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PubMed1994

Use and misuse of statistics for epidemiological studies of multiple sclerosis.

Despite a vast literature on the epidemiology of multiple sclerosis, the cause of this disease remains elusive. The majority of the studies have focused on prevalence, so that a worldwide distribution of multiple sclerosis can now be mapped. Tantalizing apparent differences in prevalence have resulted in an abundance of hypotheses about risk factors for multiple sclerosis, none of which have been firmly established. This article reviews the difficulties inherent in the use of any type of descriptive study to investigate etiology of disease and provides an update of appropriate statistical methodology to analyze study results. The major focus is on the use of analytical study design, specifically the case-control study, to investigate a specific hypothesis about association between a risk factor and multiple sclerosis. An update on new epidemiological and statistical methodology to enhance the design of future case-control studies is presented. Future opportunities to study multiple sclerosis in new ways, such as in cohort studies or nested case-control studies, using large medical insurance and other types of health-related data bases, are discussed.

Case-Control Studies↗
PubMed1997

Expression of the copper-zinc superoxide dismutase gene in amyotrophic lateral sclerosis.

The demonstration of a genetic linkage between the copper-zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patients with sporadic amyotrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative in situ hybridization technique. There were no significant differences between the amounts of SOD1 messenger RNA observed in patients with sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levels of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relationship between the SOD1 gene and the pathogenesis of amyotrophic lateral sclerosis.

Aged↗
PubMed1997

Multiple sclerosis: re-expression of a developmental gene in chronic lesions correlates with remyelination.

Central nervous system tissue from multiple sclerosis and non-multiple sclerosis subjects was studied for the expression of exon 2 myelin basic protein gene products at the protein and message levels by immunocytochemistry and in situ hybridization, respectively. The exon 2-encoded protein sequence is normally expressed during development (myelination) within the 21.5- and 20.2-kd isoforms of myelin basic protein and is downregulated in the adult central nervous system where the 18.5- and 17.2-kd isoforms predominate, the latter devoid of exon 2 owing to alternative splicing. Exon 2 myelin basic protein gene products were readily demonstrable in multiple sclerosis samples, the highest levels correlating with remyelination in chronic lesions while normal adult central nervous system and non-multiple sclerosis material showed very low levels and fetal human central nervous system tissue (a positive control) showed high levels. We conclude that recapitulation of ontogenetic events during myelin repair accounts for the increased expression of the exon 2-encoded protein sequence in the adult central nervous system during multiple sclerosis, an event that might underly the previously observed T-cell activation to this protein sequence during relapses.

Acute Disease↗
PubMed1995

Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis.

Multiple sclerosis is the most common cause of neurologic disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in multiple sclerosis patients. The authors studied 20 patients with relapsing remitting multiple sclerosis to evaluate cardiac toxicity during a one-year follow-up period. Patients were divided into 2 groups: group A, mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients. The clinical course of multiple sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow-up. Each patient had an electrocardiogram and a spectral and color flow Doppler echocardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients. No significant differences in the electrocardiograms or the echocardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow-up. Mitoxantrone treatment seems able to improve the clinical course of relapsing remitting multiple sclerosis patients. It does not show any cardiac toxicity in selected patients at this dosage.

Adolescent↗
PubMed1989

CSF T-cell subsets in multiple sclerosis: relationship to cerebrospinal fluid myelin basic protein and clinical activity.

Cerebrospinal fluid myelin basic protein and cerebrospinal fluid and peripheral blood T-cell subsets have been studied in patients with multiple sclerosis and other inflammatory and non-inflammatory nervous system diseases. These biological parameters have been correlated with clinical disease activity. No changes in peripheral blood T-cell subsets were seen in multiple sclerosis patients. Low cerebrospinal fluid T8+ cells occurred only in multiple sclerosis, while high cerebrospinal fluid T4+ cells were detected both in clinically active multiple sclerosis and in inflammatory nervous system diseases. A close relationship was found between cerebrospinal fluid T4/T8 ratio and myelin basic protein in relapsing multiple sclerosis patients.

