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PubMed2002

BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells?

Recent immunohistological and imaging studies emphasize the crucial role of axonal injury in determining the extent of permanent neurological deficits in patients with multiple sclerosis. We have recently shown that human immune cells are capable of producing the neurotrophin brain-derived neurotrophic factor (BDNF), which can prevent axonal and neuronal damage after various pathological insults. BDNF imported into the CNS by immune cells would thus be an attractive candidate for mediating neuroprotective effects in multiple sclerosis. The aim of the present study was to perform a detailed immunohistochemical analysis of the expression of BDNF and its receptor truncated trkB tyrosine kinase receptor (gp145trkB) in a series of multiple sclerosis brain lesions. Our data show that various types of neurones throughout the brain are BDNF immunopositive in multiple sclerosis patients as well as in controls. Furthermore, in multiple sclerosis lesions, BDNF is primarily present in immune cells (T cells, macrophages/microglia) and reactive astrocytes. The number of BDNF immunopositive cells correlates with lesional demyelinating activity. The BDNF receptor gp145trkB is found in neurones in the immediate vicinity of multiple sclerosis plaques as well as in reactive astrocytes within the lesion, but not in immune cells. Our results demonstrate that both BDNF and gp145trkB are expressed in multiple sclerosis lesions. This suggests that BDNF and gp145trkB are involved in immune-mediated neuroprotective interactions in multiple sclerosis, and supports the concept that immune cells produce both damaging and protective factors in multiple sclerosis lesions.

Adult↗
PubMed2002

Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis.

While much work has concentrated on focal white matter (WM) lesions in multiple sclerosis, there is growing evidence to suggest that normal-appearing WM (NAWM) and grey matter (GM) are also involved in the disease process. This study investigated multiple sclerosis disease effects on NAWM and cortical GM (CGM) metabolite concentrations, and the relationships between these metabolite concentrations and clinical impairment. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) data acquired using point resolved spectroscopic (PRESS) localization (echo time 30 ms, repetition time 3000 ms, nominal voxel volume 2.3 ml) from 27 relapsing-remitting multiple sclerosis and 29 normal control (NC) subjects were processed using LCModel to estimate metabolite concentrations in millimoles per litre. (1)H-MRSI voxel tissue contents were estimated using SPM99 tissue and semi-automatic lesion segmentations of three-dimensional fast spoiled gradient recall scans acquired during the same scanning session. NAWM and CGM metabolite concentrations estimated were: choline-containing compounds (Cho); creatine and phosphocreatine (Cr); myo-inositol (Ins); N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (tNAA); and glutamate plus glutamine (Glx). CGM data came from 24 of the multiple sclerosis (mean age 35.2 years, mean disease duration 1.7 years) and 25 of the NC (mean age 34.9 years) subjects. NAWM data came from 25 of the multiple sclerosis (mean age 35.0 years, mean disease duration 1.7 years) and 28 of the NC (mean age 36.7 years) subjects. Metabolite concentrations were compared between multiple sclerosis and NC subjects using multiple (linear) regression models allowing for age, gender, (1)H-MRSI voxel tissue and CSF contents, and brain parenchymal volume. At a significance level of P < 0.05, CGM Cho, CGM and NAWM tNAA, and CGM Glx were all significantly reduced, and NAWM Ins was significantly elevated. Spearman correlations of multiple sclerosis functional composite scores with tissue metabolite concentrations were significant for the following: CGM Cr (r(s) = 0.524, P = 0.009), CGM Glx (r(s) = 0.580, P = 0.003) and NAWM Ins (r(s) = -0.559, P = 0.004). These results indicate that metabolite changes in NAWM and CGM can be detected early in the clinical course of multiple sclerosis, and that some of these changes relate to clinical status. The correlation of clinical impairment with CGM Cr and Glx but not tNAA suggests that it is more closely associated with neuronal metabolic dysfunction rather than loss in clinically early relapsing-remitting multiple sclerosis. The correlation of clinical impairment with a raised NAWM Ins may indicate that glial proliferation also relates to function at this stage of the disease.

Adult↗
PubMed2002

The proteasome is a major autoantigen in multiple sclerosis.

