Stress In MS

  1. A temporal framework for understanding the effects of stressful life events on inflammation in patients with Multiple Sclerosis
    Brain Behav Immun 2006 Jan;20(1):27-36

  2. Disease progression in CREAE is associated with reduced inflammation-driven CorticoSterone production
    Endocrinology 2001 Aug;142(8):3616-24

  1. Combined treatment with CorticoSteroids and Moclobemide favors Normalization of Hypothalamo-Pituitary-Adrenal Axis dysregulation in R/R Multiple Sclerosis
    J Clin Endocrinol Metab 2001 Apr 1;86(4):1610-1615

  2. HypoThalamic-Pituitary-Adrenal dysfunction in MS
    Arch Neurol 1998;55:66-72 January 1998

  3. Role of the HypoThalamic Pituitary Adrenal Axis in the control of the response to stress and infection
    Braz J Med Biol Res 2000 Oct;33(10):1121-31

  4. Immune response to psychological stress In MS
    J NeuroImmunol (1996 Aug) 68(1-2):85-94

  5. Cognitive Impairment correlates with HypoThalamo-Pituitary-Adrenal Axis dysregulation in Multiple Sclerosis
    PsychoneuroEndocrinology 2002 May;27(4):505-17

  6. Hypothalamic-Pituitary-Adrenal Axis function and Cytokine production in Multiple Sclerosis with or without Interferon-beta treatment
    Acta Neurol Scand 2002 May;105(5):372-7

  7. HypoThalamo-Pituitary-Adrenal Axis activity predicts disease progression in Multiple Sclerosis
    J Neuroimmunol 2005 Aug;165(1-2):186-91

  8. The HypoThalamo-Pituitary-Adrenal Axis in Multiple Sclerosis
    Ann N Y Acad Sci 2003 May;992:118-28

  9. Stress-induced ImmunoModulation
    JAMA 1999;281:2268-2270

  10. The NeuroEndocrine axis in Multiple Sclerosis
    Brain, Vol 120, Issue 6 1067-1076

  11. Endocrine function in Multiple Sclerosis
    Acta Neurol Scand 1992 May;85(5):353-7

  12. Effect of DeMyelination on Mood in Multiple Sclerosis
    Neurology 1997;49:1105-10


Combined Treatment With CorticoSteroids And Moclobemide Favors Normalization Of Hypothalamo-Pituitary-Adrenal Axis Dysregulation In Relapsing/Remitting Multiple Sclerosis

A randomized, double blind trial
Bergh FT, Kumpfel T, Grasser A, Rupprecht R, Holsboer F, Trenkwalder C
J Clin Endocrinol Metab 2001 Apr 1;86(4):1610-1615
Max Planck Institute of Psychiatry, Dept of Neurology, 80804 Munich, Germany
PMID# 11297592

HyperResponsiveness of the HypoThalamo-Pituitary-Adrenal (HPA) axis in Multiple Sclerosis (MS), an AutoImmune Inflammatory Disease of the Central Nervous System, is presumably due to diminished CorticoSteroid Receptor function.

It probably influences the Immune Response, but its clinical significance is not clear. Similar HPA dysregulation occurs in Depression and is reversible with successful AntiDepressant treatment.

We conducted a double blind, placebo-controlled trial to evaluate the NeuroEndocrine effect of cotreatment with the AntiDepressant Moclobemide as an adjunct to oral CorticoSteroids in MS.

Twenty-one patients with definite Relapsing/Remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of Neurological Impairment, 2.0-6.5) in acute relapse were treated with placebo (n = 13) or 300 mg Moclobemide (reversible Monoamine Oxidase A Inhibitor; n = 8) for 75 days.

All received oral FluoCortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined Dexamethasone-CRH test and clinically on days 1, 30, and 75.

At baseline, the HPA Axis was mildly activated, comparably for treatment groups [area under the curve for Cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the Moclobemide group vs. 225.8 +/- 65.1 in the Steroid alone group; mean +/- SEM].

In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1.

Moclobemide cotreatment resulted in normalization of the HPA Axis response, whereas the HPA system HyperResponse was maintained with Steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 vs.177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 vs. 199.2 +/- 64.6).

The change in Expanded Disability Status Scale was comparable for both groups.

Although CorticoSteroids alone had no effect on the HPA response using the Dexamethasone-CRH test, treatment with Moclobemide combined with CorticoSteroids favors normalization of the HPA response in Relapsing/Remitting MS.


