Then Bergh F, Kumpfel T, Yassouridis A, Lechner C, Holsboer F, Trenkwalder C
Clin Endocrinol (Oxf) 2007 Feb;66(2):295-303
Max Planck Institute of Psychiatry, Section of Neurology, Kraepelinstrasse 10, 80804 Munchen, Germany
Treatment of Multiple Sclerosis with Interferon-beta (IFN-ß) results in variable responses interindividually. Cytokine-hormone interactions may modulate the therapeutic effects of IFN-ß.
Since hyperactivity of the Hypothalamo-Pituitary-Adrenal (HPA Axis) and other NeuroEndorine disturbances occur in Multiple Sclerosis, we determined the detailed NeuroEndocrine response of patients with Multiple Sclerosis to IFN-ß.
Design & Patients
Longitudinal open-label study. Eight patients with Relapsing/Remitting Multiple Sclerosis (four women, age 31.9 +/- 1.5 years, EDSS 1.5-2.5).
Plasma ACTH, Cortisol, Prolactin, GH, TSH, LH and FSH were determined in 30-min intervals during 8 h on four occasions: after intramuscular injection of saline; after the first dose of IFN-ß-1a; after the second IFN-ß dose with oral Indomethacin pretreatment; and after 3 months of IFN-ß therapy.
Dexamethasone-Corticotropin-Releasing Hormone test was performed before and at 3 months on IFN-ß.
Compared to saline, IFN injection resulted in marked rise in plasma ACTH (mean, 370% of baseline), Cortisol (214%), Prolactin (253%) and GH (756%), between 2 and 6 h after injection. With Indomethacin, Hormone secretion occurred with reduced peak values.
Endocrine response adapted partially after 3 months of treatment. HPA axis activity decreased in most patients, but increased in one patient with frequent relapses.
Marked NeuroEndocrine effects occur in response to IFN-ß in Multiple Sclerosis.
Upon prolonged treatment, these effects partially adapt, and HPA Axis hyperactivity is reduced. Prospective studies to determine the relation to individual treatment response can be based on these findings.
Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R
Glia 2007 Mar;55(4):360-8
Lerner Research Institute, The Cleveland Clinic, Department of NeuroSciences, Cleveland, OH 44195, USA
Recent studies have described significant DeMyelination and Microglial activation in the Cerebral Cortex of Brains from Multiple Sclerosis patients.
To date, however, experimental models of Cortical DeMyelination or Cortical inflammation have not been extensively studied.
In this report we describe focal Cortical inflammation induced by stereotaxic injection of killed bacteria (BCG), followed 1 month later by subcutaneous injection of the same Antigen, a protocol that overcomes the Immune privilege of the Cortex.
IntraCerebral BCG injection produced focal Microglial activation at the injection site (termed acute lesion).
Ten days after peripheral challenge (termed Immune-mediated lesion), larger areas and higher densities of activated Microglia were found near the injection site.
In both paradigms, activated Microglia and/or their processes closely apposed Neuronal Perikarya and Apical Dendrites.
In the Immune-mediated lesions, approximately 45% of the AxoSomatic Synapses was displaced by activated Microglia.
Upon activation, therefore, Cortical Microglial migrate to and strip Synapses from Neuronal Perikarya.
Since Neuronal pathology was not a feature of either the acute or Immune-mediated lesion, Synaptic stripping by activated Microglia may have NeuroProtective consequences.
Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C
Brain 2006 Aug;129(Pt 8):1972-83
Georg August University Gottingen, Department of NeuroPathology, Gottingen, Germany
Recent studies have revealed widespread DeMyelination in the Cortex of patients with Chronic Multiple Sclerosis. In contrast to White Matter lesions, Cortical Multiple Sclerosis lesions are accompanied by only minor inflammation.
Research into the pathogenesis of Cortical lesion formation has been hampered by the fact that the conventional rodent model of Multiple Sclerosis, Experimental Autoimmune Encephalomyelitis (EAE), does not regularly affect the Cortex.
To overcome this limitation we developed a new rat model of Cortical Multiple Sclerosis.
Lesions were stereotactically targeted to the Cerebral Cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with Myelin Oligodendrocyte Glycoprotein (MOG).
We thus generated highly reproducible DeMyelinated lesions in the NeoCortex with remarkable histological similarities to Cortical Multiple Sclerosis lesions.
The focal Cortical EAE model led to the typical pattern of IntraCortical and SubPial DeMyelination, infiltration with inflammatory cells, Complement deposition, acute Axonal damage and Neuronal cell death.
Surprisingly, extensive Cortical Inflammation largely resolved within 2 weeks. Furthermore, Cortical DeMyelination was readily compensated by rapid ReMyelination.
Our data thus suggest that Cortical inflammation is a transient phenomenon, and that ReMyelination of Cortical inflammatory-DeMyelinating lesions may occur rapidly.
Neuronal Injury In Multiple Sclerosis
Correale J, Meli F, Ysrraelit C
Medicina (B Aires) 2006;66(5):472-85
Instituto de Investigaciones Neurologicas Dr. Raul Carrea (FLENI), Departamento de Neurologia, Facultad de Ciencias Biomedicas Universidad Austral, Buenos Aires, Argentina
The concept of Multiple Sclerosis (MS) as a DeMyelinating Disease is deeply ingrained. Although the existence of a NeuroDegenerative component has always been apparent, it has only recently become emphasized.