Multiple sclerosis seems to be an autoimmune disease of unknown aetiology affecting the white matter of the CNS. It is generally accepted that the autoimmune response is directed against specific components of myelin. We show here that proteasome, a ubiquitous protease complex composed of 14 different subunits, is a target for autoantibodies (IgG and IgM classes) present in the serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the presence of specific autoantibodies against subunits C2, C8, C9 and C5 in multiple sclerosis patients. Recombinant C2 constructs allow us to localize an immunodominant autoepitope recognized by the sera of multiple sclerosis patients within the C-terminal of C2 proteasomal subunit (251-DEPAEKADEPMEH-263). In addition, two constructs of the recombinant proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood mononuclear cells from multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show positive proliferation with one or both of these recombinant subunits. The high prevalence of anti-proteasome autoantibodies in multiple sclerosis sera compared with sera from patients with other chronic inflammatory conditions: systemic lupus erythematosus (35%, 35 out of 100), primary Sjogren's syndrome (16%, 5 out of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet's disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome could be a useful test in multiple sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease. Finally, these results suggest that some global abnormality in B and/or T cell function is also involved in the chronic inflammatory response observed in multiple sclerosis patients, as it is frequently observed in other human organ-specific autoimmune diseases.

Adult↗
PubMed2003

Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study.

The correlation between conventional MRI lesion load accumulation and multiple sclerosis clinical evolution is only modest. The assessment of brain parenchymal volume and of its changes over time may provide adjunctive MRI markers reflecting the more disabling aspects of multiple sclerosis pathology. Magnetization transfer (MT) MRI is sensitive to 'occult' multiple sclerosis-related brain damage and might also contribute to overcome the clinical/MRI paradox. In this study, we assessed the value of conventional and MT MRI-derived metrics in predicting the medium-term clinical evolution of patients with different multiple sclerosis phenotypes. We studied 73 patients, with relapsing-remitting multiple sclerosis (n = 34), secondary progressive multiple sclerosis (n = 19) and clinically isolated syndromes suggestive of multiple sclerosis (n = 20), and 16 healthy subjects. Brain dual-echo, T1-weighted (only in patients) and MT MRI scans were obtained at baseline and after 12 months. T2-hyperintense and T1-hypointense lesion volumes, normalized brain volume and average lesion MT ratio (MTR) were measured. MTR histograms from the whole brain tissue were also obtained. Clinical multiple sclerosis evolution and neurological disability were re-assessed in all patients after a median follow-up of 4.5 years. A multivariate analysis was performed to establish which clinical and MRI-derived variables were significant predictors of neurological deterioration at the end of the study period. At the end of follow-up, 34 patients showed significant neurological deterioration. The final multivariable model included average brain MTR percentage change after one year [P = 0.02, odds ratio (OR) = 0.86] and baseline T2-hyperintense lesion volume (P = 0.04, OR=1.04) as independent predictors of medium-term disability accumulation (r2 = 0.23). In this cohort of patients, abnormal values of average brain MTR changes showed a relatively high specificity (76.9%) and positive predictive value (59.1%) for Expanded Disability Status Scale score deterioration in individual cases. In patients with multiple sclerosis, a comprehensive estimation of the short-term changes of both conventional and MT MRI-detectable lesion burden might provide useful prognostic information for the medium-term clinical disease evolution.

Adult↗
PubMed2004

Blood T-cell receptor beta chain transcriptome in multiple sclerosis. Characterization of the T cells with altered CDR3 length distribution.