Mood Disorders & Dysfunction Of The HypoThalamic-Pituitary-Adrenal Axis
In Multiple Sclerosis

Klaus Fassbender, MD; Roland Schmidt, PhD; Reinald Mössner, MD; Udo Kischka, MD; Josy Kühnen, MD; Andreas Schwartz, MD; Michael Hennerici, MD
Arch Neurol 1998;55:66-72 January 1998

PMID# 9443712; UI# 98103949

To investigate the association between Affective and NeuroEndocrine abnormalities, commonly observed in Multiple Sclerosis, with Inflammatory disease activity.

Cross-sectional design. Twenty-three patients with definite Relapsing/Remitting Multiple Sclerosis, age and sex matched control subjects were investigated.

Depression and Anxiety were assessed using structured interviews, self-report measures, and Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria.

Neurologic impairment was assessed by the Kurtzke Expanded Disability Status Scale and function of HypoThalamic-Adrenal-Pituitary Axis was analyzed using a CortiCotropin-Releasing Hormone stimulation test after Dexamethasone suppression.

Inflammatory disease activity was evaluated first by routine and experimental laboratory tests, and second by Magnetic Resonance assessment of Gadolinium uptake of Multiple Sclerotic plaques.

University hospital, a major provider of acute Neurologic care.

Compared with controls, patients with Multiple Sclerosis had higher scores on Depression and Anxiety Scales and exhibited a failure of suppression of Cortisol release after Dexamethasone pretreatment.

Both Affective symptoms and NeuroEndocrine abnormalities were correlated with CerebroSpinal Fluid white blood cell counts and presence of Gadolinium-enhancing lesions on Magnetic Resonance Images; however, no association with the degree of Neurologic impairment was observed.

Affective and NeuroEndocrine Disorders were related to Inflammatory Disease activity but not to degree of Disability, supporting the hypothesis that these symptoms are causally associated with Brain injury.


Role Of The HypoThalamic Pituitary Adrenal Axis In The Control Of The Response To Stress And Infection

McCann SM, Antunes-Rodrigues J, Franci CR, Anselmo-Franci JA, Karanth S, Rettori V
Braz J Med Biol Res 2000 Oct;33(10):1121-31
Pennington BioMedical Research Center (LSU), Baton Rouge, LA 70808-4124, USA
PMID# 11004712

The release of AdrenoCorTicotropin (ACTH) from the CorticoTrophs is controlled principally by Vasopressin and Corticotropin-Releasing Hormone (CRH). Oxytocin may augment the release of ACTH under certain conditions.

Whereas, Atrial Natriuretic Peptide acts as a CorticoTropin Release-Inhibiting Factor to inhibit ACTH release by direct action on the Pituitary.

GlucoCorticoids act on their receptors within the HypoThalamus and anterior Pituitary Gland to suppress the release of Vasopressin and CRH and the release of ACTH in response to these NeuroPeptides.

CRH Neurons in the ParaVentricular Nucleus also project to the Cerebral Cortex and SubCortical regions and to the Locus Ceruleus (LC) in the BrainStem. Cortical influences via the Limbic System and possibly the LC augment CRH release during emotional stress.

Whereas peripheral input by Pain and other Sensory impulses to the LC causes stimulation of the NorAdrenergic Neurons located there that project their Axons to the CRH Neurons stimulating them by alpha-Adrenergic Receptors.

A Muscarinic Cholinergic Receptor is interposed between the alpha-Receptors and Nitric Oxidergic InterNeurons which release Nitric Oxide that activates CRH release by activation of cyclic Guanosine MonoPhosphate, CycloOxygenase, LipoXygenase and EpoXygenase.

Vasopressin release during stress may be similarly mediated. Vasopressin augments the release of CRH from the HypoThalamus and also augments the action of CRH on the Pituitary.

CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC NorAdrenergic Neurons whose Axons project to the ParaVentricular Nucleus to augment the release of CRH.


Acute Psychological Stress In Multiple Sclerosis

Ackerman KD Martino M Heyman R Moyna NM Rabin BS
J NeuroImmunol (1996 Aug) 68(1-2):85-94
Univ of Pittsburgh, Dept of Psychiatry, PA 15213, USA
UI# 96378701

To determine whether MS patients differ from healthy subjects in Stress-related Immune changes, we examined Immunologic alterations following a public speaking task in 25 MS patients and 25 healthy controls.

Both groups demonstrated similar Autonomic, NeuroEndocrine and Immunologic responses to acute Stress.

Neutrophils, Monocytes, CD8+ Suppressor/CytoToxic T-Lymphocytes and NK Cells transiently increased, with parallel changes in NK-Cell activity.

T-Cell proliferation declined at 20 min, followed by increased reactivity at 60 min relative to baseline.

