NOTE: This Message was originally addressed to Tom Mckeever
      from 76016.3722@compuserve.com and was forwarded to you by Tom Mckeever
                           --------------------
Date:         Sun, 9 Apr 1995 19:49:12 EDT
From:         TOM WALTER 
Subject:      PPS FATIGUE PAPER
To:           Multiple recipients of list POLIO 
PROCEEDINGS OF THE MARCH OF DIMES CONFERENCE ON POST-POLIO SEQUELAE (1995)
THE  CAUSE AND TREATMENT OF POST-POLIO FATIGUE
Richard L. Bruno, Ph.D., Nancy M.Frick, Lh.D., Susan J. Creange, M.A., Todd
Lewis, Ph.D., and Terry Molzen, M.S.
        Fatigue is the most commonly reported, most debilitating and least
studied
Post-Polio Sequelae (PPS) affecting the nearly 2 million North American polio
survivors. Among polio survivors, 91% reported new or increased fatigue, 41%
reported fatigue significantly interfering with performing or completing work
and 25% reported fatigue interfering with self-care activities (1,2). Fatigue
was reported to be triggered or increased by physical overexertion in 92% and
by emotional stress in 61%. Importantly, polio survivors distinguish between
the physical tiredness and decreased endurance they associate with new muscle
weakness, and a "brain fatigue" that is characterized by problems with
attention and thinking. Between 70% and 96% of polio survivors reporting
fatigue complained of problems with concentration, memory, attention,
word-finding, maintaining wakefulness and thinking clearly, with 77% percent
reporting moderate to severe difficulty with these functions (3).
        Problems with attention, memory and thinking suggest that the 
symptoms 
f
post-polio fatigue cannot be explained merely by the poliovirus damaging
anterior horn motor neurons (4). Autopsies performed fifty years ago on
people who died after  having had polio, whether they had paralysis or not,
showed that the poliovirus almost always damaged specific areas in the brain.
These damaged areas include the brain's activating system that keeps you
awake and allows you to focus your attention. The poliovirus also damaged
neurons that produce neurotransmitters, including the enkephalins and
endorphins (called the "body's own morphine") as well as dopamine and ACTH
which activate the brain.
        With poliovirus damaging the brain's activating system, you would 
expec
that the original polio infection should cause brain activating problems.
And, reports written during the polio epidemics did describe "drowsiness,"
lethargy, prolonged sleeping and even coma during the acute polio infection
(7,12,21,22). One-third of patients with acute spinal, spinal and bulbar and
even non-paralytic  polio showed "disorientation, apathy, pronounced sleep
disorder (and) irritability" (4). These mental changes were associated with
the abnormal slowing of brain wave activity on the electroencephalogram
(EEG). Further, a high percentage of children clinically recovered from
poliomyelitis insofar as motor disability is concerned, had qualitative
difficulties in mental functioning such as "fatiguability and fleeting
attention" for months after the acute polio (5).
        These reports of persistent drowsiness, fatigue and fleeting 
ttention
following the acute poliovirus infection are similar to polio survivors'
recent complaints of late-onset fatigue and impaired attention (25).
And, both acute and late-onset post-polio fatigue are reminiscent of nearly
two dozen outbreaks during this century of post-viral fatigue syndromes (PFS)
that are related clinically, historically or anatomically to poliovirus
infections (26-28). These relationships and recent studies comparing
post-polio fatigue and chronic fatigue syndrome will be described in an
attempt to understand the cause and treatment of post-polio fatigue.
CAN THE POLIOVIRUS CAUSE FATIGUE?
        Type II Poliovirus and Decreased Brain Activation. During the polio
epidemics of the 1950's, there were several small outbreaks of patients
having drowsiness, prolonged sleeping, slowing of brain waves, as well as
some of the symptoms of both bulbar polio and Parkinson's disease (e.g.,
tremor and rigidity) (29-30). In 1952, Type II poliovirus was isolated from
one group of patients having these symptoms and it was found that the neurons
in their brain activating system had been damaged.
        The association of decreased brain activation and Parkinson's disease
symptoms remind Dr. Oliver Sachs of the "sleeping sickness" patients with
Parkinson's disease he described Awakenings. The relationship between
"sleeping sickness," Parkinson's disease and polio may be important for
understanding post-polio fatigue, since all of these conditions are
associated with damage to a part of the brain activating system called the
basal ganglia.  For example, Parkinson's disease (PD) patients have severe
damage to one of the basal ganglia, the substantia nigra (sub-STAN-sha
NYE-gra), which produces the neurotransmitter dopamine (doe-PAH-mean). PD
patients often describe fatigue. "Excessive fatigue" was reported by 48% of
PD patients in one study (40) while nearly one-third of PD patients reported
that fatigue was their "most disabling symptom" (39).  As a matter of fact,
one of the first descriptions of Parkinson's disease (41) could serve as a
definition of post-polio fatigue, i.e., a syndrome "characterized by a
diminution of voluntary attention, spontaneous interest, initiative and the
capacity for effort and work, with significant and objective fatiguability,
and a slight diminution of memory" (38).