Multiple sclerosis is an inflammatory demyelinating disease of the CNS associated with T cells autoreactive for myelin components. In this study, we analysed the T-cell receptor (TCR) usage of the variable beta (Vbeta) chain transcriptome in the blood of multiple sclerosis patients at various stages of the disease using a global and quantitative comparison of the complementarity-determining region 3 length distribution (CDR3-LD) of transcripts of the 26 Vbeta genes. We investigated 35 patients: 12 with a high risk of multiple sclerosis, 10 with clinically definite multiple sclerosis, 13 with a relapsing-remitting worsening and active multiple sclerosis and 13 healthy individuals. Cells bearing the TCR transcripts with altered CDR3-LD were sorted and studied for CD4 or CD8 phenotype, cytokine transcript accumulation and response to human myelin basic protein (MBP). We show that patients from all the groups have a significantly skewed blood T-cell repertoire. Vbeta transcriptome patterns were more altered in patients from the clinically definite multiple sclerosis group and the worsening and active multiple sclerosis group than in the high risk group. The T cells sorted from Vbeta families with altered CDR3-LD concerned both CD4 and CD8 T cells, with a more pronounced skewing in the CD8 compartment. These cells displayed a significantly increased level of interferon-gamma, interleukin-2 and tumour necrosis factor-alpha transcripts compared with their counterparts from the healthy individual group. Furthermore, using interferon-gamma enzyme-linked immunospot (ELISPOT) assays, T cells from four out of seven altered Vbeta families tested from multiple sclerosis patients responded to human MBP, whereas no response was observed with human albumin or with altered Vbeta families from healthy individuals. Our data support the concept of an early autoimmune component in the disease and emphasize the possible involvement of CD8-positive T cells in multiple sclerosis.

Adult↗
PubMed2006

Age at disability milestones in multiple sclerosis.

Many efforts have been devoted to the description of the prognosis of multiple sclerosis and its possible influential factors in terms of time to reach disability milestones. By contrast, the age at which patients with multiple sclerosis reach these milestones has not yet stirred much interest. We have tested the hypothesis whether the prognosis of multiple sclerosis depends on the current age of patients and the initial course of the disease. We have assessed disease onset and course, and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We have used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: DSS 4 (limited walking but without aid), DSS 6 (walking with unilateral aid) and DSS 7 (wheelchair-bound). We used Kaplan-Meier analyses to estimate the age of the patients at assignment of disability milestones. The possible influence of the initial course of multiple sclerosis and of other clinical variables early assessable in the disease on these outcome measures was also studied, using the Kaplan-Meier curves for univariate analyses and Cox models for multivariate analyses. For the 1844 patients, median ages at time of assignment of irreversible disability were 44.3 years (95% CI 43.3-45.2) for a score of DSS 4, 54.7 years (95% CI 53.5-55.8) for DSS 6 and 63.1 years (95% CI 61.0-65.1) for DSS 7. These results were essentially similar whether the initial course of multiple sclerosis was exacerbating-remitting or progressive, and whatever the initial symptomatology. Females reached disability milestones at an older age than males. The most influential clinical factor was age at clinical onset of multiple sclerosis: the younger the onset, the younger the age at assignment of disability milestones. Therefore, prognosis in multiple sclerosis appears, at least to some extent, as age-dependent and not substantially affected by the initial course, be it exacerbating-remitting or progressive. Aside acute focal recurrent inflammation and diffuse chronic neurodegeneration, accelerated ageing-related mechanisms may operate in the central nervous system of multiple sclerosis patients.

Adult↗
PubMed1999

Relevance of temporal lobe white matter changes in hippocampal sclerosis. Magnetic resonance imaging and histology.

RATIONALE AND OBJECTIVES: To evaluate the diagnostic relevance of ipsilateral atrophy of the collateral white matter in the parahippocampal gyrus (ACWMp) and temporal lobe gray/white matter demarcation loss (GWDL) on magnetic resonance imaging in patients with histologically confirmed hippocampal sclerosis. In the second part of this investigation, histologic specimens were analyzed to find an explanation for GWDL. METHODS: Retrospective visual assessment of hippocampal signal intensity and size and of ACWMp and GWDL was performed using 4- to 5-mm coronal T2-weighted spin-echo magnetic resonance images of 80 patients with histologically proven hippocampal sclerosis and of 30 age-matched controls without epilepsy. Frequency of occurrence and likelihood ratios of ACWMp and GWDL were calculated and their contribution to the diagnosis of hippocampal sclerosis was assessed, particularly in patients with no or restricted hippocampal abnormalities (either high signal or smaller size) on magnetic resonance imaging. The second part of the study involved the morphologic histologic assessment of neocortical temporal lobe specimens of all patients. Myelin density was evaluated in specimens of a subgroup of six patients with hippocampal sclerosis and GWDL on MRI and six patients with hippocampal sclerosis without GWDL. RESULTS: ACWMp was found in 68% and GWDL in 65% of patients with hippocampal sclerosis on magnetic resonance imaging. Both features had an infinite positive likelihood ratio. Sixty-two patients (77.5%) had concomitant hippocampal signal increase and smaller size. Eighteen patients (22.5%) had no or restricted hippocampal abnormalities on magnetic resonance imaging. When using ACWMp and GWDL as additional diagnostic parameters, 13 of these 18 patients were more unambiguously diagnosed as having hippocampal sclerosis. No significant morphologic differences were found between GWDL-positive and GWDL-negative specimens. A significantly lower average myelin stain was found in the white matter of the GWDL-positive group compared to the GWDL-negative group. CONCLUSIONS: ACWMp and GWDL can improve the visual diagnosis of hippocampal sclerosis, particularly in patients with no or restricted hippocampal abnormalities. These results suggest that loss of myelin may be the underlying cause of GWDL in association with hippocampal sclerosis.

