Objectives
To explore fatigue in Multiple Sclerosis and evaluate the specificity of Three Fatigue Scales in this condition: the Fatigue Severity Scale, the Specific Fatigue Scale and the Fatigue Impact Scale.

Material And Methods
We sent out 60 questionnaires with the three scales and the quality of life scale, the Nottingham Health Profile, to patients with Multiple Sclerosis as clinically defined by Poser's criteria.

Answers were received to 58 questionnaires and the data correlated by Sperman's correlation and the Student t test, with demographic variables (age, age of onset and sex) and clinical variables (clinical form, time the disease was present, period of time since the previous episode and Kurtzke scale (EDSS).

Results
Fatigue was present in 78% of the patients. There was correlation between Fatigue Severity Scale and EDSS, Pyramidal function, Cerebellar function, the period of time the illness was present and the clinical form.

We found that the specific fatigue scale is independent of EDSS. The Fatigue Impact Scale was correlated with the EDSS apart from the questions concerning Cognitive function.

Conclusions
Fatigue is a common symptom of Multiple Sclerosis which has an independent effect on cognitive function.

It is also related to involvement of the Pyramidal and Cerebellar Systems, and depends on the degree of disability and time the disease has been present.

The specific Fatigue Scale is a good tool for exploration of this symptom of Multiple Sclerosis.

The interrelationship between Psychological Examination and MRI findings was studied in 70 patients with MS.

The Cognitive and emotional functions were examined by a battery of tests: Wechsler Adult Intelligence Scale, Visual Retention Test, Hamilton Depression Scale.

In MRI examination the localization, area, and the morphology of the plaques were examined. According to plaque's morphology the patients were divided into two groups:

1. With confluent plaques
2. With patchy-shaped ones

The signs of Dementia were found significantly more frequently in the group with confluent plaques (p. < 0.04).

In this group of patients also Single-Function Disorders like disturbances of Verbal Memory, Attention, Visual Memory, Cause - and Effect Thinking, Abstract Thinking, and Visual-Motor Coordination were significantly more frequent (p. < 0.01).

In the same group the signs of Fatigue Syndrome were more frequently encountered (p. < 0.02).

The authors conclude that the disturbances found in Cognitive function may reflect the symptoms of SubCortical Dementia in MS patients.

We investigated the effect of Amantadine on Cognitive processing in patients with Multiple Sclerosis (MS) and Fatigue with objective ElectroPhysiological measures.

Behavioral methods (Reaction Time, RT) and two different Event Related Potential (ERP) components measuring:

1. Stimulus selection (Selection Negativity, SN) and
2. Response selection (Lateralized Readiness Potential, LRP) were employed.

Twenty-four patients with clinical definite MS (10 Relapsing/Remitting and 14 Secondary/Progressive) and confirmed Fatigue in the past three months (Fatigue Severity Scale (FSS) > 4) were included.

Patients were randomized in a double-blind, placebo-controlled cross-over design.

We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms.

This negativity had a higher amplitude during Amantadine treatment regardless of treatment order. The RT did not differ significantly between the treated and untreated groups.

Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position (practice effect), but no treatment effect.

While patients with a longer MS duration showed no practice effect, but rather an improved reaction speed and increased ERP amplitude effects when treated with Amantadine.

The present findings suggest that Amantadine exerts beneficial effects on early Cognitive processes in patients with MS, but appears to be limited to subjects with a longer duration of the disease.

ICAM-1 is a TransMembrane GlycoProtein of the Ig superfamily involved in cell adhesion.

ICAM-1 is aberrantly expressed by Astrocytes in CNS pathologies such as Multiple Sclerosis, Experimental Allergic EncephaloMyelitis, and Alzheimer's Disease, suggesting a possible role for ICAM-1 in these disorders.

ICAM-1 has been shown to be important for Leukocyte diapedesis through Brain MicroVessels and subsequent binding to Astrocytes.

