Detection Of OligoClonal Free kappa Chains In The Absence Of OligoClonal IgG In The CSF Of Patients With Suspected Multiple Sclerosis
Goffette S, Schluep M, Henry H, Duprez T, Sindic CJ
J Neurol NeuroSurg Psychiatry 2004 Feb;75(2):308-10
Cliniques universitaires Saint Luc, Service de Neurologie, UCL, Brussels, Belgium
OligoClonal free kappa Bands are present as frequently as OligoClonal IgG Bands in the CerebroSpinal Fluid (CSF) from patients with Definite Multiple Sclerosis (MS) and can even occur in the absence of OligoClonal IgG.
As such, they too are markers of an ongoing Intrathecal Immune process.
To determine how frequently OligoClonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted OligoClonal IgG.
An ImmunoAffinity mediated ImmunoBlotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and Serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF OligoClonal IgG.
CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al.
Eighteen CSF samples contained OligoClonal free kappa Bands (54%), mainly from patients with motor dysfunction (83%) and Optic Neuritis (64%).
All patients with a positive MRI according to Barkhof's Criteria (n = 6) had free kappa bands in their CSF.
- OligoClonal free kappa Bands in the CSF are related to the dissemination of MS lesions.
- Such bands should be looked for in OligoClonal IgG negative CSF.
- The presence of free kappa Bands in the CSF may be a substitute for OligoClonal IgG in the McDonald's Criteria for diagnosis of MS.
Short-Term Brain Atrophy Changes In Relapsing/Remitting Multiple Sclerosis
Zivadinov R, Bagnato F, Nasuelli D, Bastianello S, Bratina A, Locatelli L, Watts K, Finamore L, Grop A, Dwyer M, Catalan M, Clemenzi A, Millefiorini E, Bakshi R, Zorzon M
J Neurol Sci 2004 Aug 30;223(2):185-93
University of Trieste, Department of Clinical Medicine and Neurology, Trieste, Italy
The objective of this study was to establish whether the time interval of 3 months is sufficient to detect whole-Brain Atrophy changes in patients with Relapsing/Remitting (RR) Multiple Sclerosis (MS).
Another aim was to assess the value of monthly gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) and of different Gd-enhancement patterns as predictors of Brain Atrophy.
Thirty patients with RRMS (mean disease duration 4.9 years, mean age 34.4 years and mean Expanded Disability Status Scale [EDSS] 1.4) were assessed at baseline and monthly for a period of 3 months with clinical and MRI examinations.
Calculations of baseline and monthly absolute and percent changes of MRI measures have been obtained using two semiautomated (Buffalo and Trieste) and one automated (SPM99) segmentation method.
Changes of Brain Parenchymal Fraction (BPF) were investigated according to Gd-enhancement patterns. Mean absolute and percent changes of BPF did not significantly differ at any time point in the study for any of the three methods.
There was slight but not significant decrease of BPF from baseline to month 3: -0.0004 (0.05%), p=0.093 for Trieste; -0.0006 (0.07%), p=0.078 for Buffalo; and -0.0006 (0.08%), p=0.081 for SPM99 method.
In ring-enhancement positive patients, there was a significant difference between baseline and month 3 changes of BPF, EDSS, and number of relapses. Over the study period, we did not demonstrate differences between changes of BPF according to the presence of Gd enhancement.
Longitudinally, multiple regression analysis demonstrated that the only clinical or MRI parameter that predicted BPF decrease was the mean absolute change of ring-enhancing lesion load (R=0.62, p=0.003).
The noteworthy findings of this study are:
- The observation that a significant Brain Atrophy progression cannot be detected over a 3-month period in RRMS.
- The demonstration that the ring-enhancement pattern may contribute to more severe Brain tissue loss in the short term.
- The lack of relationship between the presence and duration of Gd-enhancement activity and Brain Volume changes in the short term.