Adolescent↗
PubMed1997

Needle EMG of the tongue: motor unit action potential versus peak ratio analysis in limb and bulbar onset amyotrophic lateral sclerosis.

OBJECTIVES: To find out if conventional and automatic needle EMG of the tongue can be helpful in the diagnosis and differentiation of limb and bulbar onset amyotrophic lateral sclerosis. METHODS: Motor unit action potential (MUAP) analysis and peak ratio interference pattern analysis were performed in the right genioglossus muscle of 30 healthy subjects aged 30-81 years, 10 patients aged 49-73 years with limb onset amyotrophic lateral sclerosis, and eight patients aged 52-75 years with bulbar onset amyotrophic lateral sclerosis. Electrical activity was sampled via standard concentric needle electrodes with a commercially available EMG recorder. RESULTS: Normal mean (2SD) MUAP duration was 6.6 (1.5) ms. Normal mean (2SD) MUAP amplitude was 224 (97.4) microV. Normal mean (2SD) peak ratio (PR), turns/second (T/s), amplitude/turn (A/T), and time intervals (TI1, TI2, TI3) were 1.68 (0.56), 732 (303.9), 446 (180.3) microV, 2.62 (0.34), 2.31 (0.14), and 1.01 (0.50) respectively. Mean MUAP duration and amplitude were significantly increased in limb onset (P=0.0001 and P=0.013) and bulbar onset amyotrophic lateral sclerosis (P=0.0001 and P=0.017). Peak ratio indices stayed unchanged in limb onset amyotrophic lateral sclerosis but were significantly decreased (PR, T/s, A/T, TI1, and TI2) or increased (TI3) in bulbar onset disease. The sensitivity of the MUAP analysis was 70% in limb and 75% in bulbar onset amyotrophic lateral sclerosis. The sensitivity of the peak ratio interference pattern analysis was 20% in limb and 100% in bulbar onset amyotrophic lateral sclerosis. Subclinical involvement of the tongue was found in 20% of the patients with limb onset amyotrophic lateral sclerosis and could be more accurately assessed with MUAP analysis than with automatic EMG. CONCLUSIONS: Both conventional and automatic needle EMG of the tongue are valuable electrophysiological devices to assess the clinical and subclinical involvement of the tongue in patients with limb and bulbar onset amyotrophic lateral sclerosis.

Action Potentials↗
PubMed1994

Value of laryngeal cartilage sclerosis as a predictor of outcome in patients with stage T3 glottic cancer treated with radiation therapy.

PURPOSE: To determine whether sclerosis of the laryngeal cartilages was a predictor of a poor outcome in patients with stage T3 glottic cancer treated with radiation therapy. MATERIALS AND METHODS: Thirty-three patients with stage T3 glottic cancer underwent computed tomography (CT) before radiation therapy. Twenty-two patients underwent posttreatment CT. The presence of cartilage sclerosis, cartilage erosion, marrow invasion, and cartilage necrosis was determined. RESULTS: Nineteen of the 33 patients had cartilage sclerosis at CT. Seventeen patients had sclerosis of a single laryngeal cartilage (14 arytenoid, two cricoid, and one thyroid), and two had sclerosis of adjacent laryngeal cartilages (arytenoid and cricoid in both cases). Of the 17 patients with isolated laryngeal cartilage sclerosis, disease was controlled with radiation therapy alone in 15 and with salvage laryngectomy in two. Both patients with cricoid and arytenoid sclerosis died of their original cancer despite undergoing early salvage laryngectomy. Of the 14 patients without sclerosis, eight had no evidence of disease, two died of their disease, and four died of intercurrent disease. CONCLUSION: T3 glottic cancer with isolated laryngeal cartilage sclerosis can be cured with radiation therapy.

