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PubMed2004

Pathogenesis of brain and spinal cord atrophy in multiple sclerosis.

For more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neurologic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for < 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis.

Apoptosis↗
PubMed2000

[Multiple sclerosis and new imaging methods].

UNLABELLED: BACKGROUND OF PROBLEM: The recognition of the power of MRI and CT to show the involvement of the central nervous system in multiple sclerosis, as well as in other neuropathological phenomena, stimulate considerably their use in the assessment of diagnosis. Much experience gained during the development and clinical application of imaging on the basis of magnetic resonance (MRI) justify the use of this method also in verification of the diagnosis of multiple sclerosis. The development and clinical application of specific pulse sequences and unconventional techniques as e.g. "magnetisation transfer imaging", and other new methods with greater resolution are used in applied research. Routine clinical examinations of the brain and spinal cord are performed especially by use of "dual echo spin images". Flair sequences are not always more significantly sensitive, however, they can provide surprisingly remarkable facts. SUBJECTIVES: The aim of this study is to support the firm or tentative clinical diagnosis of multiple sclerosis. METHODS AND MATERIAL: 131 patients with multiple sclerosis were hospitalized at our clinic and examined by use of computerised tomography (CT) and magnetic resonance (MRI). The results of these examinations confirmed firmly the diagnosis of multiple sclerosis in 98 patients. The tentative diagnosis assessed in 33 patients was not supported by MRI. The findings gained by brain examination were evaluated according to the conditions assessed by Fazekasz and American Multiple Sclerosis Association. Examinations were performed by Signa Contour 0.5 Tesla magnetic resonance on transverse planes, and on sagital planes in T1 VO and T2 VO. RESULTS: During the initial period (1995-1996), CT examination of the brain was performed in 16 patients with firm diagnosis of multiple sclerosis, out of whom only 24% had the pathological periventricular finding within the white matter. Therefore, a majority of patients were subdued to MRI. In these patients, the characteristic finding of hyperintensive lesions were found within T2 VO. They were situated within periventricular white matter as well as in cerebellum, and in 24 patients they were located within the cervical part of the spinal cord. The patients forming the latter group had severe neurologic findings, and ranged 4-9 of the Kurtzke scale. MRI enabled to assess the diagnosis of multiple sclerosis in all patients. Out of the group of 33 patients, only 2 were subdued to CT of the brain. Their findings did not yield any changes in shape of brain tissue structures. MRI findings in these patients did not verify the diagnosis of multiple sclerosis sufficiently. The neurological findings were not pronounced, achieving the 1-3 degree of Kurtzke scale. CONCLUSION: Current techniques of CNS imaging, either by use of computerised tomography of MRI do not enable the assessment of the firm diagnosis of multiple sclerosis to full extent. MRI is capable only of supporting it. (Ref. 7.)

Brain↗
PubMed2001

Mean diffusivity and fractional anisotropy histograms of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Compared with conventional T2-weighted MR imaging, diffusion tensor MR imaging provides quantitative indices with increased specificity to the most destructive aspects of multiple sclerosis. In this study, we obtained brain mean diffusivity (_D) and fractional anisotropy histograms of patients with multiple sclerosis to compare them with those of healthy volunteers and to investigate the correlation between diffusion tensor MR imaging histogram-derived measures and the level of disability and quantities derived from conventional MR imaging. METHODS: Dual-echo and diffusion tensor MR images were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive multiple sclerosis and from 20 healthy control volunteers. After obtaining mean diffusivity (_D) and fractional anisotropy images and image coregistration, _D and fractional anisotropy histograms were created. From each histogram, the following measures were derived: the average _D and fractional anisotropy, the histogram peak heights, and the histogram peak locations. RESULTS: All the _D and fractional anisotropy histogram-derived measures were different between patients and controls at a significance level of P <.001. No differences were found in any of the considered quantities among the three multiple sclerosis phenotypes. In patients with relapsing-remitting multiple sclerosis, disability was correlated with histogram average_D (r = 0.4, P =.01) and peak height (r = -0.4, P =.01). In patients with secondary progressive multiple sclerosis, disability was correlated with fractional anisotropy histogram peak position (r = -0.6, P =.01). Significant correlations were also found between T2 lesion load and various diffusion tensor MR quantities. CONCLUSION: This study shows that brain _D and fractional anisotropy histograms are different for patients with multiple sclerosis compared with control volunteers. This study also shows that quantities derived from diffusion tensor MR imaging are correlated with disability in patients with relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, suggesting that they might serve as additional measures of outcome when monitoring multiple sclerosis evolution in these patients.