Adolescent↗
PubMed1990

Immunological differentiation between neuroborreliosis and multiple sclerosis.

Neuroborreliosis, a tick-borne spirochaetosis of the central nervous system, is diagnosed by the presence of intrathecally synthesized Borrelia burgdorferi-specific antibodies. Multiple sclerosis and neuroborreliosis can show similarities in clinical symptoms as well as lymphocytic cell reactions and oligoclonal bands in the isoelectric focusing of cerebrospinal fluid. To differentiate between multiple sclerosis and neuroborreliosis we tested intrathecally synthesized IgM and virus antibodies. The IgM indices were higher for most of the neuroborreliosis patients studied than for those with multiple sclerosis, and cell counts were also significantly higher in the acute stage of the disease. In 84% of multiple sclerosis patients we were able to demonstrate intrathecal antibody production against measles, rubella or mumps virus. Neuroborreliosis patients had no intrathecal virus antibody synthesis. The specification of oligoclonal bands resulting from isoelectric focusing of cerebrospinal fluid with an ELISA for B. burgdorferi can further substantiate the diagnosis of neuroborreliosis or help to rule it out in multiple sclerosis patients with positive borrelia-specific serology.

Adult↗
PubMed1987

Radiopaque markers transit and anorectal manometry in 16 patients with multiple sclerosis and urinary bladder dysfunction.

Fecal incontinence and/or constipation are frequent complaints in multiple sclerosis associated with urinary bladder dysfunction, incontinence, and/or retention. Total and segmental colonic transit were studied by determination of radiopaque markers, and anorectal function by anorectal manometry, in 16 multiple sclerosis patients clinically defined (with urinary bladder dysfunction shown by urodynamic examination). Fifteen multiple sclerosis patients had constipation and 14 had increased colonic transit time; ten multiple sclerosis patients had fecal incontinence and five had spontaneous rectal contractions. It is suggested that increased colonic transit and anorectal dysfunction were secondary to neurologic disorders just as urinary bladder dysfunction is due to neurologic disorders in multiple sclerosis.

Adult↗
PubMed1997

The role of nitric oxide in multiple sclerosis.

During the past decade nitric oxide has emerged as an important mediator of physiological and pathophysiological processes. Elevated nitric oxide bio-synthesis has been associated with nonspecific immune-mediated cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid arthritis, insulin-dependent diabetes, inflammatory bowel disease, and multiple sclerosis. Recent evidence suggests, however, that nitric oxide is also immunoregulatory and suppresses the function of activated proinflammatory macrophages and T lymphocytes involved in these diseases. This article reviews the role of nitric oxide in the biology of central nervous system glial cells (astrocytes and microglia) as it pertains to the pathogenesis of multiple sclerosis in humans and experimental allergic encephalitis, the animal model of this disease. Although nitric oxide has been clearly implicated as a potential mediator of microglia-dependent primary demyelination, a hallmark of multiple sclerosis, studies with nitric oxide synthase inhibitors in the encephalitis model have been equivocal. These data are critically reviewed in the context of what is know from clinical research on the nitric oxide pathway in multiple sclerosis. Specific recommendations for future preclinical animal model research and clinical research on the nitric oxide pathway in patients are suggested. These studies are necessary to further define the role of nitric oxide in the pathology of multiple sclerosis and to fully explore the potential for nitric oxide synthase inhibitors as novel therapeutics for this disease.

Animals↗
PubMed2001

Tuberous sclerosis: diffusion MRI findings in the brain.

