To assess the predictive significance of different sets of Demographic, Clinical and ExtraClinical variables in identifying Multiple Sclerosis patients with various risk levels of worsening during the follow-up.

Two hundred and twenty-four patients at their first diagnosis of Multiple Sclerosis admitted to our Dept between 1983 and 1990.

In order to provide clues to inclusion criteria and selection of primary clinical end-points in therapeutic trials, were prospectively followed-up until the end of 1996.

We considered as end-points time to reach non-reversible Disability levels corresponding to EDSS scores of 4.0 and DSS 6 and the beginning of a Secondary/Progressive phase in the Relapsing/Remitting subgroup of patients.

For the statistical treatment of our data we used the Kaplan-Meier survival curves and the Cox regression analysis.

Factors Predictive Of Outcome:
• Unfavorable Prognosis:
  1. An initially Progressive course
  2. Higher basal EDSS scores
  3. More Functional Systems involved at Onset
  4. Higher residual Motor System deficits in:
     • Pyramidal, Visual, Sphincteric, Cerebellar
  5. Presence of OligoClonal Banding in CSF
  6. Cerebral MRI suggestive of MS

• Favorable Prognosis:
  1. Sensory System involvement at Onset
  2. Longer first inter-attack interval

• No Prognostic Value:
  1. Number of relapses in the first two years

Multiple Sclerosis is a chronic disease that begins in late adolescence or adulthood. It is highly variable in its expression and severity.

It is believed to be AutoImmune in nature. The cause is unknown; both Genetic and Environmental factors have been implicated in the PathoGenesis.

MS generally presents with the Acute or SubAcute Onset of Neurologic Abnormalities that may wax and wane over many years. Diagnosis is generally made by means of observation of the clinical course in conjunction with a Neurologic Examination and laboratory tests.

These tests may include Magnetic Resonance Imaging of the Head and Spine, Lumbar Puncture, and Evoked Potentials.

Treatment is based on general supportive care, the use of CorticoSteroids for relapses, and symptomatic management of ongoing problems.

The frequency of relapses can be reduced with Interferon-ß (Betaseron). Copolymer-1 and Interferon-ß 1a are being evaluated by the U.S. Food and Drug Administration for approval for use for reduction in the frequency of Relapses in Relapsing/Remitting MS.

Treatment of Chronic Progression is often attempted with ImmunoSuppressive agents such as CorticoSteroids, Azathioprine, and Cyclophosphamide. Use of other agents is being investigated.

Multiple Sclerosis (MS) is the most common idiopathic inflammatory disease of the Central Nervous System.

The distinction between MS and other Benign or Fulminant Inflammatory DeMyelinating Disorders is based on quantitative, rather than qualitative, differences in chronicity and severity.

Primary/Progressive MS may differ from Relapsing/Remitting MS in MRI lesion frequency, ImmunoGenetic profile, responsiveness to ImmunoSuppressive treatment, and Histology.

In 60% of patients, MS begins as a Relapsing/Remitting disease and evolves Secondarily into a Progressive Neurological illness.

Life expectancy is not substantially altered in patients with MS, particularly in the early years of the illness. The rate of suicide has been reported to be increased sevenfold in MS patients.

Up to 40% of patients with attacks severe enough to render them nonambulatory may not recover. At 15 years from MS Onset, 50% of patients are disabled to the point at which they at least require a cane to walk a half block.

Early age at Onset, female sex, Relapsing/Remitting course at Onset, and perhaps Optic Neuritis or Sensory symptoms at Onset and relatively few attacks in the first two years are associated with a favorable course.

A regional survey of Multiple Sclerosis (MS) patients in Wellington, New Zealand in 1983 identified 245 patients, giving a prevalence (all categories included) of 72 per 100,000.

Retrospective review of the history and medical records identified a poorer prognosis for disability where there was Progressive Onset of symptoms, Secondary/Progression after a Remitting phase, older age of Onset (40 years or more), or a Motor Syndrome involving the limbs at presentation.

In 1983 follow up data were obtained on 96 patients who were seen during a previous survey in 1968.

For those with Definite or Probable MS, progression to severe disability (Kurtzke Disability Status Scale (DSS) DSS 6-9) or death (DSS 10) was seen in 26/34 with moderate disability (DSS 3-5) in 1968 and in only 5/29 with mild disability (DSS 0-2).

When the analysis is confined to those with symptoms for at least five years in 1968, severe disability or death from MS occurred in 22/30 with moderate and 4/19 with mild disability (chi 2 = 10.8, p = 0.001).

It is concluded that the patient's established Disability level after five years of illness is a useful, but not infallible, prognostic indicator.

From the follow up of the 1968 patients, the probability of MS-related Mortality for a given disease duration was calculated.

Using this survival distribution to adjust the disability ratings in the 1983 population, it was found that the proportion with mild disability decreased steadily with increasing disease duration, reaching 14% when the disease duration was more than 25 years.

Current clinical scales in Multiple Sclerosis (MS) are often complicated to administer, suffer from interrater variability and lack of uniform representation across grades, and are insensitive to progression at certain stages.

Furthermore, they are not easily applied by Neurologists and do not clearly differentiate among functional stages of MS. For these reasons, we developed Disease Steps to assess disability in MS.

A total of 1,323 patients were classified using both Disease Steps and the Expanded Disability Status Scale (EDSS) for a total of 2,755 assessments.