However, other functional roles for ICAM-1 expression on Astrocytes have not been well elucidated. Therefore, we investigated the IntraCellular signals generated upon ICAM-1 engagement on Astrocytes.

ICAM-1 ligation by a mAb to rat ICAM-1 induced mRNA expression of proinflammatory Cytokines such as IL-1alpha, IL-1beta, IL-6, and TNF-alpha.

Examination of Cytokine protein production revealed that ICAM-1 ligation results in IL-6 secretion by Astrocytes, whereas IL-1beta and IL-1alpha protein is expressed IntraCellularly in Astrocytes.

The involvement of mitogen-activated protein kinases (MAPKs) in ICAM-1-mediated Cytokine expression in Astrocytes was tested, as the MAPK ExtraCellular signal-regulated kinase (ERK) was previously shown to be activated upon ICAM-1 engagement.

Our results indicate that ERK1/ERK2, as well as p38 MAPK, are activated upon ligation of ICAM-1.

Studies using pharmacological inhibitors demonstrate that both p38 MAPK and ERK1/2 are involved in ICAM-1-induced IL-6 expression, whereas only ERK1/2 is important for IL-1alpha and IL-1beta expression.

Our data support the role of ICAM-1 on Astrocytes as an inflammatory mediator in the CNS and also uncover a novel signal transduction pathway through p38 MAPK upon ICAM-1 ligation.

Background
Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care. A variety of oral and parenteral medications are available.

Objectives
To assess the absolute and comparative efficacy and tolerability of Anti-Spasticity agents in Multiple Sclerosis (MS) patients.

Search Strategy
Randomized controlled trials (RCTs) of Anti-Spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies.

Selection Criteria
Double-blind, randomized controlled trials (either placebo-controlled or comparative studies) of at least seven days duration.

Data Collection And Analysis
Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators.

A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed.

Main Results
Twenty-three placebo-controlled studies (using Baclofen, Dantrolene, Tizanidine, Botulinum Toxin, Vigabatrin, Prazepam and Threonine) and thirteen comparative studies met the selection criteria.

Only thirteen of these studies used the Ashworth Scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs.

Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive.

Conclusions
The absolute and comparative efficacy and tolerability of Anti-Spasticity agents in Multiple Sclerosis is poorly documented and no recommendations can be made to guide prescribing.

The rationale for treating features of the Upper Motor Neuron Syndrome must be better understood and sensitive, validated Spasticity measures need to be developed.

Background
CorticoSteroids are often used to improve the rate of recovery from acute exacerbation in Multiple Sclerosis (MS) patients.

However, it is still unclear just how relatively effective these agents are and the type of drug, optimal dose, frequency, duration of treatment and route of administration are unknown.

Objectives
The object of this review was to determine the efficacy and safety of CorticoSteroids or ACTH in reducing the short and long term morbidity from MS.

Moreover, we wished to examine from indirect comparisons if the effect of CorticoSteroids is different according to different doses and drugs, routes of administration, length of treatment.

Search Strategy
A search strategy developed for the Cochrane MS Group (last searched: June 1999) completed with handsearching and personal contacts with trialists and pharmaceutical companies was used.

Selection Criteria
All randomized, double-blind, unconfounded trials comparing CorticoSteroids or ACTH to placebo in patients with MS, treated for acute exacerbations, without any age or severity restrictions, were evaluated.

Data Collection And Analysis
Two reviewers independently selected articles for inclusion, assessed trials' quality and extracted the data. A third reviewer cross-checked them and disagreements were resolved by a joint discussion.

Main Results
Six trials contributed to this review; a total of 377 participants (199 treatment, 178 placebo) were randomized. The drugs analyzed were MethylPrednisolone (MP) (four trials, 140 patients) and ACTH (two trials, 237 patients).

Overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first five weeks of treatment (odds ratio[OR]=0.37, 95% confidence interval [CI] 0.24-0.57) with some but non significant greater effect for MP and intravenous administration.

Short (five days) or long (15 days) duration of treatment with MP did not show any significant difference.

