EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study Group
Schwid SR, Thorpe J, Sharief M, Sandberg-Wollheim M, Rammohan K, Wendt J, Panitch H, Goodin D, Li D, Chang P, Francis G
Arch Neurol 2005 May;62(5):785-92
University of Rochester, Department of Neurology, Rochester, NY 14642, USA
The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study demonstrated that patients with Multiple Sclerosis (MS) who initiate Interferon-ß-1a therapy with 44 microg 3 times weekly (TIW) were less likely to have a relapse.
Or, activity on Magnetic Resonance Imaging (MRI) compared with those who initiate therapy at a dosage of 30 microg 1 time weekly (QW).
To determine the effect of changing the dosage from 30 microg QW to 44 microg TIW in this extension of the EVIDENCE Study.
Patients with Relapsing MS originally randomized to Interferon-ß-1a, 30 microg QW, during the comparative phase of the study changed to 44 microg TIW, whereas patients originally randomized to 44 microg TIW continued that regimen.
Patients were followed up, on average, for an additional 32 weeks.
Main Outcome Measure
The within-patient pretransition to post-transition change in relapse rate.
At the transition visit, 223 (73%) of 306 patients receiving 30 microg QW converted to 44 microg TIW, and 272 (91%) of 299 receiving 44-microg TIW continued the same therapy.
The post-transition annualized relapse rate decreased from 0.64 to 0.32 for patients increasing the dose (P < .001) and from 0.46 to 0.34 for patients continuing 44-microg TIW (P = .03). The change was greater in those increasing dose and frequency (P = .047).
Patients converting to the 44-mug TIW regimen had fewer active lesions on T2-weighted MRI compared with before the transition (P = .02), whereas those continuing the 44-microg TIW regimen had no significant change in 2 active lesions.
Patients who converted to high-dose/high-frequency Interferon-ß-1a therapy had increased rates of adverse events and treatment terminations consistent with the initiation of high-dose subcutaneous Interferon therapy.
Patients receiving Interferon-ß-1a improved on clinical and MRI disease measures when they changed from 30 microg QW to 44 microg TIW.
Gallo A, Rovaris M, Riva R, Ghezzi A, Benedetti B, Martinelli V, Falini A, Comi G, Filippi M
Arch Neurol 2005 May;62(5):803-8
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Milan, Italy
Diffusion-Tensor (DT) Magnetic Resonance Imaging (MRI) has the potential to elucidate some characteristics of tissue microstructure inaccessible to other MRI techniques.
To investigate whether Normal-Appearing Brain Tissue abnormalities occur in patients with Multiple Sclerosis at the earliest clinical stage and whether their severity is predictive of a short-term disease evolution by using DT MRI.
Forty-five patients and 22 healthy control subjects were studied. All patients had had a Clinically Isolated Syndrome within the 3 months preceding study enrollment and paraclinical evidence of disease dissemination in space.
During a single session, dual-echo, pulsed-gradient spin-echo echo-planar, and post Gadolinium T1-weighted images of the Brain were obtained from each subject.
In patients, dual-echo and enhanced images were obtained after 3 and 12 months, to detect MRI signs of disease dissemination in time. An on-study Neurological Examination was also conducted to ascertain the occurrence of clinical relapses.
Mean Diffusivity and Fractional Anisotropy maps were derived from DT images.
Normal-Appearing White Matter (NAWM) and Normal-Appearing Gray Matter Mean Diffusivity and Fractional Anisotropy Histograms were produced and analyzed.
During the study period, 29 patients showed MRI evidence of disease dissemination in time.
When compared with healthy controls, patients showed higher average NAWM Mean Diffusivity (P = .01), lower average NAWM Mean Diffusivity peak height (P < .001), and Fractional Anisotropy (P < .001).
The DT MRI characteristics of patients did not differ between those with and those without disease dissemination in time at follow-up.
In patients with Multiple Sclerosis at the earliest clinical stage, the severity of NAWM damage does not predict new lesion formation in the short term.
Suggesting that the "diffuse" component of tissue damage is, at least partially, independent of the "discrete," predominantly inflammatory aspects of the disease since its clinical onset.
Kinin B1 Receptor Expression On Multiple Sclerosis MonoNuclear Cells: Correlation With Magnetic Resonance Imaging T2-Weighted Lesion Volume And Clinical Disability
Prat A, Biernacki K, Saroli T, Orav JE, Guttmann CR, Weiner HL, Khoury SJ, Antel JP
Arch Neurol 2005 May;62(5):795-800
Montreal Neurological Institute, McGill University, NeuroImmunology Unit, Montreal, Quebec, Canada
We have previously shown that the inducible Kinin B1 Receptor is expressed on T-Lymphocytes during relapses and progression in Multiple Sclerosis.
To evaluate the correlation between the expression of B1 Receptor on peripheral blood MonoNuclear Cells derived from patients who have Multiple Sclerosis with serial, clinical Magnetic Resonance Imaging and Immunological study-derived measures.
Using frozen samples obtained from a high-frequency Magnetic Resonance Imaging-Immunological study, we analyzed B1 Receptor messenger RNA (mRNA) expression in peripheral blood-derived MonoNuclear Cells serially.
Collected from 6 patients with Multiple Sclerosis and 8 healthy control subjects by semiquantitative radioactive duplex reverse transcriptase-polymerase chain reaction amplification.
Time-course Kinin B1-Actin mRNA ratios were subsequently compared with corresponding clinical Magnetic Resonance Imaging and Immune parameters.
The time-course Kinin B1-Actin mRNA ratio correlated positively with the Expanded Disability Status Scale index (P < .001), occurrence of clinical relapse (P = .02), volume of lesion on T2-weighted images (P < .003).
