Disability Progression In Multiple Sclerosis Is Slower Than Previously Reported
Tremlett H, Paty D, Devonshire V
Neurology 2006 Jan 24;66(2):172-7
University of British Columbia, Department of Medicine (Neurology), Vancouver, Canada
To investigate disease progression and risk factors in a large geographically based population with Multiple Sclerosis (MS), using two different inception points--clinical onset and date of birth.
The authors reviewed a database of subjects with definite MS and symptom onset prior to July 1988.
The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6 (requires a cane), using the date of birth and date of MS onset as inception points in separate analyses.
Risk factors examined were sex, Relapsing vs Primary/Progressive course, onset age, and onset symptoms.
The study included 2,837 patients, followed prospectively for 22,723 patient years.
The median time to EDSS 6 was 27.9 years, 15 years after onset; only 21% reached EDSS 6, and by age 50, 28% required a cane.
Men progressed 38% more quickly than women from onset (p < 0.0005), yet both required canes at similar ages: 58.8 years for men and 60.1 for women (p = 0.082).
A younger onset age predicted a slower progression, but those older at onset were consistently older when reaching EDSS 6.
A Primary/Progressive course predicted a more rapid progression from both onset (p < 0.0005) and birth (hazard ratio = 2.7 [95% CI: 2.2 to 3.3]). No onset symptom consistently predicted progression.
Disability progression in Multiple Sclerosis (MS) accrued more slowly than found in earlier longitudinal studies.
The authors also challenged two fundamental concepts in MS, demonstrating that neither male sex nor older onset age was associated with worse disease outcome.
Age At Disability Milestones In Multiple Sclerosis
Confavreux C, Vukusic S
Brain 2006 Mar;129(Pt 3):595-605
The European Database for Multiple Sclerosis (EDMUS) Coordinating Center and Service de Neurologie A, INSERM U 433, Hopital Neurologique, Hospices Civils de Lyon, Lyon, France
Many efforts have been devoted to the description of the prognosis of Multiple Sclerosis and its possible influential factors in terms of time to reach disability milestones.
By contrast, the age at which patients with Multiple Sclerosis reach these milestones has not yet stirred much interest.
We have tested the hypothesis whether the prognosis of Multiple Sclerosis depends on the current age of patients and the initial course of the disease.
We have assessed disease onset and course, and assignment of scores of irreversible disability in 1844 patients with Multiple Sclerosis.
We have used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: DSS 4 (limited walking but without aid), DSS 6 (walking with unilateral aid) and DSS 7 (wheelchair-bound).
We used Kaplan-Meier analyses to estimate the age of the patients at assignment of disability milestones.
The possible influence of the initial course of Multiple Sclerosis and of other clinical variables early assessable in the disease on these outcome measures was also studied, using the Kaplan-Meier curves for univariate analyses and Cox models for multivariate analyses.
For the 1844 patients, median ages at time of assignment of irreversible disability were 44.3 years (95% CI 43.3-45.2) for a score of DSS 4, 54.7 years (95% CI 53.5-55.8) for DSS 6 and 63.1 years (95% CI 61.0-65.1) for DSS 7.
These results were essentially similar whether the initial course of Multiple Sclerosis was Exacerbating/Remitting or Progressive, and whatever the initial symptomatology. Females reached disability milestones at an older age than males.
The most influential clinical factor was age at clinical onset of Multiple Sclerosis: the younger the onset, the younger the age at assignment of disability milestones.
Therefore, prognosis in Multiple Sclerosis appears, at least to some extent, as age-dependent and not substantially affected by the initial course, be it Exacerbating/Remitting or Progressive.
Aside acute focal recurrent inflammation and diffuse chronic NeuroDegeneration, accelerated ageing-related mechanisms may operate in the Central Nervous System of Multiple Sclerosis patients.