Adult↗
PubMed1994

Magnetization transfer: a potential method to determine the age of multiple sclerosis lesions.

PURPOSE: To determine whether magnetization transfer contrast can differentiate acute from chronic lesions in multiple sclerosis. METHODS: Thirteen patients with multiple sclerosis and eight healthy patients were studied with MR using a 0.1-T system. Relatively T2-weighted spin-echo images were obtained without and with magnetization transfer contrast. The magnetization transfer effect of multiple sclerosis lesions was calculated and compared with the ages of the lesions. The magnetization transfer effect of normal-appearing white matter in patients with multiple sclerosis was calculated and compared with the magnetization transfer effect of white matter in healthy volunteers. Statistical analysis was performed. RESULTS: White matter in the healthy volunteers had values from 0.40 to 0.45. Normal-appearing white matter in the patients with multiple sclerosis had magnetization transfer effect values ranging from 0.41 to 0.45. Multiple sclerosis plaques of less than 1 year's duration had magnetization transfer effect values ranging from 0.05 to 0.26; older plaques had values from 0.25 to 0.41. The difference in the distributions of these values for acute and chronic multiple sclerosis plaques is statistically significant. CONCLUSION: Current imaging modalities do not differentiate acute multiple sclerosis lesions from chronic ones. Our data on magnetization transfer show a statistically significant difference in magnetization transfer effect values between lesions of less than 1 year's duration and older lesions. The different values may correspond to the histologic changes of multiple sclerosis plaques over time. Magnetization transfer may be a reliable method for determining the age of multiple sclerosis lesions.

Acute Disease↗
PubMed2003

Serum autoantibodies to cell surface determinants in multiple sclerosis: a flow cytometric study.

Multiple sclerosis is thought to be an autoimmune, inflammatory, cell-mediated disease. However, there is evidence suggesting that autoantibodies could play a role in the pathogenesis of multiple sclerosis. Many studies have looked for antibodies to candidate antigens such as myelin basic protein or myelin-oligodendrocyte glycoprotein, with inconclusive results. In order to determine whether antibodies to cell surface determinants on oligodendrocyte or neuronal cells were present in multiple sclerosis, we used flow cytometry to detect antibody binding to intact cultured human cell lines, comparing sera from multiple sclerosis patients with sera from patients with other inflammatory CNS diseases. Sera from healthy individuals were used to determine a normal range. Significant surface binding of IgG or IgM antibodies to oligodendrocyte precursor (OPC)-derived cell lines was seen in 50% of multiple sclerosis sera with no significant difference between secondary progressive (SPMS) and relapsing-remitting (RRMS) subgroups. In contrast, binding to a neuronal cell line, SK-N-SH, was seen with 70% of SPMS sera compared with 25% of RRMS sera (P < 0.001). No significant difference in antibody binding between multiple sclerosis sera and control sera was seen when OPCs were differentiated or when the cells were permeabilized to expose intracellular antigens. Results from all nine patients with 'benign' multiple sclerosis were indistinguishable from controls. This study represents a systematic approach to begin to define new antigenic targets in multiple sclerosis and demonstrates that antibodies to accessible antigens on the cell surface of both OPCs and neurons are present in some patients. The results lend support to the possibility that autoantibody-mediated processes are important in a subgroup of multiple sclerosis patients. Identification of the cell surface determinants to which the antibodies bind may shed light on new targets for therapeutic intervention.