And InterLeukin 2 Receptor and Major Histocompatibility Complex Class II expression on CD4+ Lymphocytes, but not with Gadolinium-enhancing lesions.
The time-course Kinin B1-Actin mRNA ratios were 5 to 25 times lower in samples derived from healthy controls.
The correlation of Kinin B1 Receptor mRNA levels with dynamic clinical and Magnetic Resonance Imaging measures suggests that expression of this Receptor can serve as an index of disease activity in Multiple Sclerosis.
A Longitudinal fMRI Study On Motor Activity In Patients With Multiple Sclerosis
Pantano P, Mainero C, Lenzi D, Caramia F, Iannetti GD, Piattella MC, Pestalozza I, Di Legge S, Bozzao L, Pozzilli C
Brain 2005 May 18
University of Rome 'La Sapienza', Section of NeuroRadiology, Department of Neurological Sciences, Italy
Using Functional MRI (fMRI), patients with Multiple Sclerosis showed a greater extent of motor activation than controls.
Although functional changes are often interpreted as adaptive and as a contributing factor in limiting the clinical deficit, no longitudinal studies have yet been performed for Multiple Sclerosis.
Sixteen patients with Multiple Sclerosis, two patients with Possible Multiple Sclerosis and nine age-matched controls underwent two fMRI studies with a time interval of 15-26 months.
The Motor task consisted of a self-paced sequential finger opposition movement with the right hand. Patients with Multiple Sclerosis exhibited greater BiLateral activation than controls in both fMRI studies.
At follow-up, patients showed a reduction in functional activity in the IpsiLateral SensoriMotor Cortex and in the ContraLateral Cerebellum. No significant differences between the two fMRI studies were observed in controls.
Activation changes in IpsiLateral Motor Areas correlated inversely with age, extent and progression of T1 lesion load, and occurrence of a new relapse.
This study may help the understanding of the evolution of Brain plastic changes in Multiple Sclerosis.
Indicating that, in younger patients with a less structural Brain damage and Benign clinical course, the Brain reorganizes its functional activity towards a more lateralized pattern of Brain activation.
The tendency towards a normalization of Brain functional activity is hampered in older patients and in those developing relapses or new irreversible Brain damage.
J Neurol Sci 2005 May 14
Ottawa Health Research Institute, Division of NeuroScience, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4K9
Axonal degeneration is a prominent pathological feature in Multiple Sclerosis observed over a century ago. The gradual loss of Axons is thought to underlie irreversible clinical deficits in this disease.
The precise mechanisms of Axonopathy are poorly understood, but likely involve excess accumulation of Ca Ions. In healthy fibers, ATP-dependent pumps support homeostasis of Ionic gradients.
When energy supply is limited, either due to inadequate delivery (e.g., Ischemia, Mitochondrial dysfunction) and/or excessive utilization (e.g., Conduction along DeMyelinated Axons), Ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload.
During Na pump dysfunction, Na can enter Axons through non-inactivating Na Channels, promoting Axonal Na overload and depolarization by allowing K egress.
This will gate Voltage-sensitive Ca Channels and stimulate reverse Na-Ca exchange, leading to further Ca entry. Energy failure will also promote Ca release from IntraCellular stores.
NeuroTransmitters such as Glutamate can be released by reverse operation of Na-dependent transporters, in turn activating a variety of Ionotropic and metabotropic receptors, further exacerbating overload of cellular Ca.
Together, this Ca overload will inappropriately stimulate a variety of Ca-dependent Enzyme systems (e.g., Calpains, Phospholipases), leading to structural and functional Axonal Injury.
Pharmacological interruption at key points in these interrelated injury cascades (e.g., at Voltage-gated Na channels or AMPA receptors) may confer significant NeuroProtection to compromized Central Axons and supporting Glia.
Such agents may represent attractive adjuncts to currently available ImmunoModulatory Therapies.
NeuroFilament Phosphoforms: Surrogate Markers For Axonal Injury, Degeneration And Loss
J Neurol Sci 2005 May 13
Institute of Neurology, University College London, Department of NeuroImmunology, Queen Square, London WC1N 3BG, UK
This review on the role of NeuroFilaments as surrogate markers for Axonal degeneration in Neurological Diseases provides a brief background to Protein synthesis, assembly, function and degeneration.
Methodological techniques for quantification are described and a protein nomenclature is proposed.
The relevance for recognizing AntiNeuroFilament AutoAntiBodies is noted. Pathological implications are discussed in view of ImmunoCytoChemical, cell-culture and Genetic findings.
With reference to the present symposium on Multiple Sclerosis, the current literature on body fluid levels of NeuroFilaments in DeMyelinating Disease is summarized.
Sodium-Mediated Axonal Degeneration In Inflammatory DeMyelinating Disease
Bechtold DA, Smith KJ
J Neurol Sci 2005 May 12
Guy's Campus, King's College, Department of NeuroImmunology, London SE1 1UL, UK
Axonal Degeneration is a major cause of permanent Neurological Deficit in Multiple Sclerosis (MS).
The mechanisms responsible for the degeneration remain unclear, but evidence suggests that a failure to maintain Axonal Sodium Ion homeostasis may be a key step that underlies at least some of the degeneration.
Sodium Ions can accumulate within Axons due to a series of events, including Impulse activity and exposure to inflammatory factors such as Nitric Oxide.
Recent findings have demonstrated that partial blockade of Sodium Channels can protect Axons from Nitric Oxide-mediated degeneration in vitro, and from the effects of NeuroInflammatory Disease in vivo.
This review describes some of the reasons why Sodium Ions might be expected to accumulate within Axons in MS.
And recent observations suggesting that it is possible to protect Axons from degeneration in NeuroInflammatory Disease by partial Sodium Channel blockade.