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PubMed2007

Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis.

The occurrence of multiple sclerosis (MS) in subjects clustering to a particular mitochondrial DNA (mtDNA) haplogroup/haplotype or carrying mtDNA mutations associated with Leber's hereditary optic neuropathy (LHON) has suggested that mitochondrial genome may contribute to susceptibility to MS. In the present study, 58 unrelated Bulgarian patients with relapsing remitting form of MS and 104 randomly selected healthy individuals were analysed for the presence of 14 mtDNA polymorphisms determining major European haplogroups as well as three (4216, 14 798, 13 708) secondary LHON mutations. Restriction enzyme analysis used to screen patients and controls for the common haplogroup-associated polymorphisms showed that each of these changes was present in MS patients at a similar frequency to control subjects. However, 21 of the 58 patients (36.2%) were positive for T4 216C mutation, while only 11.3% of the controls carried this secondary LHON base change (P < 0.01; OR = 4.38). Our finding indicated that 4216C base substitution could be considered as a predisposing marker for MS and supported the hypothesis that particular mtDNA variants could contribute to genetic susceptibility of MS, and merits further investigation.

Adult↗

PubMed2004

Role of magnetic resonance imaging within diagnostic criteria for multiple sclerosis.

The diagnosis of multiple sclerosis (MS) has been improved in recent decades with the incorporation of paraclinical investigations in diagnostic workup. In the last 15 years, magnetic resonance imaging (MRI) has become an especially valuable tool for supporting MS diagnosis, and specific imaging criteria became fundamental to the guidelines for the diagnosis of MS published in 2001 by an international panel (IP). The new IP criteria include MRI evidence of dissemination in space and time, making it possible to diagnose MS after a single clinical episode. This review considers current evidence concerning the reliability of the new IP criteria for the diagnosis of relapsing-onset MS, discusses strengths and weaknesses of the criteria, and outlines areas which may need modification or should be the focus of future research directed toward improving diagnostic accuracy. It also makes practical recommendations when using MRI and the IP criteria in MS diagnosis, especially in patients with clinically isolated syndromes or atypical presentations. The IP criteria are timely and concrete and introduce an important concept to MS diagnosis. Future modifications, based on emerging evidence, should further facilitate their implementation and improve their accuracy.

Humans↗

PubMedDate not supplied

New insights into the genetics of multiple sclerosis.

Tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develop in genetically susceptible individuals after exposure to a causal agent that is yet undefined. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.

Female↗

PubMed1998

Molecular approach to find target(s) for oligoclonal bands in multiple sclerosis.

OBJECTIVES: Oligoclonal bands are a characteristic finding in the CSF of patients with multiple sclerosis, yet their target antigen(s) remain unknown. The objective was to determine whether a filamentous phage peptide library could be employed to allow the oligoclonal bands to select their own target epitopes. METHODS: CSF IgG antibody from 14 patients with multiple sclerosis and 14 controls was used to select individual phage clones from a bacteriophage library containing approximately 4 x 10(7) different hexamers expressed on its surface pIII protein. The amino acid sequence selected was deduced by sequencing the DNA of the genetically engineered insert. RESULTS: In general, after three rounds of selection, CSF from both patients with multiple sclerosis and controls selected one to two consistent peptide motifs. Five out of 14 patients with multiple sclerosis, and one control, selected the amino acid sequence motif, RRPFF. Given 20 possible amino acids per position, the likelihood of five patients selecting the same linear five amino acid sequence is at most 1.6 x 10(-3), corrected for the number of clones sequenced. A GenBank computer search showed that this sequence is found in the Epstein-Barr Virus nuclear antigen (EBNA-1), and a heat shock protein alphaB crystallin. Human serum antibodies to a synthetic peptide containing RRPFF were virtually exclusively found in patients with prior infection by Epstein-Barr virus. Other studies have suggested a relation between Epstein-Barr virus infection and multiple sclerosis, including nearly 100% Epstein-Barr virus seropositivity among patients with multiple sclerosis and increased concentrations of antibody to EBNA in CSF of patients with multiple sclerosis. By antigen specific immunoblotting, antibodies to the RRPFF motif in the CSF were shown to correspond to a subset of oligoclonal bands in the CSF from the same patient. CONCLUSION: This study shows that phage epitope display libraries may be used to select amino acid motifs which are potentially relevant to the pathogenesis of multiple sclerosis.

Amino Acid Sequence↗

PubMed2005

Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis.