Correction For IntraCranial Volume In Analysis Of Whole Brain Atrophy In Multiple Sclerosis: The Proportion vs. Residual Method
Sanfilipo MP, Benedict RH, Zivadinov R, Bakshi R
NeuroImage 2004 Aug;22(4):1732-43
SUNY-University at Buffalo School of Medicine and Biomedical Sciences, Department of Neurology, NY 14203, USA
Two techniques that correct (normalize) Regional and Whole Brain Volumes according to head size-the proportion method (Tissue-to-IntraCranial Volume Ratio) and the residual method.
Regression-based predicted Brain tissue volumes are used pervasively in NeuroImaging research, but have received little critical evaluation or direct comparison.
Using a quantitatively derived MRI data set of patients with Multiple Sclerosis (n = 18) and age-/sex-matched normal controls (n = 18), we introduced various types of error into estimates of IntraCranial Volume (ICV) and Absolute Parenchymal Volume (APV).
To observe how this error affected the final outcome of normalized Brain measures and their ability to detect group differences, as computed by a proportion (Brain Parenchymal Fraction [BPF]) and residual method (Predicted Parenchymal Volume [PPV]).
The results indicated that systemic error in ICV and APV values considerably affected BPF means based on the proportion method, except with dependent-related systematic APV error, but essentially did not change statistical power associated with group differences in BPF.
Random error altered BPF means to a much smaller extent, but was associated with moderate reductions in statistical power.
On the other hand, PPV estimates based on the residual method were unaffected by these same ICV and APV errors, except with dependent-related systematic APV error, and were not associated with reductions in statistical power.
Our findings suggest that head size correction of Brain regions with the residual method generally may provide advantages over the proportion method.
Zivadinov R, Bakshi R
J NeuroImaging 2004 Jul;14(3 Suppl):27S-35S
University at Buffalo, SUNY School of Medicine and Biomedical Sciences, Department of Neurology, The Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203, USA
In this review, the authors focus on clinical aspects of Central Nervous System (CNS) Atrophy in Multiple Sclerosis (MS), including the relationship between Atrophy and Disability, disease course, disease duration, quality of life, and Fatigue.
Cross-sectional studies have demonstrated a moderate but significant correlation between Brain or Spinal Cord Atrophy and physical disability in patients with MS.
Longitudinal studies (>/= 5 years) have shown that CNS Atrophy is a significant predictor of subsequent long-term Neurologic deterioration.
The clinical relevance of CNS Atrophy is reinforced by studies showing that Atrophy accounts for more variance than conventional lesion measures in predicting disability.
Impaired quality of life and both Urodynamic and Sexual Dysfunction, but not Fatigue, are associated with Brain Atrophy.
It is likely that once the level of CNS Atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression.
Longitudinal studies suggest that CNS Atrophy may occur in patients with Clinically Isolated DeMyelinating Syndromes who are at high risk for developing Clinically Definite MS.
Longitudinal natural history studies in Relapsing/Remitting, Secondary/Progressive, and Primary/Progressive MS have suggested that patients develop CNS Atrophy at a faster rate in the first few years of disease than later in the disease course.
Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of Brain Atrophy. The authors conclude that measurement of Atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.
Minagar A, Toledo EG, Alexander JS, Kelley RE
J NeuroImaging 2004 Jul;14(3 Suppl):5S-10S
Louisiana State University Health Sciences Center, Department of Neurology, 1501 Kings Highway, Shreveport, LA 71130, USA
For more than a century, Multiple Sclerosis was viewed as a disease process characterized by Oligodendrocyte and Myelin loss, and research into the pathogenesis of Multiple Sclerosis was mainly focused on the mechanisms of inflammation.
However, with development of more sophisticated NeuroImaging and Molecular Biology techniques, attention has shifted to new aspects of pathogenesis of Multiple Sclerosis: Axonal Loss and NeuroDegeneration.
Evidence is increasing that tissue destruction, primarily Axonal Loss and NeuroDegeneration, is a key element in the pathogenesis of Multiple Sclerosis.
