From: Healthy
Partnerships. Ontario: March of Dimes, 1995
By: 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 muscles 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 of 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 (Figure 1).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 expect 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 attention 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
Sacks of the 'sleeping sickness' patients with Parkinson's disease he described
in his book Awakenings.The relationship between 'sleeping sickness,'
Parkinson's disease and polio may be important for understanding post-polio
fatigue, since all of these have 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 in 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 inacute 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 with 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 American 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
(Table 1)(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).
Polio Survivors CFS Patients
|
Polio Survivors
|
CFS Patients
|
Sample Size
|
276
|
¥
|
259
|
Age
|
54 (±11)
|
¥
|
39 (±12)
|
College Graduates
|
40%
|
¥
|
40%
|
% Female
|
73%
|
¥
|
68%
|
I.Q.
|
111 (± 2)
|
#
|
111 (± 4)
|
Difficulty with:
|
|
|
|
Concentration
|
85%
|
¥
|
82%
|
Word Finding
|
82%
|
¥
|
|
Fatigue
|
|
|
|
does not impair functioning
|
21%
|
¤
|
0%
|
limits only social activities
|
13%
|
¤
|
43%
|
impairs work or self-care ability
|
66%
|
¤
|
57%
|
Depressive Symptoms
|
61%
|
¥
|
68%
|
Anxiety
|
74%
|
¥
|
71%
|
Table 1. Comparison of
demographic data and symptom frequency in polio survivors reporting fatigue and
in patients with Chronic Fatigue Syndrome (CFS).
* : Bruno and Frick, 1987; ¥ :
Bruno, et al., 1991; ¤: Bruno, et al., 1993; # : Buchwald, et al., 1992.
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 PFS 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 (Table
1)(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 (Table 1)(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 survivors 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
(Figure 2)(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 problems with attention in polio survivors
may be related to damage the poliovirus did to the brain activating system.This
conclusions 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).
The figure is unavailable
from the source document
Figure 2. A 24 mm2 focus
of hyperintense signal (arrow) in the centrum semiovale in a 50 year old female
polio survivor reporting moderate daily fatigue and frequent problems with
concentration, thinking clearly, short term memory and staying awake (putamen
lesion not seen in this view).
Hormonal Studies.The
association of white spots in the brain activating 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 survivors' 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 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 noACTH 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-fin) which along with
the enkephalins (en-KEF-ah-lins) are 'the body's own morphine.'Since poliovirus
also damaged the brain area that produces enkephalins, both beta-endorphin and
enkephalin production may be reduced in polio survivors.A reduction in the
body's own morphine would help to explain why polio survivors have a nearly
doubled sensitivity to pain (1).
A MODEL FOR POST-POLIO AND
CHRONIC FATIGUE
Taken together, these findings suggest a model for
the cause of post-polio fatigue:
•
Poliovirus damaged the brain activating system;
•
MRI and hormonal findings suggest that damage to
the brain activating system is present today in polio survivors;
•
Neuropsychological testing shows impaired attention
in patients with post-polio fatigue;
•
Therefore, poliovirus damage to the brain's
activating system may cause decreased brain activation, impair attention and
generate the symptoms of post-polio fatigue.
While poliovirus damage to
the brain activating system would be expected to causethe sleepiness,
inattention and fatigue reported during the original polio infection, it is the
recurrence of these symptoms, or their appearance decades after the acute
infection, that are more difficult to explain.The emergence of fatigue decades
after the acute polio may result from normal age-related changes in and loss of
brain activating system neurons that had survived the acute polio infection,
combined with an already decreased number of neurons as a result of the
original poliovirus infection.Eventually, the loss of brain activating system
neurons would decrease cortical activation, reduce attention and produce the
symptoms of fatigue as polio survivors reach mid-life (1).The occurrence of
these symptoms during physical or emotional stress in polio survivors may
reflect the ability of stressors to uncover otherwise unseen damage in the
brain activating system.
IS FATIGUE 'HARD WIRED' INTO THE BRAIN?