Diffusion MRI has mainly been used for detection of acute ischemia, and for distinction of cytotoxic and vasogenic edema. We applied diffusion MRI in patients with tuberous sclerosis in order to evaluate diffusion imaging characteristics of parenchymal changes. Five children with known tuberous sclerosis were included in this study. The MRI examinations were performed on a 1.5-T MR unit. Diffusion MRI was obtained using the echo-planar imaging sequence. Apparent diffusion coefficient (ADC) values from the abnormal brain parenchyma were calculated directly from automatically generated ADC maps. Seven normal children were available for comparison. In this control group the mean ADC value of the normal white matter was 0.84 +/- 0.12 x 10(-3) mm(2)/s. In tuberous sclerosis patients the mean ADC value of the white matter hamartomas ( n=20) was apparently high (1.52 +/- 0.24 x 10(-3) mm(2)/s) compared with that of normal white matter. The ADC value of calcified hamartomas was "zero". The ADC value within a giant cell tumor was 0.89 x 10(-3) mm(2)/s, similar to that of normal cerebral white matter. The ADC maps were superior to b=1000 s/mm(2) (true diffusion) images with respect to lesion evaluation, and they provided mathematical information on tissue integrity. With respect to detection of the exact numbers and sizes of the parenchymal hamartomas fluid-attenuated inversion recovery images were superior to ADC maps. It is believed that diffusion MRI can be useful in evaluation of various parenchymal changes associated with tuberous sclerosis. Further studies on tuberous sclerosis, and on various brain lesions, would provide increasing data on this relatively new MRI sequence.

Brain↗
PubMed2005

A possible spatial and temporal cluster of multiple sclerosis in the town of Linguaglossa, Sicily.

We carried out an epidemiological survey to determine prevalence and incidence of multiple sclerosis in the little town of Linguaglossa in the Province of Catania. We calculated prevalence rate as point prevalence at 1 January 2001 and incidence during 1991-2000. We studied the frequency of multiple sclerosis in the community of Linguaglossa in a population of 5,422 inhabitants in the 2001 census. The primary sources for the case ascertainment were the general practitioners of Linguaglossa, the local Italian Multiple Sclerosis Association and the neurological departments, Multiple Sclerosis Centers and private neurologists of the province of Catania. We considered as prevalent and incident cases all patients who satisfied the Poser's diagnostic criteria. We detected 11 patients with multiple sclerosis who had had the onset of disease on prevalent day (P.D.). The onset-adjusted prevalence rate was 203/100,000 (95% CI 107-352). Prevalence was higher in women (247/100,000) than in men (154/100,000). From 1991 to 2000, 10 subjects with MS had clinical onset of disease. The mean annual incidence risk was 18.2/100,000 (C. I. 95 % 5.9-42.5). Conversely in the same population prevalence on 1 January 1991 was 37/100,000 while the onset adjusted annual incidence risk during the previous decade (1981-1991) was 3.6/100,000. Prevalence and incidence rates of MS during the last decade in the little town of Linguaglossa are higher than those found in the same area during the previous ten years and also than those reported in other Sicilian and Italian surveys suggesting a possible cluster of MS.

Adolescent↗
PubMed1985

The acute deafness of definite multiple sclerosis: BAEP patterns.

Of 705 patients with or suspected of multiple sclerosis who underwent evoked potential recording during a 5 year period, 12 patients with definite multiple sclerosis experienced an acute hearing loss during a relapse of the demyelinating disease. Hearing loss was unilateral in all of the 12 cases but one; tinnitus was associated with hearing loss in 9 of the 12 patients. Deafness is an unfrequent symptom in the course of multiple sclerosis, being estimated to be no more than 3% in large series of multiple sclerosis. Brain-stem auditory evoked potentials were recorded in all 12 patients, during the relapse with acute hearing loss in 4 of them, after the relapse with hearing loss in the 8 others. During the relapse with hearing loss, BAEP abnormalities were present ipsilateral to the hearing loss in all 4 patients, wave I being absent in 2 of them. BAEPs were drastically improved when recorded after the relapse with hearing loss in 2 of the 3 patients in whom repeated records were made. BAEPs were abnormal on the side of the previous hearing loss in 5 out of the 8 patients recorded after the relapse with hearing loss. Clinical and BAEP data suggest that, in accordance with the anatomical organization of the auditory pathways, the lesion causing unilateral hearing loss in multiple sclerosis could be situated in the cochlear nerve or close to its entry zone in the brain-stem. However, dissociation between unilateral hearing loss and a normal peak I and I-III interval may occur.

