[Multiple sclerosis: the new frontier].
Explore the source record for details and available documents.
Brain↗
Biomedical subjects
Christian Confavreux
Publications and source records attributed to Christian Confavreux.
[Etiology of multiple sclerosis].
Multiple sclerosis is an inflammatory disease of the central nervous system responsible for demyelinating lesions within white matter in young adults. The activation of autoreactive CD4+ but also CD8+ T cells directed against myelin antigens of the central nervous system is a key phenomenon at the origin of multiple sclerosis lesions. Its etiology is unknown but implies the existence of genetic traits and a triggering by environmental factors such as viral infections. However, no virus or other environmental factor has been directly involved in the triggering of the disease. Functionnal abnormalities on regulation systems of immunity, such as regulatory T cells, could be partially involved in the triggering of the disease. However, it appears, on the basis of recent findings, that multiple sclerosis is not only a disease of the immune system but also implies specific neurobiological factors which must be determined in studies to come.
Environment↗
[The natural history of multiple sclerosis].
The course of multiple sclerosis (MS) results from the interplay of two clinical processes, relapses and progression. Three main clinical forms may be identified as relapsing-remitting, secondary progressive and primary progressive. The disease appears on average at the age of 30 and follows a remitting or a progressive course in 85% and 15% of the cases, respectively. Initial symptoms are related to an isolated or combined disturbance(s) of the long tracts of the central nervous system, of the brainstem, or of the optic nerve in 70%, 20% and 25% of the cases, respectively. The relapse rate is one relapse on average every other year. After an exacerbating-remitting onset of MS, secondary progression appears after 19 years on average. The median time to reach the landmarks of irreversible disability are 8 years regarding limitation of ambulation, 20 years for walking with a stick, and 30 years for wheel-chair dependency. In fact, MS prognosis is highly variable depending on individuals. All the intermediate types do exist between malignant forms, possibly lethal, and benign forms (circa 30% of the cases) that allow normal daily life. The clinical and paraclinical predictive factors identified so far have been acknowledged statistically. They provide little help however, if any, when an individual is concerned. Recent research has showed that relapses have only a marginal effect, relatively to progression, on the accumulation of irreversible neurological disability. Furthermore, the age when reaching the landmarks of irreversible disability is essentially similar whatever the mode of onset of MS, be it exacerbating-remitting or progressive. In spite of the outstanding clinical polymorphism of MS, a unifying concept of the disease ("complexity vs heterogeneity") can be put forward.
Disease Progression↗
[Multiple sclerosis: positive diagnosis].
The diagnosis of multiple sclerosis (MS) is based on the dissemination in time and space of inflammatory central nervous system episodes. The recently proposed criteria for MS include MRI data as a possible definition of this dissemination. These new criteria make possible a very early diagnosis of MS.
Brain↗
[Contribution of nuclear magnetic resonance imaging in multiple sclerosis].
Conventional MRI has become essential in the field of multiple sclerosis (MS). It reveals brain injury in visualising focal lesions of demyelination of the white matter, damage of the blood-brain barrier, and tissue loss within the lesions. These parameters are now used for an early diagnosis and for assessing the efficacy of new therapies. For years, neuroimaging research groups have been developing MRI techniques to get more sensitive and specific parameters of brain injury. Such techniques provide information on the extent of atrophy (volume, brain thickness), the metabolism (MR spectroscopy), the tissue structure (magnetization transfer and diffusion) and the compensation processes (functional MRI) of the brain. They lead to new approaches for analysing the pathophysiological processes at work in MS and their course in time.
Brain↗
Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.
BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).
Adolescent↗
Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment.
There is convincing evidence that neurological relapses in multiple sclerosis (MS) are the clinical counterpart of acute focal inflammation of the central nervous system (CNS) whereas neurological progression is that of chronic diffuse neurodegeneration. The classical view is to consider that MS is an organ-specific autoimmune disease, i.e. that inflammation is the cause of the neurodegeneration. The succession of relapses eventually leads to accumulation of disability and clinical progression results from subclinical relapses. A series of recent observations tends to challenge this classical concept. Important observations have come from the study of the natural history of MS. In the Lyon MS cohort, accumulation of irreversible disability appeared not to be affected by clinically detectable neurological relapses. This has also been shown to be "amnesic" for the early clinical characteristics of the disease, and essentially age-dependent. Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability. Interferons beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent. Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and cerebral atrophy still progress. The same experience has been reported with cladribine and autologous haematopoietic stem cell transplantation. All these observations give support to the fact that relapses do not essentially influence irreversible disability in the long term in MS. They are consistent with what has been shown at the individual level in the 1970s by performing serial quantitative neurological examinations over several years, and with what is currently emerging from early and serial structural brain MRI studies. These breakthroughs have immediate implications for the counselling of patients with MS. They suggest that MS is as much neurodegenerative as inflammatory, and should cause the modification of disease-modifying therapeutic strategies by focussing on the protection and repair of the nervous system and not only on the control of inflammation.