        "Atypical Poliomyelitis" and Chronic Fatigue. Beginning in Los 
Angeles 
n
1934 and continuing for more than twenty years, there were over a dozen
outbreaks of a disease that was at first thought to be poliomyelitis, was
then called "abortive" or "atypical" poliomyelitis and finally named "Myalgic
Encephalomyelitis" (ME) (6).  Like poliomyelitis, initial symptoms of ME
included headache, neck pain, low-grade fever and muscle pain that were often
followed by muscle weakness. Patients were excessively sleepy and had
"conspicuous changes in their levels of concentration" that lasted for months
after the initial illness. Slowing of the EEG similar to that seen in  acute
polio was also noted.
        Unlike poliomyelitis, there were frequent complaints of numbness or
tingling, usually no breathing problems, paralysis or muscle wasting and
almost invariably no deaths. Also unlike poliomyelitis, recovery from the
initial symptoms of ME sometimes required months with most patients being
left with a marked "exhaustion and fatiguability" that were "always made
worse by exercise (and) emotional stress." Patients continued to have
fatigue, excessive sleepiness, trouble concentrating, difficulty with word
finding, memory and thinking for years after the acute episode.
        Despite the differences between poliomyelitis and ME, an association 
wi
h
the poliovirus was suggested by the fact that, of the more than one dozen ME
outbreaks before the introduction of the Salk vaccine, nine occurred during
or immediately after outbreaks of polio and several involved hospital staff
who cared for polio patients (7).
        Type III Poliovirus and Chronic Fatigue in Iceland. A more direct
association between the poliovirus and ME was seen in 1948 in Akureyri,
Iceland. Patients there presented with fever, muscle pain and weakness and
were at first diagnosed as having poliomyelitis. After about a month, this
diagnosis was discarded as patients reported additional symptoms not typical
of polio, including tingling, numbness, "nervousness" and "general
tiredness."  Also unlike poliomyelitis, no deaths were reported and
poliovirus was never isolated from any of these patients. When patients were
reexamined six years after their original illness, 72% still had chronic
"nervousness and general tiredness" and 21% reported a of "loss of memory."
        It was suggested that either an "unusual" and mild poliovirus or some
unknown virus caused these symptoms that were called "Akureyri Disease" but
are more commonly referred to as "Iceland Disease" (ID). Support for an
"unusual" poliovirus as the cause came in 1955 (10). There was an extensive
epidemic of poliomyelitis in Iceland caused by Type I poliovirus that
coincided with and was followed by outbreaks of ID. Remarkably, two cities in
which ID outbreaks were reported in 1955, as well as the area affected by the
1948 "Akureyri Disease" epidemic, were untouched by poliomyelitis. None of
the children tested in the two ID-affected cities and only 13% of the
children in Akureyri had antibodies to Type I poliovirus as opposed to 86% of
the children tested in the polio epidemic areas. Further, following
poliovirus immunization, children in one of the ID-affected cities
demonstrated antibody titres to Type II and Type III poliovirus that were
four and twenty-five times higher than titres in a city where ID had not been
reported. It was concluded that Type I poliovirus was not the cause of ID,
but the citizens of the ID-affected areas had previously been exposed to
something that was immunologically similar to Type III poliovirus.
        An interesting coda to these findings is the report that when an 
Americ
n
airman who had contracted polio in the 1955 Iceland epidemic returned to
Massachusetts, a small outbreak of ID and polio occurred (11). More recent
support for a relationship between poliovirus and ME came in 1989 when a
"dangerously rising titre" to Type III poliovirus was documented in a patient
who did not have polio but had been diagnosed with ME (12).
        Post-Polio Fatigue and Chronic Fatigue Syndrome. A group of symptoms
resembling ME was termed "Chronic Fatigue Syndrome" (CFS) following a Nevada
outbreak in 1984 (13). Like ME and post-polio fatigue, CFS is characterized
by complaints of chronic fatigue and trouble with concentration, memory and
word finding that are triggered or exacerbated by physical exertion and
emotional stress. And, although polio survivors are on average at least ten
years older than patients with CFS, the years of education, sex distribution,
frequency of difficulty with concentration and psychological symptoms are
nearly identical in the two groups (17,18,19). However, unlike ME and PPS,
CFS patients report recurring sore throat, swollen glands and fever,
suggesting to some that CFS is caused by a recurring or chronic viral
infection. It is important to keep in mind that there is no evidence that PPS
is caused by a persistent infection by any virus, including poliovirus
(14,15).