In addition, it is now known that Brain and Spinal Cord Atrophy begins early in the disease process of Multiple Sclerosis and advances relentlessly throughout the course of the disease.
Cumulative data suggest that Axonal loss is the major determinant of progressive Neurologic disability in patients with Multiple Sclerosis.
Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in patients with Multiple Sclerosis for < 5 years indicate Brain Atrophy and loss of Axonal integrity.
NeuroDegeneration and Axonal Loss in patients with Multiple Sclerosis are initially accompanied by a local response from Oligodendrocyte Progenitor Cells and some ReMyelination.
However, these repair mechanisms eventually fail, and patients typically develop generalized Brain Atrophy, Cognitive decline, and permanent disability.
Although the exact mechanisms underlying Central Nervous System Atrophy in patients with Multiple Sclerosis are largely unknown.
Evidence exists that Atrophy may represent an epiphenomenon related to the effects of dynamic Inflammation within the Central Nervous System.
Including DeMyelination, Axonal injury, Neuronal Loss, Wallerian Degeneration, and possibly Iron deposition.
This article summarizes the potential mechanisms involved in Central Nervous System Atrophy in patients with Multiple Sclerosis.
Mycophenolate Mofetil In Multiple Sclerosis
Frohman EM, Brannon K, Racke MK, Hawker K
Clin NeuroPharmacol 2004 Mar-Apr;27(2):80-3
University of Texas, Southwestern Medical Center at Dallas, Department of Neurology, USA
To describe experience with the use of Mycophenolate Mofetil (MMF) in the treatment of Multiple Sclerosis (MS).
MMF is a potent ImmunoSuppressant that is a Selective Inhibitor of Inosine 5'-Monophosphate Dehydrogenase Type II, the enzyme responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages.
A retrospective review of experience in treating 79 MS patients with MMF (61 with Secondary/Progressive, 14 with Relapsing/Remitting, and 4 with Primary/Progressive MS) in the authors' MS center.
In most cases, MMF was added as adjunctive therapy in patients already being treated with either Interferon-beta (n = 44) or Glatiramer Acetate (n = 20).
Fifteen patients not able to use Interferon or Glatiramer Acetate were treated with MMF monotherapy.
Seventy percent of the patients continued MMF therapy. Eight patients discontinued therapy because of side effects, 7 patients continued to exhibit evidence of disease progression, 4 were denied insurance coverage, 2 were lost to follow-up.
And, 1 patient had an elevation of hepatic transaminases that resolved on discontinuation of MMF. One patient discontinued MMF therapy secondary to CytomegaloVirus Diarrhea.
MMF was well tolerated by the majority of patients treated. While these clinical observations were uncontrolled, the clinical course of MS was either unchanged or subjectively improved in many of the treated patients.
A randomized controlled trial of MMF in MS, either as monotherapy or in conjunction with Interferon or Glatiramer Acetate, appears warranted.
Early Clinical Predictors And Progression Of Irreversible Disability In Multiple Sclerosis: An Amnesic Process
Confavreux C, Vukusic S, Adeleine P
Brain 2003 Apr;126(Pt 4):770-82
European Database for Multiple Sclerosis (EDMUS) Coordinating Center and Service de Neurologie A, Hopital Neurologique, Lyon, France
Prognosis of Multiple Sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability.
Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached.
We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with Multiple Sclerosis.
We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound).
We used Kaplan-Meier analyzes and Cox regression models to determine the influence of the clinical variables on the time to disability onset.
Median times from onset of Multiple Sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by:
- Symptoms and course
- Relapsing/Remitting or Progressive
- Degree of recovery from the first relapse
- Time to a second Neurological episode
- Number of relapses in the first 5 years of the disease
Similarly, times from onset of Multiple Sclerosis to a score of 6 and 7 were influenced by time to a score of 4.
In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7.
Early assessable clinical variables significantly influence the time from the onset of Multiple Sclerosis to the assignment of a Disability score of 4, but not the subsequent progression of irreversible disability.