Disability Evaluation↗
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↗
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↗
Pregnancy and multiple sclerosis: the children of PRIMS.
The influence of pregnancy on multiple sclerosis (MS) has long been a matter of controversy. Women with MS were often discouraged to consider pregnancy. The PRegnancy In Multiple Sclerosis (PRIMS) study was the first large prospective study aimed at assessing the possible influence of pregnancy and delivery on the clinical course of MS. Two hundred and fifty-four women with the diagnosis of MS were included during pregnancy and followed until the end of the second year post partum. The results were a reduction in the relapse rate during pregnancy, in comparison to the year before pregnancy, especially marked in the third trimester, and a significant increase in the relapse rate in the first trimester post partum. Starting in the second trimester post partum, the relapse rate did not significantly differ from the pre-pregnancy rate. About one third of the women experienced a post partum relapse. Pregnancy did not influence disability progression. Women with greater disease activity in the year before and during pregnancy had a higher risk of relapse in the first three months post partum. Neither breastfeeding, nor epidural analgesia correlated with the presence of a post partum relapse. When comparing predicted and observed status, 72% of the women were correctly classified by the multivariate model; it therefore seems unwise to use such a model to select women who would benefit from a putative preventive therapy. The PRIMS study had other major consequences: it fostered the development of specific therapeutic strategies to prevent post partum relapses (i.v. immunoglobulins, i.v. methylprednisolone), and suggested a potential role for sex hormones in the natural history of MS during pregnancy and the post partum. The preventive effect of progesterone combined with estradiol on post partum relapses is about to be tested in a large randomized and placebo-controlled European trial, the POPART'MUS study.
Adult↗
Secondary progressive multiple sclerosis: current knowledge and future challenges.
The secondary progressive phase of multiple sclerosis (MS), which is characterised by a steady accrual of fixed disability after an initial relapsing remitting course, is not clearly understood. Although there is no consensus on the mechanisms underlying such a transition to the progressive phase, epidemiological and neuroimaging studies indicate that it is probably driven by the high prevalence of neurodegenerative compared with inflammatory pathological changes. This notion is lent support by the limited efficacy of available immunomodulating and immunosuppressive treatment strategies, which seems to be further decreased in the late stages of secondary progressive MS. No established clinical or paraclinical predictors of the transition from relapsing remitting to secondary progressive MS have been described. However, the use of quantitative MRI-derived measures is warranted to monitor natural history studies and therapeutic trials of secondary progressive MS with increased reliability. In view of the small effects of immunomodulating and immunosuppressive treatments in preventing the transition to secondary progression, the development of treatments promoting neuroaxonal repair remains an important goal in this disease.
Adjuvants, Immunologic↗
Mismatch negativity (MMN) in multiple sclerosis: an event-related potentials study in 46 patients.
OBJECTIVE: To assess pre-attentive detection mechanisms indexed by MMN component of auditory Event-Related Potentials (ERPs) in Multiple Sclerosis (MS) patients. METHODS: 46 MS patients (mean age 43.7 years, mean disease duration 10.1 years, mean EDSS 4.6) and 46 matched controls were assessed with ERPs elicited by a passive oddball paradigm using duration deviants. Auditory P50, N1, P2 components were recorded. MMN and P3a components were calculated as the difference potential between deviants and standard stimuli. Eighteen of these 46 patients underwent also global psychometrical assessment and were sorted in cognitively normal and impaired patients. ERPs of these two groups of patients were compared. RESULTS: MS patients showed reduced MMN and P3a areas as compared to controls, besides exogenous N1-P2 complex amplitude reduction. Among the 18 patients investigated with neuropsychological testings, six were cognitively impaired and 12 cognitively unimpaired. Patients with a global cognitive impairment had reduced MMN as compared to cognitively unimpaired patients. CONCLUSIONS: Auditory MMN and P3a components of auditory ERPs are altered in MS patients. MMN alterations are more pronounced in cognitively impaired patients. SIGNIFICANCE: MMN and P3a areas reduction suggests that MS patients are prone to pre-attentive auditory information processing deficits, besides previously described controlled information processing difficulties. Moreover, MMN alterations may represent an objective index of cognitive disturbances in MS patients.