Adolescent↗
PubMed1984

Ferritin deposition in the glomerular deposits of focal glomerular sclerosis in the rat.

The glomerular lesions of focal sclerosis clinically associated with a steroid-resistant nephrotic syndrome, are of unknown origin. IgM and C3 deposits and electron dense material found in areas of sclerosis are not convincing evidence of an immune pathogenesis. These deposits have been studied in a rat model of focal sclerosis induced by uninephrectomy and repeated aminonucleoside administration. Sclerotic lesions closely resembling human disease developed in the remaining kidney. There was a severe progressive proteinuria. Seventy-eight days after initial aminonucleoside injection 65 per cent of glomeruli were sclerotic with IgM, IgG, C3 and fibrinogen deposits, and electron dense deposits by electron microscopy. To study macromolecule in this model of focal sclerosis, ferritin uptake 4 and 24 h after intravenous ferritin given at 77 days was compared in focal sclerosis rats with control rats without sclerosis (uninephrectomy plus saline-only injections). In focal sclerosis rats sclerotic areas contained massive accumulations of ferritin. In unaffected segments of sclerotic glomeruli, and normal glomeruli of focal sclerosis rats, ferritin concentration was no different from controls. Abnormal ferritin trapping in areas of sclerosis suggests that the presence of IgM and C3 may be due to a similar mechanism, and is not indicative of an immune pathogenesis for focal sclerosis.

Animals↗
PubMed1996

Signal-averaged electrocardiography and echocardiography in the evaluation of myocardial involvement in progressive systemic sclerosis.

To assess the myocardial involvement in progressive systemic sclerosis we evaluated the presence of late potentials by signal-averaged electrocardiography (signal-averaged ECG) and the left ventricular function by M-mode, two dimensional and Doppler echocardiography. Fifteen outpatients, 7 with diffuse progressive systemic sclerosis and 8 with CREST syndrome variant, without clinical or electrocardiographic evidence of cardiac disease were studied and compared with 18 normal subjects. Late potentials occurred in 5 out of 15 progressive systemic sclerosis patients (33%) with a significant difference versus controls (P < 0.05) and were present only in the patients with diffuse progressive systemic sclerosis (P < or = 0.001 vs. controls). All progressive systemic sclerosis patients showed a normal left ventricular systolic function. Abnormal left ventricular filling was found in 9 progressive systemic sclerosis patients (5 with diffuse progressive systemic sclerosis and 4 with CREST). A more severe impairment of the mean values of diastolic function indexes was found in diffuse progressive systemic sclerosis than in CREST. In all diffuse progressive systemic sclerosis patients at least one method showed altered results, whereas half the CREST patients showed no pathological findings with both techniques. These results confirm a lower myocardial involvement in the CREST syndrome than in diffuse progressive systemic sclerosis and consequently this is probably related to a better prognosis.

Adult↗
PubMed1996

Electrophysiologic abnormalities of cardiac function in progressive systemic sclerosis.

The heart has been generally recognized as a target organ in progressive systemic sclerosis. Noninvasive studies have assessed the incidence and prognostic importance of cardiac arrhythmias in these patients. However, detailed exploration of the function of impulse formation and the conduction system of the heart in these patients has never been reported. Therefore, invasive electrophysiologic studies were performed in 30 patients with systemic sclerosis, all of whom had neither obvious cardiac involvement nor cardiac arrhythmias, and in 32 subjects with no evidence of heart disease, who served as a control group. Corrected sinus node recovery time in patients with systemic sclerosis was significantly longer (P < .001) than in the control group, as was the HV interval (P < .05). Of the 30 patients with systemic sclerosis, 10 had an HV interval of 60 ms or longer. In four patients with systemic sclerosis, the recorded AH interval exceeded 125 ms. The intra-atrial conduction time tended to increase to a significant degree (P < .05) in patients with systemic sclerosis. The interatrial conduction time was much longer (P < .001), and the maximal conduction delay to the atrioventricular junction and to the distal coronary sinus was much greater in the patients with systemic sclerosis than in the control group (P < .001 for both). Supraventricular tachyarrhythmias were induced in 15 patients with systemic sclerosis versus 3 control group subjects (P < .001). With respect to corrected sinus node recovery time, AH and HV intervals, atrial vulnerability, and ventricular tachycardia, 3 of the 30 patients with systemic sclerosis had abnormal findings in one of these parameters and 14 had abnormalities in more than one. These results suggest that a broad spectrum of electrophysiologic abnormalities is present in patients with systemic sclerosis, which can be revealed only by invasive studies. Furthermore, this study provides additional support for the hypothesis that diffuse myocardial involvement is characteristic of scleroderma patients, since a number of these patients showed more than one electrophysiologic defect.