Malignant forms of multiple sclerosis (MS) represent a limited group of very aggressive demyelinating diseases, which rapidly progress to severe disability leading often to life-threatening conditions. On these clinical entities, currently available therapies for MS are not very effective. Recently, it has been demonstrated that intense immunosuppression followed by autologous stem cell transplantation (ASCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by magnetic resonance imaging (MRI). We report on the treatment with intense immune ablation followed by ASCT of three patients with malignant MS whose clinical course indicated a dramatically poor prognosis. This procedure succeeded in halting the rapidly worsening course of disease. The effect was long lasting, as demonstrated by a sustained efficacy over a two-year period in two subjects and 12 months in the third case. In addition, a striking effect on inflammation-related MRI findings was obtained. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving malignant MS cases unresponsive to conventional therapies.

Adolescent↗

PubMed1985

Response to platelet-activating factor of platelets from patients with multiple sclerosis.

The response of Multiple Sclerosis (MS) and control platelets to different concentrations of platelet-activating factor was studied. At concentrations in the range 10(-7) to 10(-5)M, it was found that the MS platelets tended to aggregate fully at lower concentrations than was the case with control platelets. At a concentration of 10(-6)M, it was found that in 19 cases the MS platelets gave a full aggregation response whilst 4 cases showed biphasic but full aggregation, whereas at this concentration the control platelets showed full aggregation in only 2 cases, biphasic but less complete aggregation in 5 cases and reversible aggregation in 16 cases. In crossover studies, it could be shown that MS platelets resuspended in control platelet-poor plasma still showed enhanced aggregability and that the response of control platelets was unaffected by resuspension in MS platelet-poor plasma. Differences were also seen in susceptibility of platelets of MS and control subjects to inhibition by indomethacin, bromophenacyl bromide (a phospholipase inhibitor) and verapamil (a Ca2+ antagonist). It is suggested that the hyperaggregability of the MS platelets could reside in the platelets themselves, and may be associated with enhanced phospholipase activity.

Acetophenones↗

PubMed2003

CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, thought to be mediated in part by an autoimmune response of T cells to protein components of the myelin sheath. The reaction of naïve T cells against these antigens requires co-stimulation through CD28. However, the proliferative response of peripheral blood mononuclear cells isolated from patients with MS and stimulated with myelin basic protein (MBP) has been shown to be relatively independent of B7-CD28 co-stimulation, suggesting that dysregulation of co-stimulatory pathways may be involved in the pathogenesis of MS. Here, the role of CTLA-4 engagement was investigated. As expected, blocking CTLA-4-mediated signaling during stimulation of MBP-reactive T cells from healthy controls enhanced the proliferative and cytokine responses. In contrast, CTLA-4 blockade had less effect in patients with MS, suggesting that at least two regulatory mechanisms may be impaired in these individuals. Understanding how co-stimulatory signals may be dysregulated in patients with MS is important at a time when targeting of these pathways is being developed.

Adult↗

PubMedDate not supplied

[Approach to quality of life changes in patients with multiple sclerosis].

INTRODUCTION AND OBJECTIVES: Multiple sclerosis (MS), as a chronic, incurable and often severely disabling disease, greatly affects patients normal life. The objectives of the study are to analyze which aspects of daily life are more affected by the disability and to investigate whether the degree of support demanded by patients is related to their level of incapacity. PATIENTS AND METHODS: Group of 60 ambulatory patients with Poser defined MS, mean age of 44.5 years, Expanded Disability Status Scale (EDSS) of 3.1, and average period of disease evolution 13.2 years. Test instrument was a structured 12 items questionnaire given during a visit to the attending physician and regarding social and family aspects, financial needs, professional life and emotional well being. RESULTS: 58.3% of the professionally active patients had to give up their jobs; 8.3% experienced changes in their marital status and general family life somewhat changed in 41.7% of the cases due to either physical or psychical disease consequences. Social relationships were altered in 68.2% of the cases; 43.3% required some level of economical support, and 80% went through episodes of emotional distress. CONCLUSION: Statistically significant relationships exist between level of incapacity and professional and social life changes but not with family life changes, emotional alterations and level of support required.

Adult↗

PubMed1996

Disturbances of ano-rectal function in multiple sclerosis.

