Bromley, a very good post and I quite agree with you on the need to increase international collaboration in MS research and many of the other issues you raised as well. A world summit on MS may be just what’s needed to kick it off.
Wesley, I can’t really comment on your ideas, they’re far too scientific for me to understand, but I do appreciate your interest in MS research and certainly support that.
Joyce, I hope they answer your question as well. Perhaps the NMSS could issue a request for research proposals on LDN, one of those $50,000 new investigator grants or something just to get things started in the US.
Now, on to another recommendation for the NMSS research department.
I would like to recommend that the NMSS investigate the question: Are high levels of the stress hormone in cortisol in people with MS a major factor in the MS disease process and/or the disease process itself?
I’ve tried to summarize my rationale for this recommendation because this is a really long post.
MS is a disease with an unknown cause and an unknown cure. It seems to me that undetected and undiagnosed persistently high levels of the stress hormone cortisol (AKA hypercortisolemia and/or HPA hyperactivity) in the CNS of people with MS could be a major factor in the brain and spinal cord atrophy found in people with MS that results in the progression of disability. Gender differences may be involved in this too.
I think this may be a possibility since Cushing’s Syndrome, one of a few diseases known to be associated with high cortisol levels, appears to result in significant brain atrophy. Thus, if high cortisol levels are known to produce brain atrophy in people with Cushing’s Syndrome, it seems reasonable to ask if high cortisol levels in people with MS contribute to the brain and spinal cord atrophy and subsequent disability we experience.
Now, on to some back up information
. I’ve organized it by topic areas,
The MS Disease Process and Brain Atrophy in MS,
Spinal Cord Atrophy in People with MS,
High Cortisol (Stress Hormone) Levels in People with MS,
Links to Brain Atrophy in Cushing’s Syndrome, and lastly,
Gender Differences in Stress (Cortisol) Related Factors
finally noting that both progesterone and desipramine may help reduce high levels of cortisol but that the most important reason to study stress (and the stress hormone cortisol) is because many people with MS associate stress with MS symptoms.
The MS Disease Process and Brain Atrophy in MS
Some highly regarded MS researchers question the auto immune theory of MS and others see a neurodegenerative disease process.
Patricia K. Coyle, M.D., Professor of Neurology, School of Medicine, SUNY at Stony Brook, NY notes the following in an e-article from Medscape, entitled Perfect Pitch: Fine-tuning the Management of Multiple Sclerosis
. I have added the emphasis to these quotes from that article.
“MS is now believed to involve a biphasic disease process
. Early on, inflammation is prominent, corresponding to the relapsing and potentially reversible phase of MS. Later, there is transition to a primarily neurodegenerative phase
, corresponding to progressive MS with irreversible deficits. Although inflammation and neurodegeneration are detected at all time points, 1 process appears to dominate
. This concept is consistent with natural history studies of MS, since most patients begin with relapsing disease but ultimately transition to secondary progressive disease. The presence of distinct MS phases argues for therapy that is tailored to the nature of the disease process.
The classic view of MS is that it is a disease that involves CNS inflammation and demyelination. It is now clear from direct pathologic data and indirect neuroimaging data that it also involves damage to axons and neurons.
Both axon density and volume are reduced in MS, not just within the plaque but also in normal-appearing CNS tissue…. Loss or shrinkage of axons is a major contributor to brain and spinal cord volume loss (atrophy). In patients with MS, prominent CNS atrophy is present very early, even at the time of the first clinical attack. On a yearly basis, brain volume loss in MS is accelerated 3- to 10-fold over that of matched controls.
The importance of axon damage in MS cannot be overstated; it is believed to be the neuroanatomic substrate of permanent disability and disease progression
. Injury to axons undoubtedly reflects multiple factors. At least some of the immune and inflammatory elements that injure axons are distinct from those that damage myelin. Axons or axon components (such as ion channels and neurofilaments) could be the target of a direct primary or secondary immune attack.’’
To reinforce Dr. Coyle’s perspective, an abstract entitled Measures of brain and spinal cord atrophy in multiple sclerosis states
that the measurement of atrophy probably represents axonal loss. “Several recent studies have shown that atrophy is a process closely linked with the progressive phase of multiple sclerosis and worsening disability.
Furthermore it has also been shown that atrophy may evolve despite the absence of inflammatory activity as judged by gadolinium enhanced MRI and thus its measurement gives information in addition to that obtained from conventional MRI.”
Spinal Cord Atrophy in People with MS
A very recent MS research abstract, Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions
“The multiple sclerosis cords were found to be significantly smaller than the controls. The duration of the disease played the most important role in determining spinal cord atrophy. The degree of atrophy varied in different parts of the cord. Individual lesions played a minor role
in local atrophy. Our findings suggest that axonal degeneration
, possibly caused by the cumulative number of lesions in the brain or cord, or an alternative atrophic process
, is responsible for spinal cord atrophy in multiple sclerosis, rather than tissue loss within individual lesions.” (2005)
High Cortisol (Stress Hormone) Levels (aka hypercortisolemia and/or HPA hyperactivity) in People with MS
While people with MS have long associated stress with relapses and worsening symptoms, the bulk of that research in the U.S. has primarily focused on connecting psychosocial stressors of various kinds with MS relapses. An examination of how the stress hormone cortisol may impact people with MS and the MS disease process itself seems to be very low profile in the US MS community.