Adolescent↗
PubMed2003

Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis.

Systemic sclerosis is characterized by fibrosis and systemic autoimmunity; however, roles of autoantibodies in the development of fibrosis remain unknown in systemic sclerosis. The net accumulation of extracellular matrix is dependent on the balance between the synthesis and degradation of extracellular matrix components, the latter process regulated by matrix metalloproteinases. Matrix metalloproteinase-1 (interstitial collagenase-1) can initiate degradation of collagen types I-III that are major extracellular matrix constituents in affected skin of systemic sclerosis. In this study, we tested the hypothesis that systemic autoimmunity in systemic sclerosis induced anti-matrix metalloproteinase-1 autoantibodies that inhibited matrix metallo-proteinase-1 activity, resulting in collagen accumulation. Enzyme-linked immunosorbent assay using human recombinant matrix metalloproteinase-1 revealed that IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly elevated in sera from patients with systemic sclerosis, but not patients with active systemic lupus erythematosus or dermatomyositis, relative to normal controls. IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly higher in patients with diffuse cutaneous systemic sclerosis than those found in patients with limited cutaneous systemic sclerosis. Furthermore, IgG anti-matrix metalloproteinase-1 antibody levels significantly correlated with the extent of fibrosis in the skin, lung, and renal blood vessels. The presence of IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients was confirmed by immunoblotting analysis. Remarkably, IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients inhibited matrix metalloproteinase-1 collagenase activity. Collectively, the results of this study suggest that anti-matrix metalloproteinase-1 autoantibody contributes to the development of fibrosis by inhibiting matrix metalloproteinase-1 collagenase activity and reducing the extracellular matrix turnover and suggest that the presence of anti-matrix metalloproteinase-1 autoantibody in systemic sclerosis is the link between systemic autoimmunity and fibrosis.

Adult↗
PubMed1997

Survival prognostic factors and markers of morbidity in Spanish patients with systemic sclerosis.

OBJECTIVE: To identify survival prognostic factors and markers of morbidity among patients with systemic sclerosis (SSc). PATIENTS AND METHODS: The study included 72 patients diagnosed with SSc. According to the extent of skin involvement, three groups of patients were established: group 1, without sclerosis and with sclerosis of fingers and neck; group 2, with sclerosis of face and distal to elbows and knees; group 3, with generalised sclerosis including the trunk. All patients were included in a study protocol to determine visceral involvement. Cumulative survival after first symptom has been estimated according to the Kaplan-Meier method. The association between a hypothetical prognostic factor and cumulative survival after first symptom was assessed by log rank test. The association between a hypothetical risk factor and the prevalence of severe morbidity was assessed by the odds ratio. Multiple logistic regression models were used to identify the main predictors of severe morbidity. RESULTS: Survival was estimated to be 85% 10 years after first SSc symptom. Survival was higher among SSc patients with skin involvement distal to elbows and knees than among the rest of patients; a forced vital capacity (FVC) on spirometry lower than 70% of expected value was associated with a shorter survival, even after adjustment for diffuse SSc. Skin involvement proximal to elbows or knees was associated with a higher prevalence of severe morbidity (OR = 46.57; p < 0.001). According to a multiple logistic regression, severe morbidity was higher among patients with skin involvement proximal to knees or elbows (OR = 40.92; p < 0.001) or among patients with pulmonary hypertension detected by Doppler echocardiography (OR = 23.66 p < 0.001). CONCLUSIONS: In patients with SSc the extent of skin sclerosis was found to be a determining factor on the prognosis. According to skin sclerosis extent two main subsets of SSc patients with different survival incidence and degree of morbidity could be clearly established: limited SSc, formed by patients with no skin sclerosis or with sclerosis distal to elbows and knees and diffuse SSc, formed by patients with skin sclerosis distal and proximal to elbows and knees. Moreover, lung involvement (FVC < 70% on survival study and pulmonary hypertension on morbidity study) was an important and independent prognostic factor.