Accumulation Of Irreversible Disability In Multiple Sclerosis: From Epidemiology To Treatment
Confavreux C, Vukusic S
Clin Neurol NeuroSurg 2005 Dec 31
Hopital Neurologique Pierre Wertheimer, Service de Neurologie A, 59 Boulevard Pinel, 69677 Lyon-Bron Cedex 03, France
There is convincing evidence that Neurological relapses in Multiple Sclerosis (MS) are the clinical counterpart of acute focal inflammation of the Central Nervous System (CNS) whereas Neurological progression is that of chronic diffuse NeuroDegeneration.
The classical view is to consider that MS is an organ-specific Autoimmune Disease, i.e. that inflammation is the cause of the NeuroDegeneration.
The succession of relapses eventually leads to accumulation of disability and clinical progression results from subclinical relapses.
A series of recent observations tends to challenge this classical concept. Important observations have come from the study of the natural history of MS.
In the Lyon MS cohort, accumulation of irreversible disability appeared not to be affected by clinically detectable Neurological relapses.
This has also been shown to be "amnesic" for the early clinical characteristics of the disease, and essentially age-dependent.
Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability.
Interferons-beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent.
Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged Lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and Cerebral Atrophy still progress.
The same experience has been reported with Cladribine and Autologous Haematopoietic Stem Cell Transplantation. All these observations give support to the fact that relapses do not essentially influence irreversible disability in the long term in MS.
They are consistent with what has been shown at the individual level in the 1970s by performing serial quantitative Neurological Examinations over several years, and with what is currently emerging from early and serial structural brain MRI studies.
These breakthroughs have immediate implications for the counselling of patients with MS.
They suggest that MS is as much NeuroDegenerative as inflammatory, and should cause the modification of disease-modifying therapeutic strategies by focussing on the protection and repair of the Nervous System and not only on the control of inflammation.
Quantification Of Central Motor Conduction Deficits In Multiple Sclerosis Patients Before And After Treatment Of Acute Exacerbation By MethylPrednisolone
To compare the effects of IntraVenous MethylPrednisolone (IVMP) in patients with Relapsing/Remitting (RR-MS), Secondary/Progressive (SP-MS), and Primary/Progressive Multiple Sclerosis (PP-MS).
Clinical and NeuroPhysiological follow up was undertaken in 24 RR-MS, eight SP-MS, and nine PP-MS patients receiving Solu-Medrol 500 mg/d over five days for exacerbations involving the motor system.
Motor Evoked Potentials (MEPs) were used to measure Central Motor Conduction Time (CMCT) and the Triple Stimulation Technique (TST) was applied to assess conduction deficits.
The TST allows accurate quantification of the number of conducting Central Motor Neurons, expressed by the TST amplitude ratio.
There was a significant increase in TST amplitude ratio in RR-MS (p < 0.001) and SP-MS patients (p < 0.02) at day 5, paralleling an increase in muscle force. TST amplitude ratio and muscle force remained stable at two months.
In PP-MS, TST amplitude ratio and muscle force did not change. CMCT did not change significantly in any of the three groups.
In RR-MS and SP-MS, IVMP is followed by a prompt increase in conducting Central Motor Neurons paralleled by improvement in muscle force, which most probably reflects partial resolution of Central Conduction Block.
The lack of similar clinical and NeuroPhysiological changes in PP-MS corroborates previous clinical reports on limited IVMP efficacy in this patient group and points to PathoPhysiological differences underlying exacerbations in PP-MS.
Gray And White Matter Brain Atrophy And NeuroPsychological Impairment In Multiple Sclerosis
Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R
Neurology 2006 Mar 14;66(5):685-92
SUNY-University, School of Medicine and Biomedical Sciences, Department of Neurology, Buffalo, NY, USA
The relationship of Gray and White Matter Atrophy in Multiple Sclerosis (MS) to NeuroPsychological and NeuroPsychiatric impairment has not been examined.
In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain Whole Brain normalized volumes of Gray and White Matter, as well as measured conventional lesion burden (total T1 HypoIntense and FLAIR HyperIntense lesion volume).
The whole Brain segmentation was corrected for misclassification related to MS Brain lesions.
To compare the effects of Gray Matter, White Matter, and lesion volumes with respect to Brain-behavior relationships, the MS group (disease duration = 11.2 +/- 8.8 years;
EDSS score = 3.3 +/- 1.9) underwent NeuroPsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83).