However, there have been some studies, primarily at the Netherlands Institute for Brain Research in Amsterdam, funded by a Dutch foundation, “Friends MS Research
” focused on high cortisol levels and the HPA axis in people with MS.
Some of the scientific research I’ve uncovered so far is arranged chronologically by date.
Adrenal size is increased in multiple sclerosis. concludes
: “The increased adrenal size in patients with MS may allow excessive glucocorticoid secretion in response to stress and affect immune regulation.” (1994)
Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS
“The degree of hyperactivity was moderate in relapsing-remitting MS patients, intermediate in secondary progressive MS patients, and marked in primary progressive MS patients. Differences were significant between the three patient groups, and between control subjects and each patient group. Indicators of HPA axis activation correlated with neurologic disability (EDSS), but not with the duration of the disease, number of previous relapses, previous corticosteroid treatments, or depressed mood.” This study concludes: “HPA axis hyperactivity in MS is related to the clinical type of disease, with a suggestion of increasing HPA axis dysregulation with disease progression.” (1999)
Dehydroepiandrosterone (DHEA) response to the adrenocorticotropin test and the combined dexamethasone and corticotropin-releasing hormone test in patients with multiple sclerosis. concludes
: “As with the HPA axis system, our results suggest a dysfunction in the DHEA secretion in patients with MS.” (1999)
Hypothalamic lesions in multiple sclerosis concludes
: “We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.” (2001)
Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis
: “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.” (2002)
Cortisol is increased in postmortem cerebrospinal fluid of multiple slcerosis patients: relationship with cytokines and sepsis concludes:
“We concluded that basal level of cortisol is significantly increased in the CSF of MS patients
and that IL-6 is not responsible for this rise. The relationship between cortisol and IL-6 in sepsis is discussed.” (2002)
The hypthalamo-pituitary-adrenal axis in multiple sclerosis.
: “Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions. We propose that this suppression of CRH neurons by active hypothalamic MS lesions causes the concomitant unfavorable disease course via an inadequate cortisol response during relapses of MS.” (2003)
The Exacerbation of Hippocampal Excitotoxicity by Glucocorticoids is Not Mediated by Apoptosis
concludes “Thus, GCs appear to augment excitotoxic death in hippocampal neurons without augmenting the occurrence of apoptosis.” (2003)
Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions which concludes
: “Thus, MS patients have a chronically activated CRH system, but, in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse.” (2004)
Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production concludes
: “We also found a trend towards worsening of clinical status over time with increasing corticosteroid resistance. These data suggest that coticosteroid sensitivity may be a factor in the pathogenesis and could be used for prognosis for MS.”
Links to Brain Atrophy in Cushing’s Syndrome here
, begins "Decreased hippocampal volume is observed in patients with Cushing's syndrome and other conditions associated with elevated cortisol levels, stress, or both
. and here.
Gender Differences in Stress (Cortisol) Related Factors
Contribution of Sex and Cellular Context in the Regulation of Brain Corticosteroid Receptors following Restraint Stress concludes
“These findings provide further evidence for the existence of both regional and gender specificity in the regulation of brain and pituitary corticosteroid receptors following stress, and support the hypothesis of a distinct male and female neuroendocrine axis in response to stress.”
Gonadal hormones affect neuronal vulnerability to excitotoxin-induced degeneration concludes
“These findings are relevant to possible modifications in neurodegenerative risk
in humans as endogenous levels of gonadal hormones change during the menstrual cycle and during aging
Sex Differences and Opposite Effects of Stress on Dendritic Spine Density in the Male versus Female Hippocampus concludes
: “In summary, males and females have different levels of dendritic spine density in the hippocampus under unstressed conditions, and their neuronal anatomy can respond in opposite directions to the same stressful event.” (2001)
Hopefully by now you have some idea of my rationale for asking the NMSS to investigate the question: Are high levels of the stress hormone cortisol in people with MS a major factor in the MS disease process and/or the disease process itself?
It has been demonstrated that people with MS have high cortisol levels and exhibit both brain and spinal cord atrophy that some researchers correlate with the MS disease progress and disability. In another disease, Cushing’s Syndrome, high levels of cortisol are known to result in brain atrophy.
A real “kicker” for me personally is that progesterone (you remember that potentially neuroprotective and myelin repairing hormone
) was recently shown in a very small study to reduce high levels of nocturnal cortisol in women.
And Deb, you might find it interesting that a study involving desipramine seems to suggest that it can possibly reverse glucocorticoid hypersecretion.
However, perhaps the most important reason for the NMSS to investigate this question is that many people with MS think stress is associated with their symptoms (myself included
). The voices and experiences of people with MS need to be recognized and heard.
Having been diagnosed over a year ago now I personally find it astonishing that the MS research community may not have an answer to the cortisol question. This is not a comment about the NMSS. It’s a comment about the status of MS research and the need to listen to people with MS. We have been talking about stress for some time it seems to me.
Thanks again Deb and special thanks to This is MS members whose valuable experiences, knowledge, expertise, support and challenges have prompted me to recommend that NMSS investigate the question I’ve posed.
May we all experience less stress.
--sharon (with no progesterone and high cortisol