Adolescent↗
PubMed2005

Cigarette smoking and the progression of multiple sclerosis.

An increased risk of multiple sclerosis among smokers has been found in several prospective epidemiological studies. The association between smoking and progression of multiple sclerosis has not been examined. We identified patients who had a first multiple sclerosis diagnosis recorded in the General Practice Research Database (GPRD) between January 1993 and December 2000. Their diagnosis and date of first symptoms were confirmed through examination of medical records. Smoking status was obtained from the computer records. To assess the association between smoking and risk of multiple sclerosis, we conducted a case-control study nested in the GPRD. Up to 10 controls per case were randomly selected, matched on age, sex, practice, date of joining the practice and availability of smoking data. To assess the association between smoking and progression of multiple sclerosis, we conducted a cohort study of multiple sclerosis cases with a relapsing-remitting onset. Our nested case-control study included 201 cases of multiple sclerosis and 1913 controls. The odds ratio [95% confidence interval (CI)] of multiple sclerosis was 1.3 (1.0-1.7) for ever smokers compared with never smokers. Our cohort study included 179 cases with a mean (median) length of follow-up of 5.3 (5.3) years. The hazard ratio of secondary progression was 3.6 (95% CI 1.3-9.9) for ever smokers compared with never smokers. These results support the hypothesis that cigarette smoking is associated with an increased risk of multiple sclerosis, and suggest that smoking may be a risk factor for transforming a relapsing-remitting clinical course into a secondary progressive course.

Adult↗
PubMed2006

Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis.

The trend to start disease-modifying therapy early in the course of multiple sclerosis makes it important to establish whether the benign form is a real entity. In previous studies, measures of magnetization transfer (MT) ratio (MTr) have been shown to provide good estimates of the amount of tissue damage occurring in multiple sclerosis brains. Thus, with the hypothesis that if benign multiple sclerosis patients were really benign, sensitive measures of subtle tissue damage would be less pronounced in these patients than in very early relapsing-remitting (RR) multiple sclerosis patients. We carried out conventional MRI and MT imaging in 50 patients with benign multiple sclerosis [defined as having Kurtzke Expanded Disability Status Score (EDSS) <3 and disease duration >15 years] and in 50 early RR patients selected to have similar disability (EDSS <3) and short disease duration (<3 years). Data were compared with those of 32 demographically-matched normal controls. We used a fully automated procedure to measure lesional-MTr, perilesional-MTr, normal-appearing white matter (NAWM) MTr and cortical-MTr. We found that, after correction for common effects of age, lesional-MTr and perilesional-MTr of benign patients were significantly (P < 0.0001) lower than WM of normal controls, but significantly (P < 0.0001) higher than corresponding tissues of RR patients. In NAWM and cortex, MTr values of benign patients were similar to those of normal controls (P > 0.5) and significantly higher than those of the RR patients (P < 0.0001 and P < 0.01, respectively). Similar differences in MTr measures between benign and RR patients were found when patient groups were selected to have no disability (EDSS < or = 2) and, for benign multiple sclerosis, very long disease duration (>20 years) or when both groups were matched for high lesion load (T2-weighted lesion volume >10 cm3). We conclude that lesional and non-lesional MTr values can be significantly less pronounced in benign multiple sclerosis than in a cohort of RR patients at their earliest disease stages, suggesting that brain tissue damage is milder in benign multiple sclerosis than in early RR disease. This can be due to an extraordinary beneficial response to demyelination of benign patients and may represent the evidence that benign multiple sclerosis truly exists and might be differentiated from other forms of this illness.

