells from two unrelated MS patients. In addition, several TCRs with motifs homologous to those found in MS brain and MBP specific T cell clones in EAE and MS were also detected. Future characterization of the function and specificity of these clonally expanded populations may provide insight into the nature of immune dysregulation in this autoimmune disorder.

Restricted heterogeneity of antibody to gp120 and p24 in AIDS.

Neurologic complications and cerebrospinal fluid (CSF) abnormalities are common in AIDS. We found that a substantial number of AIDS patients with neurologic involvement had oligoclonal IgG bands in CSF and sera by IEF. Using an IEF-Ag overlay technique, anti-gp120 antibody activity was demonstrated more frequently than anti-p24 antibody activity. These antibody activities exhibited restricted heterogeneity of their IEF pattern; this restriction may contribute to the relatively low titers of neutralizing antibody found in AIDS sera. None of the CSF and serum oligoclonal bands showed anti-HIV antibody activity, suggesting that they are directed against opportunistic agents or result from immunodysregulation.

Neuroleukin: a lymphokine product of lectin-stimulated T cells.

Neuroleukin is a lymphokine product of lectin-stimulated T cells that induces immunoglobulin secretion by cultured human peripheral blood mononuclear cells. Neuroleukin acts early in the in vitro response that leads to formation of antibody-secreting cells, but continued production of immunoglobulin by differentiated antibody-secreting cells is neuroleukin-independent. Although the factor is not directly mitogenic, cellular proliferation is a late component of the response to neuroleukin. Neuroleukin does not have B-cell growth factor (BCGF) or B-cell differentiation factor (BCDF) activity in defined assays. Neuroleukin-evoked induction of immunoglobulin secretion is both monocyte- and T-cell-dependent.

Suppression of terminal axonal sprouting at the neuromuscular junction by monoclonal antibodies against a muscle-derived antigen of 56,000 daltons.

After the partial denervation or paralysis of a muscle, the remaining motor axon terminals may sprout fine, neuritic processes (terminal sprouts) which escape the endplate region of the neuromuscular junction. We previously identified a muscle-derived, protein antigen of 56,000 daltons (56 kD) which plays a necessary role in terminal sprouting. A panel of monoclonal antibodies have been produced against the 56-kD antigen, some of which also partially suppress motor axon terminal sprouting. These monoclonal antibodies define at least two different epitopes upon the surface of the antigen, one of which is necessary for it to effect its biological role in vivo.

Large acquired nevocytic nevi induced by the Koebner phenomenon.

A patient with characteristic clinical, histopathological, ultrastructural and family history of epidermolysis bullosa simplex (EBS) developed large acquired nevocytic nevi at the sites of some healing blisters. An isomorphic reaction may have initiated the development of these nevi. Such large acquired nevi should be considered in the differential diagnosis of large and giant congenital nevi which have the potential to evolve into malignant melanoma.

Synaptic facilitatory and depressant actions of 3,4-diaminopyridine: correlation with anticurare properties.

This study aimed to define the complete concentration-effect relationship for anticurare effects of 3,4-diaminopyridine (3,4-DAP) in the isolated sympathetic ganglion of the bullfrog. Synaptic transmission was monitored by extracellular and intracellular recordings of the postganglionic response to preganglionic stimulation. A previous study showed that in the bullfrog sympathetic ganglion 3,4-DAP caused stimulus-bound repetitive postganglionic responses (SBR) to each single preganglionic stimulus. The concentration-effect relationship for 3,4-DAP-induced SBR was bell-shaped, and the descending limb of the curve reflected progressive suppression of SBR while normal synaptic transmission was maintained. In the present study a detailed concentration-effect analysis of 3,4-DAP's anticurare action also resulted in a bell-shaped curve nearly congruent with that for SBR. SBR and anticurare effects of 3,4-DAP therefore occupy a common concentration-effect domain, and this suggests that a common mechanism (increased transmitter release) may account for both effects.

The actions of 3,4-diaminopyridine in bullfrog sympathetic ganglia.

The effects of 3,4-diaminopyridine (3,4-DAP) on isolated sympathetic ganglia were studied by means of intracellular and extracellular recording techniques. 3,4-DAP in micromolar concentrations caused a single orthodromic stimulus to generate a brief burst of repetitive postganglionic discharges. Such stimulus-bound repetition (SBR) appeared to represent a presynaptic action of 3,4-DAP, as no repetitive firing could be evoked by antidromic or direct stimulation of ganglion cells. 3,4-DAP also increased the latency to the onset of the synaptic potential at concentrations paralleling those responsible for SBR. The actions of 3,4-DAP on synaptic transmission extended over a 10,000-fold concentration range, beginning with synaptic facilitation at micromolar concentrations (1-500 microM), and proceeding to depressant effects at millimolar concentrations (0.5-10 mM). The postganglionic repetitive discharges (SBR) induced by 3,4-DAP could be selectively suppressed by D-tubocurarine (D-Tc) or tetraethylammonium (TEA), at concentrations of these antagonists below those required to block transmission. 3,4-DAP had significant anti-curare effects, producing a four-fold shift of the D-Tc concentration-effect curve for transmission block. In contrast, 3,4-DAP neither antagonized nor enhanced the transmission block produced by TEA. These results are incompatible with traditional concepts of ganglionic blockade by D-Tc and TEA, and suggest the possibility of presynaptic sites of action in ganglion block.