Acoustic Stimulation↗
[Hepatitis B vaccination and multiple sclerosis].
Explore the source record for details and available documents.
Hepatitis B Vaccines↗
Steroid hormones in multiple sclerosis.
The possible influence of steroid hormones in multiple sclerosis (MS) has been a matter of great interest. A first illustration comes from the analyses of the influence of gender on susceptibility to MS and on MS severity. A series of arguments emerge in favour of a possible influence of steroid hormones in MS. The menstrual cycle, and even more pregnancy, may influence the clinical evolution of MS. In the PRIMS study, there was a dramatic decrease in the relapse rate during pregnancy, especially in the third trimester, with a rebound increase in the 3 months post partum. Animal studies have provided further confirmatory results. Many experiments have shown that sex steroids may have immunological effects, in preventing or treating experimental allergic encephalomyelitis. They could also have an effect on myelinating and remyelinating the peripheral and possibly the central nervous system. These clinical and experimental data have led to consider sexual steroids as potential therapeutic tools for preventing relapses in women with MS, in particular in the post-partum period.
Animals↗
[Cytoimmunological profile of cerebrospinal fluid in diagnosis of multiple sclerosis].
The purpose of this paper is to report cerebrospinal fluid (CSF) findings in multiple sclerosis (MS) from our laboratory, to discuss the implications of CSF abnormalities in terms of diagnosis. Paired CSF-serum samples from of 1533 on 3893 patients with suspected neurological diseases over a 10 year period were analysed by routine laboratory microscopy and assays of immunoglobulin G by isoelectric focusing for the detection of intrathecal oligoclonal IgG. Patients were grouped further into four headings according to their disorders: MS (625 cases), definite (246 cases) probable (123 cases) and possible (256 cases) according to Poser, others inflammatory neurological diseases (91 cases), various non-inflammatory neurological disorders (732 cases) and uncertain neurological disorders (85 cases). Definite MS group (16%) was compared to non-inflammatory neurological disorders (48%). Important signs for activity of multiple sclerosis are observed. Cell counts were 10/microl in 71% (N < or =2/microl). Inflammatory cytology is observed after concentration and cytocentrifugation on slides with activated B-lymphocytes, lymphoplasmocytes and/or plasmocytes (76%), total protein concentration is increased in 37% (N < 0.40g/l), CSF/serum albumin quotient with age dependent references for the blood-CSF barrier dysfunction is increased in 26% (N < 0.65 x 10(-2)), IgG index for intrathecal synthesis of IgG is increased in 69% (N < 0.70), sensitive detection of oligoclonal IgG restricted to CSF by isoelectric focusing is positive in 91% (86-96%) with a specificity of 96% (93-99%).
Diagnosis, Differential↗
Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages.
Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KDelta75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KDelta75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KDelta75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KDelta75 mice.
Adaptor Proteins, Signal Transducing↗
MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood.
The prognostic factors for relapse of the initial MRI findings after a first episode of acute CNS inflammatory demyelination are unclear in children. In this study we aimed to identify initial MRI factors that are predictive of a second attack and disability after a first episode of acute CNS inflammatory demyelination in childhood. A cohort of 116 children who had a first episode of acute CNS inflammatory demyelination between 1990 and 2002 was studied using survival analysis methods. The initial MRI data were reviewed in a systematic, standardized, double-blind manner. The average follow-up was 4.9 +/- 3 years. Multivariate analysis showed that the rate of second attack was higher in patients with corpus callosum long axis perpendicular lesions (34 out of 116 patients, 30%) on the initial MRI [hazard ratio (HR) 2.89; 95% confidence interval (CI) 1.65-5.06] and/or with the sole presence of well-defined lesions (46 out of 116 patients, 40%) (HR 1.71; 95% CI 1.29-2.27). Both criteria were more specific predictors (100%) of relapse, demonstrating conversion to multiple sclerosis, than the three Barkhof criteria (63%), but were less sensitive (21% compared with 52%). None of the MRI criteria was predictive of severe disability. Using initial MRI and survival analysis methods, we identified two specific predictors of relapse and conversion to multiple sclerosis after a first episode of acute CNS inflammatory demyelination in childhood. Their low sensitivity, however, shows that this prediction remains difficult.
Acute Disease↗