Acoustic Stimulation↗
PubMed1985

Multiple sclerosis: incorporation of results of laboratory techniques in the diagnosis.

In a retrospective study of 100 multiple sclerosis patients we compared the diagnostic classification according to the Schumacher/Rose criteria and the newest criteria, proposed by Poser et al. It is clear that by incorporating the results of laboratory investigations in the diagnostic criteria a firm diagnosis of multiple sclerosis can be reached more often and at an earlier stage of the disease. Evaluating abnormal laboratory findings, we found that it was possible to detect more than 90% of diagnostically important findings, i.e. findings effecting a change in diagnostic classification (from possible multiple sclerosis to probable or definite, from probable to definite), using only two of the laboratory tests: cerebrospinal fluid analysis and visual evoked response. Because the results of laboratory tests contributing to diagnostic classification are not specific for multiple sclerosis, the importance of evaluating the complete differential diagnosis of diseases that can be confused with multiple sclerosis is stressed.

Adolescent↗
PubMed1992

Monoamine oxidase-B in motor cortex: changes in amyotrophic lateral sclerosis.

The occurrence of monoamine oxidase-B in cerebral cortex and white matter in brains from three patients with the diagnosis of amyotrophic lateral sclerosis and three controls was quantified by means of an autoradiographical method. [3H]L-Deprenyl, an irreversible and selective monoamine oxidase-B inhibitor, was used as ligand and the autoradiographs were analysed by computer-assisted densitometry. In both amyotrophic lateral sclerosis and control cerebral cortex, lamina I showed the highest, laminae II and III intermediate, laminae IV, V and VI the lowest [3H]L-deprenyl binding. White matter showed about one-third of the binding in the cortex. Amyotrophic lateral sclerosis cases showed significantly higher binding of [3H]L-deprenyl in all the cortex laminae of the pre- and postcentral gyri. There was no difference in the binding between the amyotrophic lateral sclerosis cases and the controls in area 7 of the occipital cortex, an area which is relatively spared in amyotrophic lateral sclerosis.

Aged↗
PubMedDate not supplied

Concurrence of multiple sclerosis and Hodgkin's disease.

Although multiple sclerosis and Hodgkin's disease are reported to have similar epidemiologic features, this is only the first case report in which there was concurrence of these diseases. Fourteen years after successful treatment of Hodgkin's disease, this 31-year-old white male developed multiple sclerosis. The diagnosis of multiple sclerosis was made on the basis of clinical and paraclinical findings that were characteristic of multiple sclerosis. In addition, specific tests were performed to rule out a variety of infectious, metabolic, and neoplastic diseases that simulate multiple sclerosis.

Adult↗
PubMed1995

Varicella zoster virus and multiple sclerosis in a Hutterite population.

There are similarities between multiple sclerosis and varicella. They are common in the same parts of the world and both are scarce in other areas. Immigration studies suggest the environmental cause of multiple sclerosis (MS) must be contracted prior to age 15 years and will usually remain dormant for years. At age 10 years varicella has occurred in greater than 95% of children living in the high-risk areas for both of these diseases. The varicella zoster virus (VZV) could be etiologically important in multiple sclerosis. The known host containment of the virus for decades with recrudescence and the variable cell-mediated immunity of the host, which can wax and wane without clinical manifestations, all lend themselves to the natural history of multiple sclerosis. A population-based study of the medical records of 5601 Hutterite Brethren was performed to determine the occurrence of multiple sclerosis, varicella, and herpes zoster. Compared to their matched non-Hutterite neighbors who acted as controls, these events were significantly less common among the Hutterites. Included in the study was an assessment of other common neurological diseases and "autoimmune" diseases among the Hutterites and the controls. There is evidence of a relationship between MS and VZV that may not be coincidental.

Adolescent↗
PubMed2005

Inhibition of skin sclerosis by 15deoxy delta12,14-prostaglandin J2 and retrovirally transfected prostaglandin D synthase in a mouse model of bleomycin-induced scleroderma.

