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Sandra Vukusic

Publications and source records attributed to Sandra Vukusic.

17 recordsLinked to original sources
PubMed2006

[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↗
PubMed2006

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↗
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↗
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↗
PubMed2006

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↗
PubMed2006

Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.

OBJECTIVE: We investigated whether neuromyelitis optica (NMO) IgG seropositivity at the initial presentation of longitudinally extensive transverse myelitis (LETM) predicts relapse of myelitis or development of optic neuritis. METHODS: Prospective study of patients with initial LETM who were tested for the presence of NMO-IgG. RESULTS: Eleven of 29 patients (37.9%) were seropositive after a first attack of LETM spanning three or more vertebral segments on magnetic resonance imaging. Of 23 patients followed up for 1 year, none of 14 who were seronegative experienced a relapse or developed optic neuritis. Of 9 seropositive patients, 5 developed a second event: 4 of 9 (44%) developed recurrent transverse myelitis and 1 of 9 (11%) developed optic neuritis (p = 0.004). INTERPRETATION: LETM represents an inaugural or limited form of NMO in a high proportion of patients. The 40% of patients who are seropositive for NMO-IgG are at high risk for relapse.

Adult↗
PubMed2005

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↗
PubMed2005

[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↗
PubMed2004

Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse.

The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimed to assess the possible influence of pregnancy and delivery on the clinical course of multiple sclerosis. We report here the 2-year post-partum follow-up and an analysis of clinical factors which might predict the likelihood of a relapse in the 3 months after delivery. The relapse rate in each trimester up to the end of the second year post-partum was compared with that in the pre-pregnancy year. Clinical predictors of the presence or absence of a post-partum relapse were analysed by logistic regression analysis. Using the best multivariate model, women were classified as having or not having a post-partum relapse predicted, and this was compared with the observed outcome. The results showed that, compared with the pre-pregnancy year, there was a reduction in the relapse rate during pregnancy, most marked in the third trimester, and a marked increase in the first 3 months after delivery. Thereafter, from the second trimester onwards and for the following 21 months, the annualized relapse rate fell slightly but did not differ significantly from the relapse rate recorded in the pre-pregnancy year. Despite the increased risk for the 3 months post-partum, 72% of the women did not experience any relapse during this period. Confirmed disability continued to progress steadily during the study period. Three indices, an increased relapse rate in the pre-pregnancy year, an increased relapse rate during pregnancy and a higher DSS (Kurtzke's Disability Status Scale) score at pregnancy onset, significantly correlated with the occurrence of a post-partum relapse. Neither epidural analgesia nor breast-feeding was predictive. When comparing the predicted and observed status, however, only 72% of the women were correctly classified by the multivariate model. In conclusion, the results for the second year post-partum confirm that the relapse rate remains similar to that of the pre-pregnancy year, after an increase in the first trimester following delivery. Women with greater disease activity in the year before pregnancy and during pregnancy have a higher risk of relapse in the post- partum 3 months. This is, however, not sufficient to identify in advance women with multiple sclerosis who are more likely to relapse, especially for planning therapeutic trials aiming to prevent post-partum relapses.

Adult↗
PubMed2004

European validation of a standardized clinical description of multiple sclerosis.

OBJECTIVES: The EDMUS system is a clinical database specifically tailored to the description of multiple sclerosis (MS). The EVALUED (Evaluation of the EDMUS system) study is an European project with two objectives: 1) to assess the inter-examiner reliability of the whole EDMUS system; 2) to validate the EDMUS-Grading Scale (EGS),which is a simplified version of the Kurtzke Disability Status Scale (DSS). METHODS: The protocol included 12 neurologists working in pairs within six European centres (Bari, Basel, Florence, London, Lyon, Würzburg). They assessed independently 30 MS patients in their centre, filling in the EDMUS forms. The reliability of the system was assessed on selected key items in the history of the MS onset, the clinical course and the disease course classification. The clinical examination of the patients permitted an assessment of the Kurtzke Expanded Disability Status Scale (EDSS) and the EGS. Level of agreement was measured in terms of kappa and weighted kappa indexes whenever appropriate. RESULTS: The study included 180 patients with definite or probable MS of whom 37% were males. Age was 35.8+/-9.6 years (mean +/- SD), disease duration 7.8+/-5.7 years, and mean EDSS score 4.1+/-2.2. The disease course was relapsing-remitting in 67%, secondary progressive in 22%, and progressive from disease onset in 11%. For key items of the history, the inter-examiner reliability level ranged from moderate to excellent. Concerning the disability scales, perfect agreement was reached in 59 % for EDSS and 78% for EGS. The close correlation and linear association (r=0.94, p<0.0001) between both scales demonstrated EGS's construct validity. CONCLUSION: The EDMUS system allows a consistent clinical description of MS using a common language. This standardized follow-up of MS patients is valuable especially in studies requiring a critical mass of informative patients.

Adult↗
PubMed2004

Non-specific immunosuppressants in the treatment of multiple sclerosis.

Immunosuppressants have been proposed as disease-modifying treatments in multiple sclerosis (MS) for almost 40 years, but only one, mitoxantrone, has recently been approved, whereas beta-interferons and glatiramer acetate have been licensed since the mid-90s. Recent therapeutic trials of potent immunosuppressive agents such as Campath-1H, mitoxantrone and cyclophosphamide of MS patients with high relapse rates, rapid accumulation of disability and high degree of MRI activity, have resulted in strong suppression of clinical and MRI inflammatory activity, provided that profound and prolonged lymphopenia was achieved. Clinical experience during the past decades has amply demonstrated that some patients with MS respond to immunosuppressants. The odds ratios of relapsing-remitting MS patients to remain relapse-free after a 2-year period of treatment are similar for Betaseron, Avonex, Rebif, Copaxone, intravenous immunoglobulins or azathioprine compared to placebo. The risk of cancer induction is not significant for up to 10 years of daily usage of azathioprine. Currently available non-specific immunosuppressants are able to control inflammation and reduce relapses in MS, but cannot prevent neurodegeneration and the progression of irreversible disability; specific tools need to be developed for that purpose.

Azathioprine↗
PubMed2003

Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis.

Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.

Disability Evaluation↗
PubMed2003

Primary and secondary progressive multiple sclerosis.

The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS.

Disability Evaluation↗
PubMed2003

Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.

Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan-Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing-remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.

Adolescent↗
PubMed2002

Natural history of multiple sclerosis: implications for counselling and therapy.

Recent advances in our knowledge of the natural history of multiple sclerosis deal with the influence of pregnancy and vaccination, the predictive value of magnetic resonance imaging-based criteria in terms of activity and severity of the disease, and the weighting of the interplay between relapses and clinical progression. These advances have implications for counselling of patients and adjusting the classification of the disease course. Thus multiple sclerosis should be considered to be as much neurodegenerative as inflammatory and disease-modifying therapeutic strategies should be reconsidered by focusing on protection and repair of the nervous system.

Biomarkers↗