Adult↗
PubMed1993

Hippocampal sclerosis and human memory.

OBJECTIVE: To study the effects of hippocampal sclerosis on preoperative neuropsychological memory tests. DESIGN: Analyses of variance and chi 2 tests were used to compare patient groups (divided retrospectively) with a control group. SETTING: Hospital epilepsy unit. PATIENTS AND OTHER PARTICIPANTS: All patients who underwent a temporal lobectomy for intractable seizure relief during the preceding 18 months were included if the following criteria were met: (1) age was between 15 and 55 years; (2) IQ was 80 or greater; (3) the left hemisphere was dominant for speech; (4) there had been no previous brain surgery; (5) sufficient hippocampal tissue had been supplied for pathologic study; and (6) there was no hippocampal abnormality other than sclerosis. The 40 patients who met all of these criteria were divided into groups based on pathological classification (presence or absence of hippocampal sclerosis) and side of excision. Ten normal control subjects, matched to the patients based on age and education, were also asked to perform the memory tests. All subjects approached gave their informed consent to participate in the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: No group demonstrated impairments on measures of attention or recognition memory. A deficit in learning paired-word associates was found for the left hippocampal sclerosis, right hippocampal sclerosis, and left no-hippocampal sclerosis groups, but on tests requiring the delayed recall of information, only patients with hippocampal sclerosis were impaired. For verbal tasks, the delayed recall deficit was limited to patients with left-sided sclerosis. CONCLUSIONS: Hippocampal sclerosis impairs the ability to learn associations and to retain information over a delay interval. For the learning and retention of verbal material, the left hippocampus is more important than the right.

Adolescent↗
PubMed2006

Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.

CONTEXT: Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis. OBJECTIVE: To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms. MAIN OUTCOME MEASURES: Odds ratios of multiple sclerosis associated with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group. RESULTS: Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P = .006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found. CONCLUSION: The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.

Adolescent↗
PubMed2004

Aortic sclerosis--a marker of coronary atherosclerosis.

Aortic valve sclerosis is defined as calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Its frequency increases with age, making it a major geriatric problem. Of adults aged > 65 years, 21-29% exhibit aortic valve sclerosis. Incidence of aortic sclerosis increases with age, male gender, smoking, hypertension, high lipoprotein (Lp) (a), high low-density lipoprotein (LDL), and diabetes mellitus. Aortic valves affected by aortic sclerosis contain a higher amount of oxidized LDL cholesterol and show increased expression of metalloproteinases. Clinically, it can be suspected in the presence of soft ejection systolic murmur at the aortic area, normal split of the second heart sound, and normal volume carotid pulse, but it can be best detected by echocardiography. Aortic sclerosis may be accompanied by mitral annulus calcification up to 50% of cases. It is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction. The mechanism by which aortic sclerosis contributes to or is associated with increased cardiovascular risk is not known. Aortic sclerosis is associated with systemic endothelial dysfunction, and a small percentage of cases may progress to aortic stenosis. Lowering of LDL cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to decrease progression of aortic valve calcification. Aortic sclerosis is not a mere benign finding. Once diagnosis of aortic sclerosis has been made, it should be considered a potential marker of coexisting coronary disease. Aggressive management of modifiable risk factors, especially LDL cholesterol lowering, may slow progression of the disease.

Adult↗
PubMed2004

Magnetic resonance imaging detection of mesial temporal sclerosis in children.

