Current developments in the area of multiple sclerosis

The expression pattern of transforming growth factor-beta 1 (TGF-beta 1) during the stages of complete carcinogenesis in the hamster cheek pouch model was studied. The right cheek pouches of 18 male hamsters were treated with 0.5%, 7,12-dimethylbenz[a]anthracene (DMBA) for 16 wk. TGF-beta 1 was detected immunohistochemically in the resulting samples with two different polyclonal monospecific antibodies that recognize intracellular and extracellular forms of TGF-beta 1. In the normal cheek pouch, extracellular protein stained the corium strongly, but the reaction was not evenly distributed. As treatment progressed, the reaction increased in both area and intensity; the peak was reached at 8 wk. Intracellular TGF-beta 1 expression followed a similar pattern, with a peak at 4 wk of treatment. The results of northern blot analysis were concordant with the immunohistochemical results. Overexpression of TGF-beta 1 was also observed in the malignant tumors, but only the extracellular form of the protein was present; intracellular TGF-beta 1 was not detected in these tumors. The expression of TGF-beta 1 in this carcinogenesis model seems to have two formal stages, the first being an overexpression step as a reaction to the uncontrolled growth and the second being one in which tumors have no internal expression of TGF-beta 1 but in which external protein accumulates in the surrounding stroma. A possible explanation of this paradox may be that TGF-beta 1 has functions other than its growth-repressing activity.     

The prevalence, structure and clinical problems of multiple sclerosis in the Transcarpathian area based on epidemiological study data

As many as 230 patients with disseminated sclerosis were examined in the Transcarpathian region. Sick male- and female populations were found out to be almost similar. There were more sick persons in the medium-range areas of the Carpathian Mountains, with a mean age being 35 +/- 5 years. It has been established that intake of spirulina makes for lengthening of remission in those patients with disseminated sclerosis.     

Epidemiology of multiple sclerosis in the county of Vestfold, eastern Norway: incidence and prevalence calculations

The county of Vestfold in the South-eastern part of Norway has undergone two incidence and prevalence surveys on multiple sclerosis. The prevalence of definite/probable MS on January 1, 1963 was 61.6/100,000. Based on the same diagnostic criteria, the present study reports a slight increase in prevalence to 86.4/100,000 on January 1st 1983. The average annual incidence was calculated for 5 years periods from 1953 to 1983. The time periods 1953-1962 and 1973-1977 showed age-adjusted incidence rates between 4.50 and 5.49/100,000 while the 10-year period 1963-1972 showed significantly lower rates. The fluctuating pattern of MS incidence and prevalence over time supports the view that MS is not a stable disease, and that exogenous factors are influencing the disease pattern.     

Epidemiology of systemic sclerosis

Systemic sclerosis is a family of disorders most appropriately considered in the category of the connective tissue diseases. Two major forms are recognized (diffuse cutaneous and limited cutaneous involvement subtypes), each with distinctive clinical and serologic findings as well as natural history. Scleroderma is characterized epidemiologically by several distinctive features. From a demographic viewpoint, the disease spares children and its incidence increases steadily with age among adults. If occurs much more frequently in women, especially during the child-bearing years, and most often and most severely in young black women, though there is no overall prominent racial predilection. The annual incidence approaches 20 per million population, and may be considerably underestimated. Both incidence and mortality have increased during the past several decades, but these changes are most likely a result of improved case detection rather than a true increase in incidence. Prevalence studies have not been undertaken, but 500 per million population may be a reasonable estimate. Family and genetic studies suggest a weak genetic predisposition, but several strong HLA associations with scleroderma-specific serum autoantibodies are evident. Certain environmental agents may be implicated in pathogenesis of scleroderma and closely related systemic illnesses associated with cutaneous fibrosis. The widespread pathologic process in systemic sclerosis leads to vascular insufficiency and fibrosis, which diminishes the reserve function of many organ systems. The result is considerable disability, especially affecting hand function, and a significant reduction in life span, with an overall 10-year survival from first physician diagnosis of under 70%. Further epidemiologic studies should take full advantage of established and newly proposed subsets of patients with homogeneous clinical, laboratory, serologic, and natural history features. The environment-host interactions noted here must be fully explored, especially in early untreated disease, where primary rather than secondary mechanisms are most likely to be operative.     

Epidemiology of liver cirrhosis morbidity and mortality in Iceland

Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training.     

