Address for correspondence: Inge Huitinga, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, the Netherlands. Voice: +31-20-5665503; fax: +31-20-6961006.
i.huitinga{at}nih.knaw.nl
During multiple sclerosis (MS), an inflammatory demyelinating
disease of the central nervous system (CNS), activation of the
hypothalamo-pituitary-adrenal (HPA) axis is considered to modulate
the immune system in such a way that the probability of recovery
from a relapse is increased. In a series of postmortem studies
we observed a significant activation of corticotropin releasing
hormone (CRH) neurons and increased cortisol in the cerebrospinal
fluid (CSF) of MS patients, indicating activation of the HPA
axis in this disease. On the other hand, sepsis, while elevating
cortisol in control subjects, did not associate with a further
increase of cortisol in MS patients. Thus, the activated HPA-system
in MS does not respond to an acute inflammatory stimulus. In
order to investigate the role of chronic inflammation in the
CNS in the activation of the HPA axis in MS, MS lesions in the
hypothalamus were quantified and interleukin (IL)-6 levels in
the CSF were determined. There was no difference in IL-6 levels
between MS and control patients. A positive correlation was
found between cortisol and IL-6 in control subjects with sepsis,
but not in MS patients with sepsis or MS and control groups
without sepsis. Thus, IL-6 in the CSF of MS patients is not
the cause of the activation of the HPA system in MS. We found
a remarkably high incidence (95% of the patients) of MS lesions
in the hypothalamus, of which the majority (60%) were active.
The more active lesions were present in the hypothalamus, the
shorter the disease duration to the moment of death, indicative
of a worse disease course. 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.