Thirty patients with multiple sclerosis (MS) [18 men and 12 women, mean age 40 years (range 22-50), disease duration 12 years (range 0.5-34), Kurtzke's Expanded Disability Status Score 6.0 (range 4.0-7.5)] were interviewed about bowel symptoms and studied using ano-rectal manometry. The results were compared with findings in healthy controls. Twenty-eight had bowel symptoms: 8 constipation, 10 constipation and infrequent faecal urgency, 4 infrequent faecal incontinence and 6 frequent faecal incontinence. Anal sphincter pressure at rest was significantly reduced in MS patients 69 (SD 17) cm H2O, compared with 92 (SD 15) cm H2O in controls, and the external sphincter contraction force was also significantly reduced. Rectal sensation and rectal compliance were reduced and the ano-rectal inhibition reflex (defaecation reflex) required a higher rectal pressure to be elicited in the patients. Upon rectal filling, an early external sphincter excitation was seen. The presence of faecal incontinence correlated strongly with reduced rectal sensation. The findings suggest that faecal incontinence can at least partly be explained by low anal sphincter pressure and poor rectal sensation. The findings of early sphincter excitation and increased threshold of ano-rectal inhibition reflex may be an important pathophysiological factor for constipation in MS patients.

Adult↗

PubMed2004

Human herpesvirus type 6 and multiple sclerosis.

The aetiology of multiple sclerosis (MS) is unknown, but is probably the result of an interaction between predisposing genetic and environmental factors. The potential role of an infectious agent in MS aetiology stems from evidence of a geographical risk component, with disease being more prevalent in temperate regions. Also, several epidemics of MS have been recorded, suggesting a transmittable element to the disease. Although no one particular virus has been implicated as a causative factor, several herpesviruses have been incriminated due to their neurotropism, ubiquitous nature and ability to establish latency. The majority of evidence supporting a link between MS and human herpesvirus-6 (HHV-6) comes from case control studies comparing the presence of HHV-6 in brain tissue, cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) in patients with and without MS. HHV-6 was detected in a high proportion of individuals without MS, indicating that HHV-6 polymerase chain reaction (PCR) positivity in itself is not sufficient for its causality in the development of MS. Studies of the association between HHV-6 and MS have been contradictory and the International Herpes Management Forum (IHMF) recommends that any future studies should use validated, sensitive methods and that masked samples should undergo independent analyses. If therapy trials are indicated, it is recommended that drugs with improved activity against HHV-6 are evaluated.

Herpesvirus 6, Human↗

PubMed2005

The effect of changed visual feedback on intention tremor in multiple sclerosis.

In patients with multiple sclerosis (MS), intention tremor amplitude is enhanced during the visually guided compared to the memory guided motor tasks. In the present study, the effect of visual feedback on intention tremor was investigated during visually guided wrist step-tracking tasks. Specifically, visual feedback of the hand was provided either instantly or averaged over different time windows. Thirteen MS patients with intention tremor and 14 healthy controls performed the wrist step-tracking task, while the visual representation of the actual hand position was displayed instantly or averaged over time windows of 150, 250 and 350 ms. It has been found in the patient group that, in association with a decreased initial error and decreased tremor amplitude on the screen, the amplitude of the actual performed tremor also decreased when visual feedback was changed. The tremor reduction was not different between conditions with manipulated feedback, although delays in presenting visual feedback of the hand position increased when the time window was larger. The reduction in overall tremor amplitude was unlikely related to other factors, such as eye fixation deficits or the speed of the primary hand movement. These results suggest that hand tremor severity is dependent on the visual feedback of position and movement errors.

Adult↗

PubMed2006

The effects of reward and punishment contingencies on decision-making in multiple sclerosis.

Many patients with multiple sclerosis (MS) show cognitive and emotional disorders. The purpose of this study is to evaluate the role of contingency learning in decision-making in young, non-depressed, highly functioning patients with MS (n=21) and in matched healthy controls (n=30). Executive functions, attention, short-term memory, speed of information processing, and selection and retrieval of linguistic material were also investigated. Contingency learning based on the cumulative effect of reward and punishment was assessed using the Iowa Gambling Test (IGT). In the classic ABCD version of the IGT, advantageous decks are characterized by immediate small reward but even smaller future punishment. In the modified EFGH version, advantageous decks are characterized by immediate large punishment but even larger future reward. Results revealed that patients with MS showed significant dysfunctions in both versions of the IGT. Performances on neuropsychological tests sensitive to dorsolateral prefrontal functions did not predict and did not correlate with the IGT scores. These results suggest that patients with MS show impaired performances on tasks designed to assess decision-making in a situation requiring the evaluation of long-term outcomes regardless of gain or loss, and that this deficit is not a pure consequence of executive dysfunctions.

Adult↗

PubMed2006

The prognostic value of initial relapses on the evolution of disability in patients with relapsing-remitting multiple sclerosis.