Thus, in recent years several studies have identified Axonal degeneration as the major determinant of irreversible Neurological disability in patients with MS.
Axonal injury begins at disease onset and remains clinically silent for many years; irreversible Neurological disability develops when a threshold of Axonal Loss is reached and CNS compensatory mechanisms are exhausted.
The precise mechanisms of Axonal loss are poorly understood, and three hypotheses have been proposed:
- The damage is caused by an inflammatory process
- There is an excessive accumulation of Intra-Axonal Ca2+
- DeMyelinated Axons undergo degeneration due to lack of Trophic Support by Myelin, or Myelin forming cells
Although MS has traditionally been regarded as a disease of White Matter, DeMyelination can also occur in the Cerebral Cortex. Cortical Lesions exhibit Neuronal injury represented by Dendritic and Axonal transection as well as Neuronal Apoptosis.
Because conventional Nuclear Magnetic Resonance (NMR) is limited in its ability to provide specific information about Axonal pathology in MS, new techniques such as, Diffusion-weighted MRI, Proton Magnetic Resonance Spectroscopy, Functional MRI.
As well as novel techniques designed to measure Atrophy have been developed to monitor MS evolution.
Recognition that MS is in part a NeuroDegenerative Disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment.
PROMiSe Trial Study Group
Wolinsky JS, Narayana PA, O'connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D
Ann Neurol 2007 Jan;61(1):14-24
The University of Texas Health Science Center at Houston, Department of Neurology, Houston, TX
To determine whether Glatiramer Acetate (GA) slows accumulation of disability in Primary/Progressive Multiple Sclerosis.
A total of 943 patients with Primary/Progressive Multiple Sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial.
The primary end point was an intention-to-treat analysis of time to 1- (entry Expanded Disability Status Scale, 3.0-5.0) or 0.5-point Expanded Disability Status Scale change (entry Expanded Disability Status Scale, 5.5-6.5) sustained for 3 months.
The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and Magnetic Resonance Imaging end points were performed.
There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO.
Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193).
The trial failed to demonstrate a treatment effect of GA on Primary/Progressive Multiple Sclerosis.
Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect.
Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.
Ann Neurol 2007;61:14-24.
Distinct Roles Of Protein Kinase R And Toll-Like Receptor 3 In The Activation Of Astrocytes By Viral Stimuli
Carpentier PA, Williams BR, Miller SD
Glia 2007 Feb;55(3):239-52
Northwestern University Institute for NeuroScience, Feinberg School of Medicine, Department of MicroBiology-Immunology, InterDepartmental ImmunoBiology Center, Chicago, Illinois 60611, USA
Impaired Immune surveillance and constitutive ImmunoSuppressive properties make the Central Nervous System (CNS) a particular challenge to Immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection.
We have previously shown that Astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of Innate Immune functions.
In the current study, we examine the activation of Innate Immune functions of Astrocytes by Theiler's Murine Encephalomyelitis Virus (TMEV), a PicornaVirus, which establishes a persistent infection in the CNS of susceptible strains of mice.
And leads to the development of an Autoimmune DeMyelinating Disease that resembles human Multiple Sclerosis.
Astrocytes infected with TMEV are activated to produce type I Interferons, the Cytokine IL-6, and Chemokines CCL2 and CXCL10.
We further examined the mechanisms that are responsible for the activation of Astrocytes in response to direct Viral infection and treatment with poly I:C.
We found that the cytoplasmic dsRNA-activated kinase PKR is important for Innate Immune Responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly.
In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C.
These results highlight the differences between responses induced by direct, NonLytic Virus infection and extracellular poly I:C.
The activation of Astrocytes through these different pathways has implications for the initiation and progression of Viral Encephalitis and DeMyelinating Diseases such as Multiple Sclerosis.
Copyright 2006 Wiley-Liss, Inc.
Familial Effects On The Clinical Course Of Multiple Sclerosis
Hensiek AE, Seaman SR, Barcellos LF, Oturai A, Eraksoi M, Cocco E, Vecsei L, Stewart G, Dubois B, Bellman-Strobl J, Leone M, Andersen O, Bencsik K, Booth D, Celius EG, Harbo HF, Hauser SL, Heard R, Hillert J, Myhr KM, Marrosu MG, Oksenberg JR, Rajda C, Sawcer SJ, Sorensen PS, Zipp F, Compston DA
Neurology 2007 Jan 30;68(5):376-83
University of Cambridge Clinical School, Addenbrooke's Hospital, Department of Clinical NeuroScience, Box 165, Cambridge CB2 2QQ, UK
Familial factors influence susceptibility to Multiple Sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease.
We evaluated 1,083 families with > or =2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity.
And investigated transmission patterns of these clinical features in affected parent-child pairs.
There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001).
And affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately.
Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15).
The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09).
This influence on the natural history is present in all clinical subgroups of Relapsing/Remitting, and Primary and Secondary/Progressive MS, reflecting a familial effect on episodic and Progressive phases of the disease.
There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69).
Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading.
Familial factors do not significantly affect eventual disease severity.
However, they increase the probability of a Progressive clinical course, either from onset or after a phase of Relapsing/Remitting disease. The familial effect is more likely to reflect genetic than environmental conditions.
The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.