The natural history of multiple sclerosis

Studies which have attempted to define the outcome of multiple sclerosis (MS) have methodologic difficulties arising from patient referral biases and the length of follow-up required, which make prospective studies of an inception cohort unrealistic. Means to improve the validity of retrospective natural history studies are suggested. Results of existing series are summarized and compared. Survival is only rarely shortened by MS, but disability to the point of requiring aids for ambulation occurs in 30-70% of patients by 15 years from onset of symptoms. Disagreement as to the percentage of patients who are ultimately bedridden by MS likely arises in large part due to differences in patient ascertainment and follow-up. The need to develop early clinical markers for the patient at high risk for rapid development of major disability is stressed.     

The natural history of multiple sclerosis

The natural history of chronic diseases is generally poorly understood. Multiple sclerosis os one of the best-studied diseases and we outline here some of the information obtained from 25 000 patient-years of observation. This population-based cohort received almost no treatment and certainly none known to alter the long-term natural course of the illness. There is a possibility that such data will prove useful in new generation clinical trials which are observational in nature.     

Genetics and natural history of multiple sclerosis

Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.     

Contrast-enhanced magnetic resonance activity in relapsing remitting multiple sclerosis patients: a short term natural history study

Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual RRMS patient.     

The natural history of relapses in multiple sclerosis

Relapses are a defining feature of multiple sclerosis (MS), serving as the basis for categorizing the different phases of the disease, and providing a means of measuring treatment success, following disease activity, and defining prognostic features. While the dissociation between relapses and disease progression indicates the boundaries of relapse history in determining disease course over time, it also highlights the importance of relapses to overall disease evolution. A broad understanding of relapse definition and dynamics is important to promote accurate diagnosis, patient management, and treatment decisions. In an attempt to describe the underlying etiology and clinical impact of relapses in MS, this review will examine relapse findings from natural history studies, the utility of relapse as a predictor of disease course, the factors that may contribute to relapse, and data on relapse resolution. The relationship of clinical relapses to MRI disease activity and to the onset of progressive disease will also be addressed.     

The natural history of multiple sclerosis with childhood onset

Multiple sclerosis with childhood onset has been extensively studied recently, increasing the knowledge of the characteristics and long-term evolution of the disease in this age group. It is a rare condition accounting for less than 5% of all cases with multiple sclerosis. Exacerbating-remitting forms are, by far, the most common presentation at onset. The evolution to the secondary progressive phase as well as the assignment to irreversible disability landmarks take longer in patients with childhood onset compared with patients with adult onset, as shown in the KIDMUS study. However, patients with childhood onset reach these different critical phases of the disease at a younger age than patients with adult onset, therefore contradicting the notion of a more favorable prognosis in this age group. With respect to the pathophysiology of the disease, age at onset probably influences mainly the clinical phenotype of multiple sclerosis but not the underlying biological process, suggesting a similar pathophysiology of the disease whatever age at onset.     

Cyclophosphamide in relapsing remitting multiple sclerosis

7 patients with relapsing-remitting multiple sclerosis (MS) were subjected to an intensive course of intravenous (I.V.) cyclophosphamide (CY) therapy. All patients received induction therapy with 11 daily doses of 300 mg/m² and then a single dose every six months for three years. After one year of follow-up all patients showed a decrease in relapse rate (0.57.57); in the two subsequent years of follow-up 2 patients showed a mild worsening while the others were clinically stable. As suggested by others, our results indicate that I.V. CY therapy may influence the clinical course of relapsing-remitting MS.

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Sommario Sette pazienti affetti da Sclerosi Multipla di tipo remittente sono stati sottoposti a terapia immunosoppressiva con ciclofosfamide. Il trattamento consisteva di un ciclo di induzione con dosi di 300 mg/m2 di ciclofosfamide e.v. somminsstrate giornalmente per 11 giorni e di successive singole dosi di mantenimento di 300 mg/m² somministrate ogni 6 mesi per un periodo di 3 anni. Non sono stati osservati gravi effetti collaterali durante lo studio. Dopo il primo anno di trattamento tutti i pazienti hanno mostrato miglioramento nella frequenza di ricaduta; nei due anni successivi 4 pazienti sono rimasti stabili mentre gli altri hanno mostrato un nuovo peggioramento. Come indicato da altri Autori, i risultati dello studio indicano che la terapia immunosoppressiva con ciclofosfamide ad alte dosi non presenta gravi effetti collaterali e può modificare il decorso della Sclerosi Multipla di tipo remittente.