The evolution of multiple sclerosis (MS) and the resulting disability are unpredictable. To identify clinical variables that could be potential prognostic factors, we followed a cohort of 288 patients diagnosed as having relapsing-remitting MS between 1990 and 2003. The end point was the first occurrence of a non-reversible EDMUS-GS score >or=3 (moderate disability). The impact of the number of MS attacks during the first 2 years of the disease as well as the first interattack interval were assessed in two Cox models, one using a fixed-in-time covariate, the other using a time-dependent covariate. Older age at onset and a higher number of MS attacks during the first 2 years of MS proved to be predictors of unfavourable prognosis. The first interattack interval had no influence on the evolution of the disability, conversely to the first relapse which had a short-term impact on the prognosis. We confirmed that the age at onset and the number of MS attacks during the first 2 years of MS are predictors of the evolution of the disability and demonstrated the importance of using time-dependent covariates.

Adolescent↗

PubMed2000

Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis.

Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.

Animals↗

PubMed1985

Auditory brainstem responses (ABR) in multiple sclerosis.

Thirty-two multiple sclerosis (MS) patients, 10 males and 22 females, aged between 21 and 55, underwent pure-tone audiometry and testing of auditory brainstem response (ABR). Thirteen were classified as 'definite', 12 as 'probable' and 7 as 'possible', according to the McAlpine criteria. Each ear of each patient was tested monoaurally. The most common alterations were seen in the parameters of the cross-correlation between the normal template and the template of the individual MS patient. The second most altered parameters were those concerning the V wave which was absent in most cases but, when present, rarely showed latency-amplitude values falling outside the 90% confidence limit ellipses. Test-retest replicability and stimulations with increasing numbers of stimuli per second were useful in detecting intra-individual variability of waveform characteristics. When considering all the tests performed, 88% of the 'definite', 71% of 'probable' and 64% of 'possible' MS patients' ears showed ABR abnormalities. We stress the importance of a separate evaluation of the two ears due to the frequent unilateral alterations, and of an accurate evaluation of the ABR characteristics. We conclude that brainstem audiometry is a more reliable test for detecting demyelinating processes than is usually described in the literature.

Adult↗

PubMed1992

Treatment of multiple sclerosis with mitoxantrone.

Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.

Adult↗

PubMed2004

Disappearing "T1 black holes" in an animal model of multiple sclerosis.

Brain MRI in multiple sclerosis (MS) frequently shows areas of hypointensity in the white matter on T1 weighted sequences ("T1 black holes"). These areas are thought to be consistent with irreversible axonal loss. In this study T1 black holes were characterized in Theiler's Murine Encephalitis Virus infection, an established model of demyelinating diseases in mice. The spectrum of TMEV is broad in different strains. C57BL/6J mice develop a self-limited brain disease, which resolves within 4-6 weeks. We followed six mice with serial MRI and MRS on days 0, 3,7,21 and 45. The studies were performed in a 7 Tesla magnet. Periventricular and parahippocampal T1 black holes seen as early as 3 days, with decreasing NAA/Cre ratio on MRS. The extent of pathology was most severe on days 3 and 7. T1 black holes are thought to be consistent with areas of irreversible axonal loss. This is challenged by our observations of resolution of T1 black holes by day 45. This was concomitant with the normalization of MRS findings in the areas of interest. We conclude that T1 black holes may represent a transient phenomenon in this model of MS. The recovery of these areas studied suggests an active repair mechanism.

Animals↗

PubMed1987

Red cell and hemorheological changes in multiple sclerosis.

Blood rheology in multiple sclerosis (MS) was investigated in 15 subjects with varying degrees of locomotor difficulties who were members of the local MS Society. Control data were obtained from blood samples from 25 male and 25 female normal blood donors. Whole blood viscosity was measured and blood filterability was assessed. Six MS females provided blood samples for scanning electron microscopy. Erythrocyte membrane fatty acids and phospholipids were assayed. Whole blood viscosity in MS females was higher than controls at 3 of 4 shear rates (p less than 0.001) but in MS males blood viscosity was higher only at shear rate of 1.0 s-1 (p less than 0.05). MS erythrocyte filtration rates were significantly lower than controls (p less than 0.001). Leucocyte counts in MS were greater than controls both in males (p less than 0.01) and females (p less than 0.001). MS erythrocyte morphology was greatly different from controls (p less than 0.0001) and erythrocyte membranes contained less sphingomyelin than controls (p less than 0.01) but more phosphatidylinositol plus phosphatidylserine (p less than 0.02). We conclude that, because our findings indicate an identifiable and potentially correctable abnormality, it is possible to envisage an inhibition of the progressive nature of MS, with the hope of a better prognosis for patients.

Adult↗