Glottis↗
PubMed2001

Definite and suspected multiple sclerosis in children: long-term follow-up and magnetic resonance imaging findings.

Twenty-five children at the ages of 3 to 18 years with an initial diagnosis of acute disseminated encephalomyelitis were followed in the Clinic of Child Neurology for a period of 2 to 8 years. In 10 children, there were data for clinically definite or laboratory-supported definite multiple sclerosis. The other 15 children in our study were considered as having suspected multiple sclerosis. Brain magnetic resonance imaging (MRI) performed in 15 children disclosed multiple hyperintense lesions on T2-weighted imaging in 13 children: 10 with definite multiple sclerosis and 3 with suspected multiple sclerosis. The clinical manifestations did not always correspond to the size and location of the MRI lesions of demyelination. Follow-up revealed normalization of the neurologic examination in 18 patients (72%) and abnormal neurologic findings in 7 patients (28%) (6 children with definite multiple sclerosis and 1 with suspected multiple sclerosis). Magnetic resonance imaging follow-up in children with definite multiple sclerosis disclosed a reduction in the size of the lesions in 3; enlargement or new lesions were established in the other 7 cases, and 2 cases were without clinical signs of new attacks. Correlation was done concerning the findings of the cerebrospinal fluid examination, transcranial magnetic stimulation, evoked potentials, computed tomography, and MRI. The role of MRI for an early diagnosis of multiple sclerosis in children is discussed. The dynamic follow-up of the pathologic changes is of prognostic significance for the course of the disease that could be a definite cessation of the process in acute disseminated encephalomyelitis cases or transition to multiple sclerosis.

Acute Disease↗
PubMed2001

Developing a disease-specific quality of life measure for people with multiple sclerosis.

OBJECTIVES: To develop a patient-completed disease-specific measure of quality of life in multiple sclerosis and to validate the measure in a community-based population of people with multiple sclerosis. METHODS: The items in the scale were selected in focus group sessions of people with multiple sclerosis. The initial scale included 25 items and was tested in subgroups of 150 people from a population register of people with multiple sclerosis in Leeds. Following further developmental phases, a restructured 16-item scale was tested on a random sample of 200 people with multiple sclerosis from the population register, stratified according to disease course. This led to a final eight-item unidimensional scale, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. RESULTS: After initial development a 16-item scale was found to be both reliable and valid. Cronbach's alpha for the 16-item scale was 0.86. The test-retest correlation was 0.74, using a two-week retest interval. However, convergent validity with the General Well Being Index was 0.67 and with the SF-36 Physical Function Scale was 0.68. This suggested that the scale straddled these two concepts and was confirmed by fit of the data to the Rasch measurement model. This revealed the potential for a reduced eight-item version of the scale. The eight-item scale had a closer association to well-being (0.83) than to physical function (0.39), had good internal consistency (0.79) and test-retest reliability (0.85). There were virtually no floor or ceiling effects for the scale. CONCLUSIONS: The study presents a disease-specific measure of quality of life in multiple sclerosis, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. The instrument is brief, easy to use and practical to administer in clinic or as a postal questionnaire. It measures a construct related to well-being, and provides an important adjunct to the measurement of outcome in multiple sclerosis.

Adult↗
PubMed2004

Radiographic evaluation of sclerosis of the third carpal bone associated with exercise and the development of lameness in Standardbred racehorses.