     

A Markov model of the natural history of multiple sclerosis

Prior research into multiple sclerosis prognosis has produced conflicting results. This paper presents an original approach in which the disease course is described by the movements of patients through well-defined disease states. A Markov model is proposed to describe these movements and to evaluate the effect of prognostic factors on transitions from state to state. The feasibility and applicability of this model is determined using data on the course of disease in 278 diagnosed patients from Lyon. Patients with older age at onset, females, and those with monosymptomatic onset are found to be at a higher risk of transition to a worse disease state.     

Epidemiology and natural history of multiple sclerosis: new insights

PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk. Natural history studies demonstrated dissociation between relapses and disease progression, facilitated the ability to distinguish neuromyelitis optica and related syndromes from typical multiple sclerosis, and spawned the exploration of large datasets to model long-term disease activity. SUMMARY: Our understanding of the contributions of specific genetic and environmental factors that contribute to multiple sclerosis has improved. Further refinements will eventually allow powerful longitudinal studies to assess genetic and environmental interactions with implications for prediction of individual disease susceptibility, clinical course, and response to therapy.     

Clinical characteristics of progressive relapsing multiple sclerosis

OBJECTIVE: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. METHODS: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. RESULTS: Nine men and seven women had PRMS. The mean age at onset was 35.1+/-11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.1+/-8.5 years and the average time to first exacerbation was 4.1+/-3.7years. Patients had an average of 2.8+/-2.3 relapses with an annualized relapse rate of 0.6+/-0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. CONCLUSIONS: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.     

First-line therapy in relapsing remitting multiple sclerosis

Today, first-line treatments for multiple sclerosis include injectable immunomodulators – some of which have been on the market for nearly 25 years – as well as teriflunomide and dimethyl fumarate, which are more recent, but have opened the way for oral treatments. These drugs are considered similar in effectiveness, and their safety and side-effect profiles are generally reassuring. These treatments have been associated with a reduction in radiological and clinical disease activity, and a positive effect on patient quality of life, especially when introduced early in the disease process. This article will discuss data on first-line treatments currently available in France, their effectiveness and safety, and their place in pediatric patients and in woman who plan to become pregnant.     

The norepinephrine level is decreased in the lymphocytes of long-term interferon-beta-treated multiple sclerosis patients

The mutual involvement of dopamine and its metabolites in the nervous and immune systems has the potential to provide information on the interaction of these two systems. During a 24-hour period, we used capillary electrophoresis with electrochemical detection to repeatedly measure the intracellular catecholamine concentrations in the peripheral blood lymphocytes of relapsing-remitting multiple sclerosis (RRMS) patients receiving interferon (IFN)-beta-1b (n = 13), and those of IFN-na?ve RRMS patients receiving their first IFN-beta-1a injection (n = 19) during this study, and compared them with the levels in healthy controls (n = 12). At baseline, the norepinephrine level was significantly decreased (P =0.003) in the long-term IFN MS patients compared with the controls. The Time x Group interactions for dopamine (P=0.5854) and norepinephrine (P=0.6192) were not significant. The group effects for the individual drugs were P=0.3529 and 0.1282, respectively. The lower norepinephrine level at baseline in the long-term IFN MS group suggests an immunologically stable phase, in line with our previous findings. This is the first report of the effects of IFN-beta administration on intracellular catecholamines in MS patients. Further studies are necessary to elucidate the immune reactions affected by the catecholamines in MS and to evaluate the roles of these potential immunotransmitters.     

General practitioners' approach to relapsing multiple sclerosis

Management of multiple sclerosis depends on close multidisciplinary collaboration but general practitioners play a particularly important role, especially in case of relapse, due to their close relationship with the patient. The purpose of this work was to conduct a survey of general practitioners' knowledge of relapsing multiple sclerosis and ascertain their main difficulties in patient management. One hundred seventy-seven practitioners answered a written questionnaire with two headings, diagnostic criteria for relapse and therapeutic approaches. Analysis of the results showed that this common event is under recognized. While 55.9 p.cent of the general practitioners stated they diagnosed relapse by themselves, only 2.8 p.cent knew its exact definition. Differential diagnosis accounted for a large number of mistakes. Our survey also underlined the use of certain therapeutic options (low-dose oral corticosteroid therapy) for which the effectiveness has not been demonstrated. It would be important to propose specific education on relapsing multiple sclerosis for general practitioners and improve cooperation with specialists. An integrated care network might be useful.