Depression and multiple sclerosis

The objective of the present study were (1) to ascertain the lifetime risk of a depression in a representative group of multiple sclerosis (MS) patients, (2) to assess the morbidity risks for depression among first-degree relatives of these MS patients, and (3) to compare these familial risks for first-degree relatives of MS patients with those for first-degree relatives of a primary depression population, i.e., depression but no MS. We psychiatrically evaluated 221 MS patients (index cases) using a structured clinical interview for the DSM-III-R and calculated the rate and lifetime risk of depression for these index cases using the product limit estimate of survival function. We obtained psychiatric histories for all first-degree relatives of index cases, and we calculated morbidity risks for depression for these relatives using the maximum likelihood approach and compared the risks using the likelihood ratio tests. Index cases had a 50.3% lifetime risk of depression. Morbidity risks for depression among first-degree relatives of index cases were decidedly lower when compared with morbidity risks among first-degree relatives of the reference population. Although there appears to be a very high rate of depression among MS patients, the data for their first-degree relatives do not support a clear genetic basis for this depression, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS.     

Pregnancy and multiple sclerosis

In this review, we summarize the available information on the short- and long-term effects of pregnancy on the course of multiple sclerosis (MS). Published studies that used established criteria for the diagnosis of MS were given more weight than studies in which the criteria for diagnosis were unstated or unclear. Population-based studies were emphasized more than clinic-based studies, unless the clinic base was well defined and thought to be reasonably representative of the MS population in the geographic area. For completeness, small studies were also included but weighted accordingly in our overall conclusions. Methodologic limitations and biases inherent in the study methods are discussed. We conclude that patients with relapsing MS have an increased risk of relapse during the initial 6-month postpartum period. This increased risk does not seem to have a detrimental effect on the rate of developing sustained disability. In fact, a full-term pregnancy may increase the time interval to reaching a common disability endpoint-walking with the aid of a cane or crutch--or to having a secondarily progressive course. Evidence indicates that pregnancy may alter T-lymphocyte functions and cause clinically relevant consequences. The specific biochemical mechanisms responsible for these observations, however, remain undefined. Because of limitations of current knowledge, our conclusions are tentative at best. The data are most applicable to patients with relapsing-remitting MS in its early stages. MS is an unpredictable disease and is only one of many factors that patients must consider when a pregnancy is contemplated.     

Neuroimaging in multiple sclerosis

Neuroimaging in multiple sclerosis is now dominated by MR imaging. This article will focus primarily on conventional MR imaging studies in multiple sclerosis, but will also discuss briefly some of the more recent advances related to MR imaging. Fast spin-echo imaging, fluid attenuated inversion recovery MR studies, three-dimensional volumetric studies, magnetization transfer, and magnetic resonance spectroscopy as it applies to multiple sclerosis are examined.     

Prognosis in multiple sclerosis

Prognosis of the natural course of multiple sclerosis is most often measured on Kurtzke's "expanded disability status scale" (EDSS), a non-linear scale over 20 steps, heavily weighted on mobility. Optic neuritis and sensory disturbances as initial symptoms, lower age at onset of the disease, female sex and a longer interval between relapses are indicators of a more favorable prognosis. As a rule, disability as measured on this scale 5 years after onset corresponds to 3/4 of the disability status after 15 years. The number of relapses diminishes naturally over the course of the disease. Presence and extent of lesions on the initial MRI of the brain in clinically isolated syndromes are valuable predictors of dissemination of the disease process over the following 5-10 years. New therapies (e.g. interferon beta 1b and 1a, copolymer 1) reduce relapse frequency by 1/3 and diminish the extent of pathological lesions in brain MRI, but fail to show (as yet) significant influence on disability.     

Injuries in the etiopathogenesis of multiple sclerosis

An injury might derange the protective function of the blood-brain barrier, and thus it represents one of the possible pathogenetic factors in the demyelination of the neural axis. However, the effect of injury on the occurrence or deterioration of multiple sclerosis is still controversial. According to most authors, the importance of injury in individual cases of multiple sclerosis is undeniable, as well as the fact that injuries are factors of progression and deterioration of the disease, but never its cause. Consequently, injuries can cause only temporary disability, and not permanent. Nevertheless, the incidence of multiple sclerosis increases proportionally to the severity of injury. The length of the period from the occurrence of injury to possible demyelination is still not established. Studies and clinical reports point to the fact that in the evaluation of injury as a precipitating factor for the vulnerability of the blood-brain barrier, the severity of the injury is of greater importance than its site.     