REASONS FOR PERFORMING STUDY: Sclerosis of the third carpal bone is a common radiographic finding in both lame and sound racehorses, but there are no guidelines correlating degree of sclerosis and incidence of lameness. OBJECTIVES: To develop a protocol for describing subchondral bone sclerosis in C3 on dorsoproximal-dorsodistal oblique (DPr-DDiO) radiographs of the carpus and to correlate these changes with exercise history and carpal lameness. METHODS: One hundred and six Standardbreds entering their first year of training (exercise group) and 7 age-matched Standardbreds at pasture (controls) were examined at approximately 3 month intervals over 12-18 months. Examinations consisted of lameness evaluation and carpal radiographs (DPr-DDiO and flexed lateromedial projections). A grading system (very mild, mild, moderate and severe) for C3 sclerosis seen on the DPr-DDiO radiograph was developed that utilised a combination of the criteria of trabecular thickening (trabecular score; TS) and total percent area of the C3 radial facet affected (TAA). RESULTS: Exercise group horses showed significant increase in TS and TAA throughout training compared to control horses. Middle carpal joint lameness developed in 32/106 (30%) exercise group horses and none of the control horses. Incidence of middle carpal joint (MCJ) lameness was lower in horses with mild (2/30, 6.7%) than moderate (10/32, 31.2%) and severe (20/44, 45.4%) sclerosis throughout training. CONCLUSIONS: Horses with higher grades of sclerosis, as defined by this novel grading system, were more likely to develop MCJ lameness at some point of training. The proposed grading system gave a quantitative assessment of radiographic sclerosis that could then be used to correlate increasing severity of sclerosis with increasing incidences of lameness. POTENTIAL RELEVANCE: These results serve as a basis for further investigation into determining the degree of C3 sclerosis at which pathological changes and lameness can be expected.

Animals↗
PubMed1976

[Multiple sclerosis with reduced and with normal levels of complement in the blood. Clinical and genetic correlation].

The authors describe the results of immunological assay of complement factors C3, C4 (the usual path of activation of complement) and of B factor (the alternate path of activation) in 61 multiple sclerosis patients not receiving corticoids, 52 normal controls and 217 patients with other neurological disorders. Hypocomplementaemia (fall in factor C3 related to a fall in total haemolytic activity) was found in 29.5 p. 100 of the patients not on corticotherapy at the first assay, and in 36 p. 100 of the patients when repeated assays were carried out. Hypocomplementaemia is significantly more frequent in multiple sclerosis than in the normal population (0 p. 100) and in neurological patients (9.6 p. 100). In 13.1 p. 100 of the multiple sclerosis patients there was a decrease in B factor: 50.3 p. 100 of the multiple sclerosis patients exhibited no quantitative abnormality of the main factors of complement (normocomplementary multiple sclerosis). The group of multiple sclerosis patients with hypocomplementaemia was characterized by the incidence of other abnormalities in the complement system: cleavage of the C3 factor and a fall in B factor in 60 p. 100 of the cases. A more frequent increase in IgE and measles antibodies was found also while the normocomplementary multiple sclerosis patients more frequently had higher levels of IgA. Genetically, the group with hypocomplementaemia is related to a significant increase in the incidence of the HL-A W18 group while the normocomplementary multiple sclerosis patients appear closely related to the HL-A7 group. Familial investigations show that hypocomplementaemia is usually present in the ascendents and collaterals and that it seems to be transmitted with the HL-A haplotypes. Four families gave evidence of transmission with the W18 group. This transmission sometimes occurs together with transmission of an increase in IgE and/or of measles antibodies. In two pedigrees, one of the ascendents carried in his serum an activator of the alternate path of complement. There does not appear to be any prognostic difference between the two groups. In multiple sclerosis with hypocomplementaemia, the facts suggest a complex immunological abnormality, transmitted genetically to the subject and existing prior to the illness, comprising both elements of deficient and excessive immune response. The recognized presence of a gene of immunological reactivity and of genes of synthesis of complement on the 6th chromosome, in proximity with genes of histocompatability (HL-A and M.L.C.) provides a theoretical basis for this supposition.

Adult↗
PubMedDate not supplied

A molecular genetic approach to amyotrophic lateral sclerosis.