The objective of this study was to investigate the prevalence and clinical characteristics of mesial temporal sclerosis as diagnosed by brain magnetic resonance imaging in children. A total of 390 consecutive brain magnetic resonance imaging studies in children were reviewed for evidence of mesial temporal sclerosis. Subsequently, the magnetic resonance imaging scans and charts of patients with mesial temporal sclerosis were reviewed and their clinical details were evaluated. The magnetic resonance imaging studies had been performed for multiple indications, including seizures, headache, and developmental problems. In children, the prevalence of mesial temporal sclerosis among all brain magnetic resonance imaging studies was 3.1% (12 of 390 studies) and 12.1% (12 of 99 studies) among all brain magnetic resonance imaging studies performed for seizures. These children all presented with a history of seizure disorder, often had other medical problems, and histopathology (when available) nearly always (5 of 6 patients) confirmed their magnetic resonance imaging diagnosis of mesial temporal sclerosis. The prevalence of mesial temporal sclerosis is low among all pediatric patients who had magnetic resonance imaging brain studies. All our mesial temporal sclerosis patients had clinical seizures; i.e., it was never an "incidental finding". Children with mesial temporal sclerosis often had comorbid conditions, and the diagnosis of mesial temporal sclerosis made by magnetic resonance imaging was accurate when compared with the available histopathology.

Child↗
PubMed1991

Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis.

BACKGROUND: Cachectin, or tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response and may be important in the pathogenesis and progression of multiple sclerosis, an inflammatory disease of the central nervous system. METHODS: In a 24-month prospective study, we used a sensitive enzyme-linked immunosorbent assay to determine levels of TNF-alpha in cerebrospinal fluid and serum in 32 patients with chronic progressive multiple sclerosis and in 20 with stable multiple sclerosis and 85 with other neurologic diseases. An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with multiple sclerosis and with their neurologic deterioration during the 24 months of observation. RESULTS: High levels of TNF-alpha were found in the cerebrospinal fluid of 53 percent of the patients with chronic progressive multiple sclerosis and in none of those with stable multiple sclerosis (P less than 0.001). TNF-alpha was detected in the cerebrospinal fluid of 7 percent of the controls (P less than 0.01) with other neurologic disease. In patients with chronic progressive multiple sclerosis, mean TNF-alpha levels were significantly higher in the cerebrospinal fluid than in corresponding serum samples (52.41 vs. 11.88 U per milliliter; range, 2 to 178 vs. 2 to 39; P less than 0.001). In these patients, cerebrospinal fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834, P less than 0.001) and the rate of neurologic deterioration (r = 0.741, P less than 0.001) before the start of the study. Cerebrospinal fluid levels also correlated with the increase in neurologic disability after 24 months of observation (r = 0.873, P less than 0.001). CONCLUSIONS: These data provide evidence of intrathecal synthesis of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease. Our results suggest that TNF-alpha may reflect histologic disease activity in multiple sclerosis and could be used to monitor outcomes or responses to therapy.

Adult↗
PubMed1998

Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis.

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other components of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques and in brain tissue in experimental allergic encephalomyelitis. To measure quantitatively the expression of these MMPs and their endogenous inhibitors (TIMP-1 and -2), we analysed samples from 52 patients with relapsing-remitting and primary progressive multiple sclerosis by ELISA (enzyme-linked immunosorbent assay) and substrate-gel electrophoresis (zymography). MMP-9 was increased over controls in 100% of relapsing-remitting multiple sclerosis cases, with similar levels detected in relapses and clinically stable phases of disease. In primary progressive multiple sclerosis, MMP-9 was increased in 57% of CSF samples, but concentrations were below those encountered in the relapsing-remitting form. The selective upregulation of MMP-9 suggests that T-cells and macrophages invading the brain parenchyma and the CSF space are the predominant source of MMP-9 in multiple sclerosis. TIMPs and other MMPs (MMP-2 and -3) were not upregulated or not detectable (MMP-7) in CSF of patients with relapsing-remitting and primary progressive multiple sclerosis. The sustained increase of MMP-9 in clinically stable multiple sclerosis supports the concept that multiple sclerosis is associated with ongoing proteolysis that may result in progressive tissue damage. The selective inhibition of MMP-9 could be a useful approach for the prevention of disease progression in multiple sclerosis.

Cerebrospinal Fluid↗