        The recent occurrence of CFS has allowed it to be studied using
techniques
that were not available during the polio, ME and ID epidemics and now allow
neuropsychologic, neuroanatomic and neuroendocrine comparisons between this
newest CFS and post-polio fatigue.
COMPARISONS OF POST-POLIO FATIGUE AND CFS
        Neuropsychologic Studies. Some of the subjective difficulties with
attention
and cognition in CFS patients and polio survivors have been confirmed with
neuropsychologic testing. CFS patients and polio survivors with severe
fatigue have been shown to have clinical impairments of attention and
information processing speed (16,19). Polio survivors reporting severe
fatigue required 23% to 67% more time to complete tasks requiring sustained
attention and vigilance than did polio survivors with no or mild fatigue. In
spite of these marked impairments of attention, CFS patients and polio
survivors have been shown to have I.Q.s within the high normal or superior
range and have higher than average levels of educational and professional
achievement (17). Further, despite the high frequency of subjective
complaints of memory impairment in CFS patients and in 87% of polio survivors
reporting fatigue, verbal memory has been shown to be intact on testing in
both groups (16,19,20). However, polio survivors have twice been shown to
have trouble recalling visual information whether or not they report fatigue
(7,16).
        These findings indicate that fatigue in CFS patients and polio 
survivor
is
associated with impairment of attention and information processing speed but
not of memory or thinking ability. Given the findings of frequent and severe
poliovirus lesions in the brain's activating system, it was hypothesized that
damage to the brain's activating system is responsible for both fatigue and
impaired attention in polio survivors.
        Brain Scan Studies. To test this hypothesis, magnetic resonance 
imaging
(MRI) of the brain was performed to look for evidence of poliovirus lesions
in the brain's activating system. In a first study, small areas of
hyperintense signal (which look like white spots) on MRI were seen in the
brain's activating system and in the myelinated (insulated) neurons that
connect the brain stem (at the bottom of the brain) to the cortex (the
"supercomputer" at the very top of the brain) in eleven of twelve polio
survivors (1). In a second study, white spots were seen in 55% of polio
survivors with fatigue but were not seen in any of the subjects without
fatigue (21). The presence of the white spots were not only related to
increased fatigue severity, but also to problems with memory, thinking
clearly, mind wandering, attention and concentration.
        Finding white spots on MRI supports the theory that fatigue and 
problem
with attention in polio survivors may be related to damage the poliovirus did
to the brain activating system. This conclusion is supported by a number of
other studies that have shown a relationship between white spots on MRI,
fatigue and problems with attention. Notably, white spots have been seen in
between 40% and 100% of CFS patients (13) and even in healthy elderly adults
who have problems with attention similar to those seen in CFS patients and
polio survivors (22).
        Hormonal Studies. The association of white spots in the brain 
activatin
system with the symptoms of post-polio fatigue suggested that the effects of
poliovirus on other brain areas might also be evident in polio survivors.
For example, poliovirus lesions were often seen on autopsy in the
hypothalamus (hypo-THAL-ah-mus), the brain area that automatically controls
the body's internal environment and its response to stress.
        To test the functioning of the hypothalamus, we measured polio 
survivor
'
blood concentrations of ACTH (a-DRE-no cor-ti-co-TRO-pick hormone), one of
the body's stress hormones whose release is triggered by the hypothalamus.
ACTH was measured following an overnight fast, which is a mild stress known
to cause the release of ACTH (7). ACTH was increased  outside of the normal
range (as it should be following stress) in polio survivors who reported mild
fatigue. However, there was no ACTH increase in subjects reporting severe
daily fatigue. Further, the higher the ACTH level, the lower the subjects'
reported fatigue and the less the difficulty with memory, word finding,
muscle weakness and staying awake during the day.
        These findings indicate that the hypothalamus had not been activated 
in
the
subjects with post-polio fatigue and that ACTH production is reduced in these
individuals. This conclusion is interesting for two reasons. First, ACTH has
been found in humans to promote alertness, increase attention and decrease
fatigue by directly stimulating the brain activating system. Thus, a decrease
in ACTH production may prevent brain activation and contribute to the
symptoms of post-polio fatigue. Decreased activation of the hypothalamus has
already been found in patients with CFS and a decrease in ACTH stimulation of
the brain has been suggested as a cause of  CFS (23).
        Second, a decrease in ACTH production may be caused by a decrease in
production of its parent molecule, POMC. POMC also produces beta-endorphin
(BAY-ta en-DOOR
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