Only one study (with 51 patients) reported data after one year of follow-up: no difference between oral MP and placebo in the prevention of new exacerbations or improvement in long term disability was detected.

No data are available beyond one year of follow-up to indicate whether Steroids or ACTH have any effect on long-term progression. One study reported that a short term treatment with high dose intravenous MP was not attended by adverse events.

On the contrary, GastroIntestinal symptoms and Psychic Disorders were significantly more common in the oral, high-dose MP than in the placebo group.

Weight gain and Edema were significantly more frequent in the ACTH group than in controls.

Conclusions
We found evidence favoring the CorticoSteroid MP for acute exacerbation in MS patients. Data are insufficient to reliably estimate effect of CorticoSteroids on prevention of new exacerbations and reduction of long-term disability.

Studies assessing long term risk/benefit and adverse effects of CorticoSteroids in MS patients are urgently needed.

MS is a DeMyelinating Disease characterized by infiltration of Monocytes and Lymphocytes into the Brain parenchyma, destruction of Oligodendrocytes and loss of Myelin.

Since Chemokines play a major role in the migration of Monocytes and T-Cells, we here investigated the expression of the CC Chemokines MIP-1alpha, MIP-1beta, and RANTES in Brain tissue from MS patients using reverse transcriptase-polymerase chain reaction techniques.

Both MIP-1beta as well as RANTES were found to be significantly elevated in Brain tissue of MS patients. In addition, MIP-1alpha was also increased, although not significantly.

ImmunoHistoChemistry revealed that, whereas RANTES was mainly localized in reactive Astrocytes, MIP-1alpha and MIP-1beta ImmunoReactivity was predominantly found in perivascular and parenchymal Macrophages, containing Myelin degradation products.

Thus, Chemokines appear to be associated with MS and an increased Chemokine expression may further enhance disease progression by attracting more Leukocytes into the Brain parenchyma and by activation of effector functions of Astrocytes and Microglial Cells.

Context
Disease-modifying Multiple Sclerosis (MS) therapeutic trials continue to rely on physical disability as the main clinical outcome measure, while the impact of treatment on Quality Of Life (QOL) is poorly understood.

Weak correlations exist between physical disability and the disease burden as shown using conventional Brain Magnetic Resonance Imaging (MRI), indicating poor sensitivities of these measures alone in defining the clinical course of MS.

Objectives
To investigate the impact of MS on QOL; to determine whether impaired QOL in patients with MS was related to any regional Brain abnormalities assessed using conventional MRI sequences; and to determine if the severity of MS as assessed by the Expanded Disability Status Scale (EDSS) and clinical course was associated with worsening QOL.

Design, Setting, And Patients
Prospective, cross-sectional study of 60 consecutive patients with MS treated in a community-based, university-affiliated MS clinic.

Main Outcome Measures
Assessments of QOL using the Multiple Sclerosis Quality of Life-54 Instrument were correlated with the scores of the EDSS, clinical course, and findings on Brain MRI.

Results
Quality of life was significantly impaired in patients with MS and was worse in patients with Secondary/Progressive MS compared with those with Relapsing/Remitting MS.

Brain MRI lesions and Atrophy were associated with impaired QOL with respect to Sexual Dysfunction, overall Mental Health, and limitations due to Physical and Emotional Dysfunction.

Correlations between MRI results and QOL assessments were much stronger for HypoIntense lesions and Atrophy on T₁-weighted images than for HyperIntense lesions on T₂-weighted images and were insignificant for lesions on contrast-enhanced images.

Higher EDSS scores were associated with impairments in most Physical and Mental health QOL scales but were weakly correlated with Cognitive and Sexual Dysfunction.

Conclusions
In patients with MS, QOL is impaired and is associated with increasing Neurologic disability. Quality of life assessments are related in part to Brain lesions and Atrophy shown on MRI.

Assessments of QOL provide unique information not readily evaluated by EDSS and may be useful as secondary clinical outcome measures.

Arch Neurol 2000;57:1485-1491