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity. We evaluated the effect of treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or the injection of prostaglandin D(2) synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis. Daily injection of BLM (30 microg) for 4 weeks induced histological evidence of dermal sclerosis in C3H mice. We examined the effect of injection of 15d-PGJ(2) (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis. Administration of 15d-PGJ(2) (a nonenzymatic metabolite of PGD(2)) injection of PGDS cDNA-expressing fibroblasts significantly reduced dermal sclerosis, the hydroxyproline content, and dermal thickness. Moreover, 15-d PGJ2 down-regulation of the expression of transforming growth factor beta(1) and connective tissue growth factor which had been induced by BLM. Mast cells were also increased in the skin by BLM injection and there was prominent degranulation of these mast cells along with elevated plasma histamine levels. 15-d PGJ(2) and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells. These results show that 15-d PGJ(2) and PGDS-expressing cells can prevent experimental skin sclerosis induced by BLM and raise the possibility of therapeutic approaches targeting of PPARgamma for the skin lesion of scleroderma.

Animals↗
PubMed2006

Obstetric regional blocks for women with multiple sclerosis: a survey of UK experience.

BACKGROUND: There has been a reluctance to use regional blocks for women with multiple sclerosis as effects on the course of the disease are unclear. We assessed the views of UK consultant obstetric anaesthetists regarding management of women with multiple sclerosis. METHODS: Following Obstetric Anaesthetists' Association approval a questionnaire was sent to UK consultant members. Opinions were sought on antenatal assessment, labour analgesia, anaesthesia for elective and emergency caesarean section, and modification in technique for those with multiple sclerosis. Enquiries were made of postnatal problems ascribed to regional blocks. RESULTS: Of the 592 replies analysed, 91% of respondents had seen fewer than 10 cases of multiple sclerosis in the past 10 years. Antenatal assessment was recommended by many with postnatal relapse most commonly discussed (64%). Many highlighted the need for informed consent and minimising local anaesthetic dose. For labour analgesia 79% would perform a regional block; a further 20% would do so in certain circumstances. For elective caesarean section, epidural rather than spinal anaesthesia was preferred by 4%; 2% would not use a regional block, preferring general anaesthesia. For emergency caesarean section with time only for single-shot spinal, 3% would give a general anaesthetic. Deterioration of symptoms after delivery were reported by 20% with 3% attributing symptoms such as prolonged block, leg weakness, bladder dysfunction and postnatal relapse to regional blocks. CONCLUSION: Most UK anaesthetists would perform regional blocks for labour and caesarean section in multiple sclerosis, although the experience of each anaesthetist is limited. Many emphasised the need for thorough pre-assessment and informed consent.

Adult↗
PubMed1981

Hepatoportal sclerosis in childhood: a mimic of extrahepatic portal vein obstruction.

In the absence of cirrhosis, most children with portal hypertension and bleeding esophageal varices have extrahepatic portal vein occlusion. In the past 2 yr this clinical picture has been mimicked by two children with hepatoportal sclerosis causing their variceal hemorrhage. Hepatoportal sclerosis has been well described in adults. It is manifested by splenomegaly, portal hypertension, and variable ascites and hepatomegaly. Liver histology is initially normal but subsequently shows periportal fibrosis without cirrhosis. Hepatic manometrics indicate a presinusoidal block, but angiography demonstrates a patient portal vein. Typically there is abrupt narrowing of the intrahepatic portal branches, giving a "withered tree" appearance. These findings are illustrated by two children who presented with esophageal variceal bleeding at 21 and 20 mo of age, respectively. They are the youngest reported cases of hepatoportal sclerosis. The etiology of hepatoportal sclerosis is uncertain, but the disease appears to be only slowly progressive. Control of variceal bleeding by central portosystemic shunts in this condition is associated with a 50% incidence of hepatic encephalopathy. Therefore alternate methods of therapy need be considered. Endoscopic injection sclerotherapy successfully controlled variceal bleeding in one child reported here. Hepatoportal sclerosis is a distinct entity and must be considered in the differential diagnosis of portal hypertension in infants and children.

Biopsy↗