The MS group had smaller Gray (p = 0.009) and White Matter Volume (p = 0.018), impaired Cognitive performance (Verbal Memory, Visual Memory, Processing Speed, and Working Memory) (all p < 0.0001), and greater NeuroPsychiatric symptoms (Depression, p < 0.0001;
Dysphoria, p < 0.0001; Irritability, p < 0.0001; Anxiety, p < 0.0001; Euphoria, p = 0.006;
Agitation, p = 0.02; Apathy, p = 0.02; and Disinhibition, p = 0.11) vs controls.
Hierarchical stepwise regression analysis revealed that Whole Gray and White Matter Volumes accounted for greater variance than lesion burden in explaining Cognitive performance and NeuroPsychiatric symptoms.
White Matter Volume was the best predictor of mental processing speed and Working Memory, whereas Gray Matter Volume predicted Verbal Memory, Euphoria, and Disinhibition.
Both Gray and White Brain Matter Atrophy contribute to NeuroPsychological deficits in Multiple Sclerosis.
Risk Of Multiple Sclerosis After Head Injury: Record Linkage Study
Goldacre MJ, Abisgold JD, Yeates DG, Seagroatt V
J Neurol NeuroSurg Psychiatry 2006 Mar;77(3):351-3
University of Oxford, Unit of Health-Care, Department of Public Health, Old Road Campus, Oxford OX3 7LF, UK
The possibility that head injury may influence the development of Multiple Sclerosis (MS) has been studied inconclusively in the past.
To determine whether head injury is associated with an increased risk of MS.
Analysis of database of linked hospital and death records, comparing the occurrence of MS in a cohort of people admitted to hospital with head injury and a reference cohort.
The rate ratio for MS after head injury, compared with the reference cohort, was 1.1 (95% confidence interval, 0.88 to 1.36). There was no significant increase in the risk of MS at either short or long time periods after head injury.
Using length of hospital stay as a proxy for severity of injury, there was no significant increase in the rate ratio for MS after head injuries with hospital stays of less than two days (rate ratio = 1.1 (0.71 to 1.57)), two or more days (rate ratio = 1.0 (0.68 to 1.45)), or seven or more days (rate ratio = 1.3 (0.64 to 2.34)).
The method used, record linkage, ensures that patients' recollection of injury, or any tendency to attribute MS to injury, cannot have influenced the results.
Injuries to the head were not associated with either the Etiological initiation or the clinical precipitation of onset of Multiple Sclerosis.
Tellez N, Rio J, Tintore M, Nos C, Galan I, Montalban X
J Neurol 2006 Jun 13
2 feminine planta EUI Unitat de NeuroImmunologia, Clinica Hospital, Universitari Vall d'Hebron Ps, Vall d'Hebron 119-120, 08035, Barcelona, Spain
Background And Objective
Fatigue is one of the most frequent symptoms in Multiple Sclerosis (MS) but there is a lack of knowledge about its behavior over time.
The aim of our study was to investigate changes in Fatigue in a large cohort of MS patients and to determine the relationship between changes in disability and Depression with changes in Fatigue severity.
We studied Fatigue in 227 MS consecutive patients and again after one year. During the clinical interview, we recorded the patient's degree of disability using the Expanded Disability Status Scale and relapses.
Fatigue was measured by means of the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) and Depression was measured by the Beck Depression Inventory (BDI).
After a mean follow-up of 18 months, 86.8% of patients who were fatigued at study onset remained in a fatigued status, whereas 25% of those without Fatigue at onset had become fatigued at the end of follow-up.
We observed that only variations on BDI scores positively correlate with variations on Fatigue scales, mainly with MFIS (r = 0.49, p < 0.0001).
An increase of BDI score was the factor that best predicted the increase of Fatigue over time.
No differences in the increase of Fatigue were found between patients with and without progression of disability during the follow-up period, or between patients with or without relapses.
Fatigue in MS persists over time. Changes in mood status but not in disability are related to changes in Fatigue in MS patients.