This data suggests that Stress-induced Immune alterations remain intact in MS patients, and may contribute to Immune changes associated with disease exacerbation.


Cognitive Impairment Correlates With HypoThalamo-Pituitary-Adrenal Axis Dysregulation In Multiple Sclerosis

Heesen C, Gold SM, Raji A, Wiedemann K, Schulz KH
PsychoneuroEndocrinology 2002 May;27(4):505-17
University Hospital Eppendorf, Department of Neurology, Martinistrasse 52, D-20246 Hamburg, Germany
PMID# 11912002

HypoThalamo-Pituitary-Adrenal (HPA) dysregulation has recently been demonstrated in Multiple Sclerosis (MS) by means of combined Dexamethasone Corticotropin-Releasing Hormone (Dex-CRH) suppression tests.

Authors found a correlation with course of disease and to a lesser extent with Depressive symptoms. In this study, we aimed to further evaluate whether HPA disturbances in MS are correlated with Cognitive Impairment, disability status, and Fatigue.

Dex-CRH tests were performed in a total of 40 patients and 11 healthy controls. Concomitantly, Cognitive Impairment was evaluated using the symbol digit modalities test and fatigue was assessed by different fatigue severity scales.

When comparing patient subpopulations to healthy subjects, Dex-CRH stimulation tests indicated an HPA hyperactivity in primary and Secondary/Progressive MS, while Relapsing/Remitting patients had response patterns similar to controls.

However, results were only significant for one of the six analysed parameters, i.e. area under the curve calculations of ACTH stimulation.

Within the patient sample, clear-cut differences emerged between groups of different Cognitive Impairment, being significant for all ACTH response parameters.

Our results suggest an HPA hyperactivation related to increased Cognitive Impairment.

Indicators of HPA Axis activation further correlated substantially with Neurologic disability, but only moderately with duration of disease and even less with depressive symptoms and fatigue.

We conclude that the observed dysregulation is more likely a secondary effect of the extent of Brain damage rather than primarily involved in the pathogenesis of MS.


Hypothalamic-Pituitary-Adrenal Axis Function And Cytokine Production In Multiple Sclerosis With Or Without Interferon-beta Treatment

Limone P, Ferrero B, Calvelli P, Del Rizzo P, Rota E, Berardi C, Barberis AM, Isaia GC, Durelli L
Acta Neurol Scand 2002 May;105(5):372-7
University of Turin, Department of Internal Medicine, Turin, Italy
PMID# 11982488

Pro-inflammatory Cytokines mediate Brain damage in Multiple Sclerosis (MS); they can also influence the HypoThalamic-Pituitary-Adrenal (HPA) Axis function.

We evaluated the possible abnormalities of HPA Axis function in Relapsing/Remitting MS (RR-MS).

Material And Methods
IFN-gamma, TNF-alpha and IL-6 production by ex-vivo Lymphocytes from 10 normal volunteers and 10 RR-MS patients before and during IFN-ß therapy was assessed;

Pituitary-Adrenal function was evaluated by means of CRH and ACTH stimulation tests.

In untreated patients the production of IFN-gamma, TNF-alpha, IL-6 was increased, and was significantly decreased by IFN-ß.

Neither basal, nor stimulated ACTH, Cortisol, DHEA, DHEAs, 17-alpha-OH-Progesterone levels differed between controls and RR-MS patients, both before and during treatment.

Moreover, no correlation was found between Endocrine and Immune parameters.

In MS the HPA Axis function seems normal and not influenced by IFN-ß treatment. This result is discussed in relation to the increased production of pro-inflammatory Cytokines found in this disease.


HypoThalamo-Pituitary-Adrenal Axis Activity Predicts Disease Progression In Multiple Sclerosis

Gold SM, Raji A, Huitinga I, Wiedemann K, Schulz KH, Heesen C
J Neuroimmunol 2005 Aug;165(1-2):186-91
University Hospital Eppendorf, Department of Neurology, Martinistrasse 52, 20246 Hamburg, Germany
PMID# 15935481

Clinical studies have shown that groups of Multiple Sclerosis (MS) patients exhibit a chronically activated HypoThalamo-Pituitary-Adrenal (HPA) Axis. However, the association of HPA Axis activity and disease progression in MS is unknown.

In this longitudinal study over a 3-year follow-up period, we report that patients who exhibited stronger HPA reactivity at baseline were significantly more likely to experience progression as measured by the Expanded Disability Status Scale (EDSS) during the follow-up period.

Furthermore, HPA Axis activity correlated with progression ratings and Cognitive Impairment three years later. Tests of HPA Axis activity may be useful biomarkers for disease progression in MS.

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