MRI in the study of multiple sclerosis

Magnetic resonance imaging (MRI) has provided considerable insight into the pathological process and disease activity and progression in multiple sclerosis. MRI has become an important tool for the diagnosis of multiple sclerosis, and increasingly for monitoring treatment trial. The growing use of MRI calls for careful consideration in applications so that the technology is not misused. Here we propose a summary of the literature on MRI in application in clinical neurology.     

Genetics of multiple sclerosis

The cause of MS is unknown. There is considerable circumstantial evidence that MS is a complex trait, probably autoimmune in nature, and is determined by both genetic and environmental factors. At present, it must be acknowledged, however, that our understanding of the pathogenesis of MS is minimal. Very little is known about the genes determining disease susceptibility and perhaps even less is understood about environmental factors that influence penetrance or the geographic distribution. This lack of knowledge results neither from lack of effort nor from a shortage of fertile imaginations. Almost every imaginable hypothesis has, in the past, found some support. The intractability of the problem could well result from its complexity, because answers to testable hypotheses are commonly negative or ambiguous. Today, the opportunity exists for researchers to provide such answers because of recent major developments. The first development is the recognition that MS research requires a relatively large pool of well-ascertained, carefully diagnosed, and longitudinally well-characterized MS patients. The last two developments are the identification and successful application of statistical and molecular genetic techniques carrying sufficient power to allow the exploration of complex traits such as MS.     

Epidemiology of ROP in the Stockholm area of Sweden

A prospective, population-based study of the epidemiology of ROP in a well-defined geographical area of Sweden was performed. Two hundred and sixty children with a birth weight of 1500 g or less, and surviving for at least eight weeks, were included in the study. ROP was seen in 40.4% of the children. We suggest that prematurely born children with a gestational age of 32 weeks or less ought to be screened for ROP.     

Genetic factors in multiple sclerosis

OBJECTIVE: To evaluate the role of candidate genes in the susceptibility to multiple sclerosis (MS) and describe the role of T-cell receptor (TCR) gene rearrangements in the MS brain lesion in identifying a major target of the immune response in this disease. DATA SOURCES: MEDLINE, bibliography review of published data, and unpublished studies. STUDY SELECTION: Published studies using novel molecular approaches to analyze the role of the major histocompatibility complex (MHC) and TCR gene complexes, as well as other candidate genes, in susceptibility to MS. We analyze epigenetic events involving TCR genes in individuals with MS and describe recent clinical trials in which immunotherapy has been attempted. DATA SYNTHESIS: Consistent with a polygenic model for disease predisposition, MHC and TCR gene associations with MS are relatively weak. Despite intensive research, no other putative "MS genes" have been firmly established. The analysis of TCR rearrangements in the brain lesion has helped to identify a major target of the immune response in MS. CONCLUSION: Understanding the genetic basis for autoimmune demyelination will offer new possibilities for the treatment of this illness.     

Paroxysmal itching in multiple sclerosis

In three women with multiple sclerosis, paroxysmal attacks of itching occurred. There were several similarities between these attacks and other types of paroxysmal phenomena previously described in multiple sclerosis. The attacks were brief, but usually lasted several minutes, they started and ended abruptly, and recurred several times a day. The were controlled effectively by carbamazepine. It is suggested that paroxysmal itching is caused by transversely spreading ephaptic activation of axons within a partially demyelinated lesion in pain-conducting fibre tracts in the central nervous system.     

Non-specific immunosuppression and multiple sclerosis

Several series of arguments favor at least partial efficacy of immunosuppression in multiple sclerosis. Immunosuppression can often treat experimental autoimmune encephalitis, and imperfect model of multiple sclerosis. Certain agents have been shown to affect the pathophysiological processes seen indirectly on magnetic resonance imaging (mitoxantrone and Campath, for example). Therapeutic trials have their methodological weaknesses but do allow certain conclusions. The progressive forms of multiple sclerosis are the most widely studied. Massive but short-term immunosuppression does not appear to affect the course of progression but prolonged immunosuppression would appear to slow down the process, at least in responders. The effect on disease progression is modest and preference should go to well-tolerated treatments. Immunosuppression appears to effectively decrease the number of acute episodes and reduce the number of new lesions detectable by magnetic resonance imaging. The effect of immunosuppression is limited however by the fact that the clinical course of progressive forms depends less on the development of new lesions than on an aggravation of the demyelinization process and possible axon loss within constituted lesions. This is a further argument favoring early immunosuppressive treatment at a stage when it can be most effective.