Axonal Damage In Multiple Sclerosis Patients With High Versus Low Expanded Disability Status Scale Score
Brass SD, Narayanan S, Antel JP, Lapierre Y, Collins L, Arnold DL
Can J Neurol Sci 2004 May;31(2):225-8
Montreal Neurological Hospital, Department of Neurology and NeuroSurgery, Montreal, Quebec, Canada
The PathoPhysiological basis for differences in disability in patients with Multiple Sclerosis is unclear.
We used Magnetic Resonance Imaging to examine whether differences in Disability in cohorts of Multiple Sclerosis patients with similar T2-weighted lesion load and disease duration were associated with a more destructive disease process in the more disabled patients.
The Benign and severely disabled groups had similar Brain Atrophy metrics and similar decreases of the Neuronal marker, N-AcetylAspartate, in the Normal-Appearing White Matter of the Cerebrum on Magnetic Resonance Spectroscopy examination in vivo. The severely disabled cohort had more Spinal Cord Atrophy.
The dissociation of Spinal Cord Atrophy and Cerebral Atrophy between these two groups suggests that the difference between the more Benign and more disabled groups cannot be explained by a more aggressive pathological process that is affecting the entire NeuroAxis in a homogeneous fashion.
Gadea M, Martinez-Bisbal MC, Marti-Bonmati L, Espert R, Casanova B, Coret F, Celda B
Brain 2004 Jan;127(Pt 1):89-98
Universitat de Valencia, Facultat de Psicologia, Area de Psicobiologia, Avda. Blasco Ibanez 21, E. 46010, Valencia, Spain
Lower levels of N-AcetylAspartate (NAA), a marker of Axonal Damage, have been found in the Normal-Appearing White Matter (NAWM) of Relapsing/Remitting Multiple Sclerosis (RRMS) patients with low physical disability.
However, its relation to the clinical status of these patients remains unclear.
We explored the association between NAA levels [normalized to Creatine (Cr), NAA/Cr] and a Cognitive feature that is not measured by the standard scales that address functional Disability [e.g. Expanded Disability Scale Score (EDSS)] in early RRMS.
Given that a considerable number of RRMS patients present Attentional Dysfunction early in the disease and assuming a functional-anatomical oriented guide:
It was hypothesized that patients with worse Attentional performance would show lower NAWM NAA/Cr values in the Locus Coeruleus Nuclei of the Pontine Ascendant Reticular Activating-System.
Proton Magnetic Resonance Spectroscopy (1H-MRS) examinations with concurrent clinical evaluation were acquired for 19 RRMS patients with a mean evolution time of 24 months (range 10-60) and mild disability (EDSS 0-3.5, median = 1).
1H-MRS was obtained with Spectroscopic imaging and measures were taken from the Right and Left HemiPons.
Attention was measured by means of the Dichotic Listening (DL) paradigm to increase the sensitivity of the testing to subtle Attentional Deficits. A consonant-vowel DL test was measured with and without Attentional instructions.
For the Attentional condition, the test was digitally manipulated to cue automatically to the Ear to be attended, thus allowing the obtention of both a Linguistic Lateralization Index (LI) and an index of integrity of Attentional Shifts (ASI).
Attentional Impairment was demonstrated in 47.3% of the patients. Pontine NAA/Cr levels accounted for 39% of the ASI variability (beta = 0.65, P < 0.002) but did not relate to the LI.
Moreover, when NAA/Cr levels were considered separately as Left and Right HemiPons values in a multivariate stepwise linear regression model, the right NAA/Cr ratio alone explained 43% of the ASI variability (beta = 0.68, P < 0.001).
Since the RRMS patients with greater Attentional Disturbances exhibited the lowest NAA/Cr levels, it is concluded that NAA provides a specific measure of pathological changes that are also relevant for Cognitive functions.
The use of both 1H-MRS and DL showed the connection between Axonal damage at Right Locus Coeruleus and Auditive Selective Attention Dysfunction in early-stage RRMS.
Patterns Of Disease Activity: Clinical And Magnetic Resonance Imaging Study
Thompson AJ, Kermode AG, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, McDonald WI
BMJ 1990 Mar 10;300(6725):631-4
Institute of Neurology, Multiple Sclerosis NMR Research Group, London, UK
To compare the abnormalities shown by Magnetic Resonance Imaging of the Brain in three clinically distinct groups of patients with Multiple Sclerosis, and to correlate the extent of abnormality with the degree of clinical Disability in the three groups.
All patients underwent Magnetic Resonance Imaging and full Neurological Examination, and their disability was scored according to the Expanded Kurtzke Disability State Scale (EDSS).
Setting & Patients
National Hospital for Nervous Diseases (Multiple Sclerosis NMR Research Group). Three groups of patients with confirmed Multiple Sclerosis:
Main Outcome Measures
Number and size of lesions in 17 anatomically defined sites; total lesion load, estimated with an arbitrary scoring system weighted for the size of lesions; and disability score.
Magnetic Resonance Imaging showed that all 41 patients had abnormalities.
These were extensive in the groups with Secondary/Progressive and Benign disease compared with the group with Primary/Progressive disease.
The lesions in the patients with Secondary/Progressive disease were larger and more confluent than those in the two other groups (p = 0.007).
Most lesions (85%) in the patients with Primary/Progressive disease were under 5 mm in diameter; this percentage was higher than that in the two other groups (p = 0.032).
Consequently, the patients with Primary/Progressive disease had the lowest mean lesion load (36.7); that in the patients with Benign disease was 52.7 and that in the patients with Secondary/Progressive disease 64.6 (p = 0.05).
No correlation existed between Disability and total Lesion Load.
The distribution of Brain lesions and of detectable Lesions of the Spinal Cord, and the frequency of Cortical Atrophy, were similar in all groups.
No relation was found between the degree of clinical disability and the extent of abnormality shown by Magnetic Resonance Imaging.
Patients with clinically Benign disease often had extensive abnormalities and those with Primary/Progressive disease had surprisingly few lesions.
Though Magnetic Resonance Imaging increases knowledge of the disease process in Multiple Sclerosis and is invaluable in diagnosis, it is not helpful in predicting Disability in individual patients.
Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC
Brain 2006 Mar;129(Pt 3):584-94
University of Western Ontario London, Department of Clinical Neurological Sciences, Ontario, Canada
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:
- Cases of Primary/Progressive (P/P) disease
- Attack-onset disease where only a single attack has occurred before onset of progression (SAP)
- Secondary/Progressive (S/P) 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 P/P, SAP and S/P-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.