Disorders of the motor neurons may affect both the upper and lower neurons, primarily the lower motor neurons as in the spinal muscular atrophies are primarily the upper motor neurons as in the familial spastic paraplegias. Amyotrophic lateral sclerosis is a degenerative disorder of the motor neuron that results in paralysis and wasting of voluntary muscles. Large motor neurons in the cerebral cortex, brain stem and spinal cord degenerate or are lost. Hyaline inclusions may be seen in the cytoplasm of surviving motor neurons. Acute axonal degeneration of peripheral motor fibers occurs at all levels, including the distal axon. Subclinical involvement of the spinecerebellar tracts, posterior column and Clarke's column as well as loss of large neurons in the dorsal root ganglia and neurons of oculomotor nuclei has been reported. The average duration of life onset of symptoms of amyotrophic lateral sclerosis is three years and ninety per cent of patients died within 5 years. The basic mechanism of disease in amyotrophic lateral sclerosis remains unknown. There is no known treatment that will prevent, reverse or otherwise alter the course of the disease. Autosomal dominant and autosomal recessive forms of amyotrophic lateral sclerosis are genetic models of amyotrophic lateral sclerosis which may provide insight into the disease mechanism of sporadic amyotrophic lateral sclerosis, five to ten percent of adult cases of amyotrophic lateral sclerosis with early onset of symptoms and a more benign course. It is conceivable that both genetic and sporadic forms of amyotrophic lateral sclerosis result from failure of the same or similar neuronal mechanism triggered by defective genes and by an environment agent in sporadic amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed2006

[Clinic and pathology of the knee menisci injury with sclerosis denaturalization].

OBJECTIVE: To summarize the characteristics of clinic and pathology of the knee menisci injury with sclerosis denaturalization and to discuss the mechanism of the sclerosis and its clinic significance. METHODS: We retrospectively analyzed the diagnosis and treatment and healing of the knee menisci with the sclerosis denatured injury from 1989 to 2003. The changes of the partial meniscus with sclerosis denaturalization were observed in tissue section. RESULTS: Menisci with sclerosis denaturalization occupied 24.1%, and 77.6% of them subordinated to simple sclerosis denaturalization without tear. Their characteristics were that the manifestations were not except typical knee pain, tenderness at joint line,integrity shape with dull or less lubricity and tiny grand on the super face of menisci under the arthroscopy,and trembles could be touched by a probe. Pathology showed the formation of local sclerosis with the histological changes of fibro-hyperplasia, hyaline degeneration and mucous degeneration in the menisci. No operation obtained curative effects. Symptoms can be eliminated by the excision of the menisci with sclerosis denaturalization. CONCLUSION: The clinic of simple meniscus injury with sclerosis denaturalization are non-typical and arthroscopic check-up is valuable for the diagnosis. The menisci can be removed from the patients suffered from heavy symptoms for a long time.

Adolescent↗
PubMed1995

Fast spin-echo MR in hippocampal sclerosis: correlation with pathology and surgery.

PURPOSE: To identify the extent of hippocampal sclerosis in temporal lobe epilepsy with fast spin-echo MR and correlate it with histopathologic findings and surgical outcome. METHODS: MR images of 30 patients with temporal lobe epilepsy and pathologically proved hippocampal sclerosis and 30 control subjects were obtained using a fast spin-echo technique with 4000/100/4 (repetition time/echo time/excitations), 16 echo train, 2- to 3-mm section thickness with interleave, 256 x 256 matrix, and 18-cm field of view. Criteria for MR diagnosis of hippocampal sclerosis included hippocampal atrophy diagnosed with MR volumetry and/or T2-weighted signal change. Hippocampal sectional areas were plotted, and T2 signal changes were topographically evaluated to identify the extent of hippocampal sclerosis, which was subsequently correlated with histopathologic findings and surgical outcome. RESULTS: Hippocampal sclerosis was diffuse, involving both hippocampal head and body, in 96.7% of patients (29 of 30 patients). One patient had normal MR findings. Focal hippocampal sclerosis was not seen. Histopathologic findings of hippocampal sclerosis were present in all 29 patients who had abnormal MR findings. Eighty-six percent of patients (18 of 21 patients), who were followed for at least 1 year after temporal lobectomy, were seizure free (81%, 17 of 21 patients) or significantly improved (5%, 1 of 21 patients). CONCLUSION: Fast spin-echo MR enables accurate definition of the extent of hippocampal sclerosis in patients with temporal lobe epilepsy. All cases of hippocampal sclerosis identified in this study involved the hippocampus diffusely. However, leaving the posterior portion of the hippocampus during surgery does not seem to be a major factor influencing surgical outcome.