The Disease Steps Scale consists of:
• 0 = Normal
• 1 = Mild disability, mild symptoms or signs
• 2 = Moderate disability, visible abnormality of gait
• 3 = Early cane, intermittent use of cane
• 4 = Late cane, cane-dependent
• 5 = Bilateral support
• 6 = Confined to wheelchair
• U = Unclassifiable

Results demonstrate that raters could simply and quickly categorize patients using Disease Steps. Patients were uniformly distributed with Disease Steps, whereas a bimodal distribution occurred with the EDSS.

On the EDSS, 40.3% of patients scored between 1.0 and 3.5 and 36.0% scored from 6.0 to 6.5, with only 6.9% of patients scoring between 4.0 and 5.5.

For 60 patients seen by two Neurologists, concordance between raters was excellent for Disease Steps (kappa = 0.8) but only moderate for the EDSS (kappa = 0.54).

As a simple and reproducible measure of different functional steps of MS, Disease Steps can be used as a guide in therapeutic decision-making, following response to therapy, and in assessing disease progression.

An incidence cohort of 308 Multiple Sclerosis patients was followed up repeatedly during at least 25 years of disease.

In the patients with acute Onset, multivariate survival analyzes were performed and predictive models created. The endpoints DSS 6 and start of Progressive Disease were used. A number of variables were tested.

The most important of these for prediction and therefore included in these models were: age at Onset, sex, degree of remission after relapse, Mono- or PolyRegional symptoms, type of affected Nerve fibers, number of affected Neurological Systems. The relapse rate did not correlate with prognosis.

In the predictive models, coefficients and risk ratios are provided that can be used for calculating the risk of progression and DSS 6 or to predict the median time for these endpoints in individual patients.

It was also found that the risk of progression is not constant, but has a maximum a certain time after disease Onset.

For a patient with early Onset, the risk is low in the beginning, but reaches a maximum level, which is several times higher, after about 15 years.

The patient with a late Onset has a much higher risk of endpoint immediately after Onset, but reaches the maximum in a few years, and after that the risk decreases.

Two hundred and twenty-four patients at their first diagnosis of Multiple Sclerosis (MS) were prospectively followed for a mean period of 9.78 years.

We considered as endpoints the time to reach non-reversible disability levels corresponding to EDSS scores of 4.0 and 6.0, and the beginning of a Secondary/Progressive phase in the Relapsing/Remitting subgroup of patients.

An initially Progressive course and higher basal EDSS scores proved to be the best predictors of unfavorable prognosis.

A greater number of Functional Systems involved at onset as well as higher residual deficits in Pyramidal, Visual, Sphincteric and Cerebellar Systems were other factors predictive of a poor outcome, whereas Sensory System involvement turned out to be favorable.

A longer first inter-attack interval was associated with a better prognosis. However, overall number of relapses in the first two years of the disease was of no prognostic value.

The presence of OligoClonal Banding in the CerebroSpinal Fluid and a Cerebral MRI exam strongly suggestive or suggestive of MS in the early phases of the disease were associated with a higher probability of a worse outcome.

Intrathecal IgM synthesis (ITMS) predicts a worse evolution in the first stages of Multiple Sclerosis (MS).

The aim of this study was the follow-up of a group of Relapsing/Remitting MS patients for a longer time to evaluate whether the ITMS implies a poor prognosis. OligoClonal IgM Bands were performed in 29 MS patients followed up from 5 to 16 years.

Time to conversion to Secondary/Progressive MS (SP-MS), time elapsed to reach a disability of 6 in the Expanded Disability Status Scale (EDSS), percentage of patients with a Benign MS, and changes in EDSS score were evaluated.

During the follow-up, 70.8% of patients with ITMS converted to SPMS. None of the patients without ITMS did.

At the end of the study, 63.6% of patients with ITMS had reached EDSS 6, whereas none of the patients lacking ITMS reached values above EDSS 3.

When patients with Benign MS were analyzed, 82% lacked ITMS. All patients with a NonBenign MS had ITMS.

At the end of the study, the mean EDSS score was 4.64 in patients with ITMS and 1.31 in those without. The presence of OligoClonal IgM Bands in CerebroSpinal Fluid is an unfavorable prognostic marker in MS.

Objectives
To establish the prognostic role of clinical and demographic factors in a hospital-based cohort of MS patients categorized by age at clinical onset and clinical course.

Methods
Eighty-three patients with MS had a clinical onset of the disease in childhood (age < 16 years; Early-Onset MS [EOMS]) and 710 in adult age (between 16 and 65 years.

Adult-Onset MS [AOMS]). Patients were followed for a mean period of observation of 5 years.

Univariate and multivariate analyses of clinical and demographic predictors for rapid progression and disability were performed using a stepwise Cox regression model with time-dependent covariates.

Results
In EOMS, the Expanded Disability Status Scale (EDSS) evaluated at last clinical examination was lower than in AOMS, despite a longer disease duration.

The probability to reach growth disability and progression was significantly lower in EOMS than in AOMS.

Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS.

In EOMS and AOMS, an irreversible disability was related to a Secondary/Progressive course, a Sphincteric System involvement at onset, and an older age at onset (in EOMS only for the group >14 years).

In AOMS, other unfavorable factors were a Pyramidal involvement at onset and a high relapse frequency in the first 2 years.

The risk of entering secondary progression was significantly influenced by a high number of relapses in EOMS and by a higher age at onset and a short interattack interval in AOMS.