The natural history of MS is highly variable. There is substantial heterogeneity (differences) in the clinical manifestations.

But, at this point, it is reasonable to consider all Idiopathic Inflammatory DeMyelinating Diseases of the Central Nervous System as representing a spectrum of the same disease.

In large populations, 20% to 40% have "Benign disease", defined as having less than moderate disability after 10 years.

Benign is a potentially misleading term, because many of these patients subsequently WILL become disabled.

Half will develop Progressive MS within 10 years and will require some form of walking aid within 15 years following the onset of MS.

Survival is not greatly shortened in mildly disabled patients; but the observed mortality is increased four-fold, over the general population in patients with advanced disability.

Patients with the greatest risk of disability:
• Those with P/P MS or R/R MS who are older at Onset
• Have Pyramidal or Cerebellar involvement at Onset
• Have frequent or prolonged attacks with incomplete recovery

The biological basis for the variation in the course of MS is understood only in a very limited way. The short and long-term course of MS may be determined by different biological variables.

Short-term benefit in clinical trials should NOT be assumed to indicate long-term reduction in the risk of permanent Disability.

The PathoPhysiology of Multiple Sclerosis is reviewed, with emphasis on the Axonal Conduction properties underlying the production of symptoms, and the course of the disease.

The major cause of the negative symptoms during relapses (e.g. Paralysis, Blindness and Numbness) is Conduction Block.

Caused largely by DeMyelination and Inflammation, and possibly by defects in Synaptic transmission and putative circulating blocking factors.

Recovery from symptoms during remissions is due mainly to the restoration of Axonal function, either by ReMyelination, the resolution of Inflammation, or the restoration of Conduction to Axons which persist in the DeMyelinated state.

Conduction in the latter Axons shows a number of deficits, particularly with regard to the conduction of trains of Impulses and these contribute to Weakness and Sensory problems.

The mechanisms underlying the sensitivity of symptoms to changes in Body Temperature (Uhthoff's Phenomenon) are discussed.

The origin of 'positive' symptoms, such as Tingling Sensations, are described, including the generation of Ectopic trains and bursts of Impulses, Ephaptic interactions between Axons and/or Neurons.

The triggering of additional, spurious Impulses by the transmission of normal Impulses, the MechanoSensitivity of Axons underlying movement-induced sensations (e.g. Lhermitte's Phenomenon) and Pain.

The clinical course of the disease is discussed, together with its relationship to the evolution of lesions as revealed by Magnetic Resonance Imaging and Spectroscopy.

The earliest detectable event in the development of most new lesions is a breakdown of the Blood-Brain Barrier in association with inflammation.

Inflammation resolves after approximately one month, at which time there is an improvement in the symptoms.

DeMyelination occurs during the inflammatory phase of the lesion. An important mechanism determining persistent Neurological Deficit is Axonal degeneration.

Although persistent Conduction Block arising from the failure of repair mechanisms probably also contributes.

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.

The clinical features of relapses and progression largely define Multiple Sclerosis phenotypes. A Relapsing course is followed by chronic progression in some 80% of cases within 2 decades.

The relationship between these phases and long-term outcome remains uncertain. We have analyzed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years.

For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively.

Among 824 Attack/Onset patients, the great majority entered a Progressive phase with a mean time to progression of 10.4 years.

The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less.

Three subgroups allow for clarity of outcome comparison and they are:
1. Cases of Primary/Progressive (PP) disease
2. Attack/Onset disease where only a single attack has occurred before onset of progression (SAP) and
3. Secondary/Progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins

Here we compare survival curves in these three groups.

Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10.

These findings demonstrate that the Progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it.

Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome.

The site of the original attack was not usually where progression began.

The relatively stereotyped nature of the Progressive phase seen in all Progressive phenotypes, suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature.

The highly prevalent distal CorticoSpinal Tract dysfunction in Progressive disease and the pathologically demonstrated selective Axonal Loss seen in this tract raises the possibility of a dying back central Axonopathy, at least in part independent of plaque location or burden.

Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace.

And, may entail mechanisms common to all forms of Progressive Multiple Sclerosis. The possibility that this is the primary process in some cases must be considered.

Purpose Of Review
To highlight progress in the description of the natural course and prognosis of Multiple Sclerosis.

Recent Findings
The general evolution of Multiple Sclerosis is now well known at the level of patient groups.

Characteristics of relapses early in the disease and the occurrence of a Progressive phase seemed to be the most reliable prognostic factors.

Recent works suggest that the progressive phase in Multiple Sclerosis could be an age-dependent, degenerative process, independent of previous relapses, and that the initial course of the disease does not substantially influence age at disability milestones.

By contrast, a younger age at disease onset strongly correlates with a younger age when reaching disability landmarks.

Confirming that even if it takes longer for younger patients to accumulate irreversible disability, they are disabled at a younger age than patients with later onset.

Multiple Sclerosis might be considered as one disease with different clinical phenotypes, rather than an entity encompassing several distinct diseases.

Summary
Overall course and prognosis in Multiple Sclerosis is most likely to be related to age and the occurrence of the Progressive phase of the disease, rather than to relapses or other clinical parameters. Individual prognosis remains hazardous.

Background And Purpose
We sought to identify predictive clinical factors of disability during initial course in Multiple Sclerosis (MS) patients.

Methods
A total of 2,871 MS patients from the LORSEP (Lorraine Multiple Sclerosis) population-based cohort were analyzed.

The relationships between baseline demographic, clinical predictors and time to assignment of Expanded Disability Status Scale (EDSS) scores of 3, 4 and 6 were assessed using a Cox regression model.

Results
Multivariate analysis showed that, for Relapsing/Remitting patients, a shorter time to assignment of an EDSS score of 4 was associated with an older age of onset of MS.

And, incomplete recovery from the first relapse, median times were not influenced by gender or the time between the first two relapses.

The results also demonstrated that MS progression is independent of the initial clinical data once an EDSS score of 4 is reached rather than a score of 3.

Because the time from EDSS 3 to assignment of EDSS 4 were correlated with predicting variables.