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.     

New natural history of interferon-beta-treated relapsing multiple sclerosis

OBJECTIVE: To investigate the impact of interferon-beta (IFNbeta) on disease progression in relapsing-remitting multiple sclerosis patients. METHODS: A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFNbeta-treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. RESULTS: The IFNbeta-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24-0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38-0.95 for time from first visit; HR, 0.54, 95% CI, 0.34-0.86 for time from date of birth; p < or = 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings. INTERPRETATION: IFN-beta slows progression in relapsing-remitting multiple sclerosis patients.     

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.     

Models of multiple sclerosis: new insights into pathophysiology and repair

PURPOSE OF REVIEW: Experimental models are indispensable in multiple sclerosis research aimed to elucidate the pathogenesis of the disease or to test new therapeutic approaches. The purpose of this review is to discuss the relevance of different models for multiple sclerosis and new insights into pathophysiology of the disease obtained from experimental studies. RECENT FINDINGS: These studies show that tissue damage in the course of brain inflammation is induced by a variety of different components of the immune system, including T cells, autoantibodies and activated effector cells, such as macrophages and microglia. In general, different mechanisms of tissue injury act in parallel and are partly counteracted by the induction of neuroprotective factors and spontaneous regenerative processes. SUMMARY: Despite this complexity, experimental studies identified bottlenecks in the destructive process, which can be targeted by therapeutic strategies. To what extent these results can be transferred into therapy of multiple sclerosis has to be shown in the future.     

Mitoxantrone (Novantrone) in multiple sclerosis: new insights

The conclusions of a recent study of mitoxantrone (Novantrone) in multiple sclerosis and the approval of several health authorities support its use in patients with active relapsing-remitting or secondary progressive multiple sclerosis. This drug profile provides an outline on relevant preclinical and clinical studies, discusses relevant side effects of the compound and places mitoxantrone in the context of other therapeutic approaches available against this disabling disorder.     

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.     

Epidemiology of multiple sclerosis

Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This article discusses the epidemiology of MS.     

The natural history of multiple sclerosis: implications for trial design.

The understanding of the natural history of multiple sclerosis has many implications for the design and interpretation of randomized controlled trials. Selection criteria, patient stratification, outcome measurements, and definitions of treatment failure can influence randomized controlled trial results and limit comparisons among trials. The focus of future studies should shift from short-term determinations of efficacy to definitive evaluations of long-term effectiveness. This will require novel investigative strategies such as the use of historic controls derived from natural history studies.     

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.     

Prognostic factors for multiple sclerosis: the importance of natural history studies

Journal of Neurology - Detailed studies of the natural history of untreated multiple sclerosis (MS) have been carried out in London, Ontario, Canada, over the past generation. There are now some...     

Prognostic factors for multiple sclerosis: the importance of natural history studies

Detailed studies of the natural history of untreated multiple sclerosis (MS) have been carried out in London, Ontario, Canada, over the past generation. There are now some 25,000 patient-years of follow-up in a cohort of slightly more than 1,000 individuals. From the data, it is clear that a number of factors are associated with long-term outcome of the disease. The Ontario database reveals several prognostic variables that are clinical in nature, which can be used to evaluate prognosis in any clinical subtype. The most important factors include the development of a progressive deficit and time to onset of progressive deficit. In addition, and independently, a high number of relapses in the first and second year is associated with poor long-term outcome, as is the development of early unremitting disability. An important question is whether or not primary-progressive (PP) MS represents an independent entity separate from secondary-progressive (SP) MS. No specific category of PP disease is distinguishable from SP disease using available clinical measures. There is reason to believe that magnetic resonance imaging (MRI) activity (when appropriately controlled for other unequally distributed factors, such as age) will be found to be very similar.     

Understanding fatigue in multiple sclerosis: new insights in causes and assessment

Neurological Sciences - Fatigue is one of the most common symptoms encountered in multiple sclerosis (MS), and research is continuously improving the knowledge and assessment of this specific...     

Immunotherapy for multiple sclerosis: basic insights for new clinical strategies

Multiple Sclerosis (MS) is a chronic inflammatory degenerative disease of the central nervous system (CNS), first described over 100 years ago. MS is a clinically heterogeneous disease with an increasing incidence over time, and a population prevalence that increases with distance from the equator. It is postulated that environmental factors such as diet and population-specific genetics, influence the distribution of MS. Diagnosis is based on established clinical criteria, aided by magnetic resonance imaging, evoked potential recordings and cerebrospinal fluid examination. Whichever the type of clinical manifestation, MS is considered an organ-specific autoimmune disease, characterized by T-cell and macrophage infiltrates, triggered by CNS-specific CD4 T-cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN-gamma-producing Th1 cells that recognize self-peptides of the myelin sheath, such as myelin basic protein (MBP) and proteolipid protein (PLP). Current treatments for MS aim primarily to suppress T-cell-mediated immune responses, albeit non-specifically. Experimental approaches towards the therapeutic management of MS involve the use of peptide analogs of disease-associated myelin epitopes or vaccines, to help shift T helper cell responses from Type-1 (secreting pro-inflammatory cytokines) to Type-2 (secreting anti-inflammatory cytokines) or induce peripheral T-cell tolerance. Animal models of MS have been useful to dissect disease mechanisms and evaluate new therapies. Experimental clinical trials, although few, are valuable to assess new treatment regimens and clarify possible conceptual mistakes about the disease. This review attempts to link the current knowledge of MS pathogenesis with clinical and experimental protocols of immunotherapy for MS.     

Cognitive dysfunction in multiple sclerosis: natural history and impact on productive living

Studies in which groups of patients with multiple sclerosis (MS) and controls of comparable age and education are compared reveal consistent impairments by the patient groups on test of anterograde explicit memory, controlled attentional processing, information processing speed, and abstract reasoning and problem solving. Vocabulary, naming and visual perception are less often affected. However, the extent of cognitive impairment for individual patients varies from none at all to global dementia. Both physical and cognitive impairment contribute equally to predicting employment status, but some patients with global cognitive impairment can continue to work effectively at mentally demanding professional jobs. Recently developed screening examinations could detect cognitive impairment early and permit interventions when they should be maximally effective. Three key issues in clinical neuropsychology are identified which have not been addressed by traditional neuropsychology. Italian neuropsychology, because of its unique characteristics, could lead in understanding these important questions.