Adolescent↗
PubMed1994

[Multiple sclerosis with negative cerebrospinal fluid. Magnetic resonance differential diagnosis].

This study was aimed at investigating the value of MRI in the diagnosis of multiple sclerosis. In the Multiple Sclerosis Center of our University, we sorted out of the patients submitted to CSF and MR examinations, only those with clinically unquestionable multiple sclerosis, white matter abnormalities at MRI and normal CSF examination. These 21 patients were submitted to CSF and MRI examinations which were repeated whenever required if image quality was technically suboptimal; a variety of screening tests for different diseases mimicking multiple sclerosis were also performed. In 4 patients with white matter abnormalities at MRI which were considered atypical for multiple sclerosis, at image rereading and after laboratory tests the diagnosis were: coagulopathy, sarcoidosis, vasculitis and CNS lymphoma. In 2 cases with questionable white matter abnormalities at MRI, the final diagnosis were borreliosis and vasculitis. The remaining 15 patients had a diagnosis of multiple sclerosis in all but 3 cases in which subsequent clinical and laboratory examinations demonstrated the presence of vasculitis, embolism from interatrial septal aneurysm and mitochondrial disease. Our study suggests that in the patients with clinical findings of multiple sclerosis and disseminated MR lesions mimicking multiple sclerosis, but no CSF abnormalities, the classical clinical criteria may not be sufficiently specific and other diagnoses must therefore be excluded before making an "unquestionable" diagnosis of multiple sclerosis.

Blood Coagulation Disorders↗
PubMed2006

Natural history of multiple sclerosis: a unifying concept.

Multiple sclerosis can follow very different patterns of evolution and variable rates of disability accumulation. This raises the issue whether it represents one or several distinct diseases. We assessed demographic and clinical characteristics in 1844 patients with multiple sclerosis that we categorized according to the classification of Lublin and Reingold (1996) into 1066 (58%) relapsing-remitting, 496 (27%) secondary progressive, 109 (6%) progressive relapsing and 173 (9%) primary progressive cases of multiple sclerosis. Relapsing-remitting and secondary progressive cases shared similar age at disease onset (median = 28.7 versus 29.5 years; P = 0.21), initial symptoms of the relapsing-remitting phase, degree of recovery from the first neurological episode, and time from the first to the second episode. By contrast, disease duration was twice as long in secondary progressive than in relapsing-remitting cases (mean +/- SD = 17.6 +/- 9.6 versus 8.7 +/- 8.6 years; P < 0.001). Progressive relapsing and primary progressive cases were essentially similar in their clinical characteristics. In patients experiencing a progressive course, median age at onset of progressive phase was similar in secondary progressive cases and in cases who were progressive from onset (39.1 versus 40.1 years; P = 0.47). The proportion of cases with superimposed relapses during progression was approximately 40% in both categories. Finally, the 1562 patients with an exacerbating-remitting initial course and the 282 patients with a progressive initial course of the disease were essentially similar with respect to the time course of disability accumulation from assignment to a given disability score, and the age at assignment of disability landmarks. These observational data suggest that the clinical phenotype and course of multiple sclerosis are age dependent. Relapsing-remitting disease can be regarded as multiple sclerosis in which insufficient time has elapsed for the conversion to secondary progression; secondary progressive forms as relapsing-remitting multiple sclerosis that has 'grown older'; and progressive from onset cases as multiple sclerosis 'amputated' from the usual preceding relapsing-remitting phase. Times to reach disability milestones, and ages at which these landmarks are reached, follow a predefined schedule not obviously influenced by relapses, whenever they may occur, or by the initial course of the disease, whatever its phenotype. This leads to a unifying concept of the disease in which primary and secondary progression might be regarded as essentially similar. From the clinical and statistical positions, multiple sclerosis might be considered as one disease with different clinical phenotypes rather than an entity encompassing several distinct diseases-the position of complexity rather than true heterogeneity.

Adult↗