The Corpus Callosum

General Fatigue of the Insane?

This is about chronic fatigue syndrome and the association with
XMRV.  I apologize in advance for the provocative title, and the
subsequent gratuitous references to the Nobel Prize, but there is a
point to this.

Take a look at this summary of the “old-fashioned disease”:

During the nineteenth century general paresis of the insane
emerged as a new psychiatric disorder which was extremely common and
completely devastating. While retrospective studies have found earlier
instances of what may have been the same disorder, the first clearly
identified examples of paresis among the insane were described in Paris
after the Napoleonic Wars. Initially regarded as a complication of
insanity by such influential psychiatrists as Jean-Etienne Dominique
Esquirol, general paresis was first described as a distinct disease in
1822 by Antoine Laurent Jesse Bayle.

It is now known to be a late stage of the disease of syphilis…

General Paresis of the Insane was once the most common diagnosis in
psychiatric hospitals.  (Or so I recall, but can’t quickly locate
a reference.)

was granted a Nobel Prize for developing a treatment
for  General Paresis of the Insane, now known as
neurosyphilis.  He was one of only two
psychiatrists to have been a Nobel laureate.  [The other was Eric
R. Kandel
.  (Egas
, who developed the prefrontal
, doesn’t count; he was a neurologist.)]

In the history of medicine, it was an eye-opening moment: an illness
that had been thought to be psychogenic, turned out to be the result of
an infection.

Ordinarily, the discovery that an apparent mental illness was
caused by an infection would result in a reduction in stigma. 
That wasn’t the case with General Paresis of the Insane, due to
the nature of the infection. 

Another historical note: when the connection between a form of insanity
and syphilis was first postulated, it was met with great

Finally having earlier established
to his satisfaction that tabes
was due to syphilis he now pointed to
high correlation between that disorder and general paresis.  Given
the large volume of his data, these were impressive observations.
he met skepticism. ‘Several times,’ Fournier complained, ‘I had the
of having to diagnose syphilitic madness in the presence of very
and justly famous psychiatrists; and almost invariably my opinion was
as a hypothesis which was possible, rational, perhaps tolerable, but
adventurous and tainted with heresy.’

Come to think of it, this is much like the history of chronic fatigue
.  Neurosyphilis is worse than chronic fatigue
syndrome, but the mysteriousness of the loss of function, malicious
stigmatization, and the rejection of a somatic basis, plus the
skepticism heaped upon early investigators, are all similar. 

One of the big items in recent medical science
is the discovery
of a strong association between xenotropic
murine leukemia virus-related virus
and chronic fatigue
syndrome (CFS).  In fact, it is the
News of the Week
in Science Magazine (subscription required
full text).

The association will have to be replicated and otherwise
validated, preferably by the development of effective treatment based
upon the discovery.  Even so, it seems solid. 

From the NYT

“I think this establishes what had always been considered a
psychiatric disease as an infectious disease,” said Dr. Mikovits, who
is research director at the Whittemore Peterson Institute in Reno, a
nonprofit center created by the parents of a woman who has a severe
case of the syndrome.

Dr. Mikovits’ colleague, Dr. Peterson, was interviewed
on NPR
.  He emphasized the issues of stigma:

MONTAGNE: Was your work, though, in the early stages, in a
sense, you know, looked down upon. Like you’re working on something
that everyone knows isn’t really a disease.

Dr. PETERSON: Absolutely. Absolutely. It was a problem in the early
’80s, particularly, and this federal agencies never showed particular
interest in this disease as well.

Stigma is a socially-broadcast value judgment, often imbued with
moralistic overtones.  It is characteristic of a particularly
mean-spirited form of logical error.  As we see from the
reluctance of federal agencies to fund research on CFS, it can have
serious unintended consequences.


  1. #1 Janice P.
    October 12, 2009

    Yeah, just like M.S. used to be called “hysterical paralysis”. Great article!

  2. #2 daedalus2u
    October 12, 2009

    About two years ago, there was a report of a prospective study that demonstrated acute temporary resolution of some of the behavioral symptoms of autism with fever. I discuss the physiology of that in some detail.

    My hypothesis is that the cognitive effects of neurosyphilis are due to the neuroinflammation, and that neuroinflammation is reduced by an increased NO level during fever, the increased NO coming from iNOS.

    NO is a neurotransmitter, and also mediates vasodilation. The prompt vasodilation observed in the BOLD fMRI imaging is undoubtedly due to neurogenic NO release. NO is unique as a neurotransmitter, in that it is freely diffusible through lipid membranes. All NO sensors only “sense” the sum of NO from all sources, including the basal level. When the basal level is changed, that changes the range, onset time and duration of all NO mediated signals. In the case of the vasodilation observed with BOLD fMRI and which is considered to be a precise measure of functional connectivity, the range, onset time and duration would change with the basal NO level too.

    It is my hypothesis that changes to the basal NO level that occur with neuroinflammation (inflammation lowers NO levels) or fever (fever raises NO levels) changes the functional connectivity and so changes the properties of the brain producing the characteristic symptoms. This is non-linear and quite complicated.

    In the context of CFS, I subscribe to the low NO hypothesis, which is described here.

    I think the association with virus is likely to be real but non-causal. I don’t think the virus causes CFS, I think a persistent low NO state allows for virus to persist at higher levels in PBMCs. I think this is very similar to the increased levels of mycoplasmas also found in PBMCs of CFS patients. The clearance of intracellular debris (including mycoplasmas) is by autophagy, and this is triggered in PBMCs by increased ATP levels. The ATP level is controlled (in part) by the NO level (NO and ATP co-modulate sGC). Low NO levels will reduce clearance of intracellular infectious agents including mycoplasmas (and likely viruses too).

    In the brain during neuroinflammation, the low NO causes low ATP and reduces intracellular transport by ATP powered motors (i.e. transport down the axons). This shows up as reduced proton diffusion on MRI, as “white matter hyperintensities”. The cargo being moved up and down the axons entrains water and that shows up as anisotropic proton diffusion. White matter is mostly axons, so with less ATP, the movement is slowed so there is less apparent proton diffusion. This is non-linear and pretty complicated too. NO is the link between low O2 consumption, low blood flow, low ATP, neuroinflammation and white matter hyperintensities observed in essentially all neurodegenerative diseases (including neurosyphilis). Fever therapy resolved the symptoms of neurosyphilis by resolving the neuroinflammation.

  3. #3 Susan Wenger
    October 12, 2009

    Ah, what a refreshing article. Thank you.

    The link between XMRV and ME/CFS is a great discovery. But it’s not the only discovery implicating biological causes. It seems that EVERY time these sorts of findings make the news (as, say, with Kerr’s genetic subtypes), reporters make a point of saying, gosh golly gee, perhaps this isn’t just in people’s heads after all.

    Short memories. Or maybe a lack of willingness to to as much as a five-minute Google search on the issue before consulting the usual psychiatric “experts.”

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