The findings presented
above describe an intimate relationship between impaired attention and
fatigue.However, difficulty with attention is not fatigue's only symptom.Even
more disabling is the physical experience of fatigue: feelings of exhaustion,
'passivity and an aversion to continued effort' that generate an aversion to
both mental and physical activity. However unpleasant these feelings are in
man, passivity and aversion to activity have clear survival value, especially
in organisms without conscious awareness that their attention and thinking
speed are impaired. For example, an animal that continues to explore its
environment even though its attention is impaired would be less able to direct
attention on the goal of its exploration (e.g., searching for food) and would
thereby waste already diminishing energy stores.More importantly, impaired
attention could also render the animal unaware of dangers in its environment
(e.g., a predator stalking the animal in search of itsfood). Thus, there would
be survival value in a brain mechanism that monitors cortical activation,
biases an animal toward stopping motor behavior and promotes rest when
attention and thinking speed are impaired.
The Brain 'Listens' to
Itself.Groups of neurons near the bottom of brain called the basal ganglia are
in an ideal location to monitor the level of brain activation and stop an
animal when it has too little attention to allow efficient and safe activity in
its environment.All parts of the cortex connect to one of the basal ganglia,
called the putamen (pew-TAY-men), which 'listens' to the activity level of the
brain (24).If the brain is awake enough, the putamen allows us to focus
attention, to move and to act.When the brain activating system turns down, the
putamen stops the cortex from allowing us to move.Damage to the putamen in
animals has been shown to slow movement, while damage to another of the basal
ganglia, the substantia nigra, decreases or even stops movement and prevents us
from focusing attention (7).
The importance of the
basal ganglia - and especially the neurotransmitter dopamine - in focusing
attention and allowing us to move is most evident in patients with Parkinson's
disease (PD).PD patients, whose damaged substantia nigra neurons produce too
little dopamine, show not only slowed movement and an inability to focus
attention but also excessive and disabling fatigue (7, 38-41).And, remember
Oliver Sacks' Awakenings patients whose damaged basal ganglia caused both
Parkinson's disease and 'sleeping sickness.'
The Brain Fatigue
Generator.It appears that the basal ganglia could produce the mental and
physical symptoms of both normal and pathological fatigue.In normal fatigue, a
long and hard day of work would slow the firing of brain activating system
neurons.This decreased activity would impair attention and information
processing ability recognized by humans as symptoms of fatigue) and produce a
decrease in cortical activation that would slow the firing of putamen neurons,
prevent the release learned motor behaviors and slow or stop activity (Figure
3).Humans would notice problems with focusing attention, feel an aversion to
activity and would be able to move only with significant conscious
effort.Animals would slow or even stop their activity.In both man and animals,
rest or sleep would increase the firing of brain activating system neurons,
restore cortical activation, increase the firing of putamen neurons and once
again allow the release of motor behavior.
The figure is unavailable
from the source document
Figure 3. A model for the
brain fatigue generator.Fatigue would be produced by a reduction inreticular
activating system (RAS) activity that would directly decrease cortical
activation, impair attention and cognition and prevent the firing of putamen
neurons (dark lines).The reduction in putamen activity would then inhibit the
release of motor behavior, further decrease attention and produce the visceral
feelings of 'exhaustion' and aversion to effort that accompany fatigue
(stippled lines).
Pathological states such
as chronic fatigue syndromes could be produced by viral damage to the brain
activating system, putamen and/or dopamine-producing neurons.This damage would
chronically reduce the firing of brain activating system and putamen neurons,
decrease cortical activation and produce the symptoms of fatigue.Poliovirus
would be expected to cause fatigue, impaired cortical activation and decreased
attention since it damages all of these brain areas.
CLINICAL IMPLICATIONS
This description of the
basal ganglia as the brain fatigue generator suggests that increasing brain
levels of dopamine (the neurotransmitter that stimulates the basal ganglia)
might 'turn on' the brain activating system, increase cortical activation and attention,
release motor behaviors and reduce the symptoms of chronic fatigue.We are
currently studying the use of a drug that stimulates dopamine receptors on
brain neurons to treat post-polio patients whose fatigue has not responded to
the current treatments of choice, i.e., adequate rest, energy conservation, the
pacing of activities and reducing physical and emotional stress (2,17,27,28).
Preliminary results show that fatigue, impaired attention and difficulty
staying awake during the day decrease as the dose of the drug increases.
However, there is the very
real danger that taking a drug that reduces fatigue will allow polio survivors
to resume their hyperactive, Type A lifestyles (as they do now when they feel
better following physical, occupational and psychological therapy for PPS) and
further stress poliovirus-damaged, 'metabolically vulnerable' neurons in the
brain and spinal cord. Decreasing 'overuse abuse' will always be
necessary to treat PPS, regardless of whether a drug is found that decreases the
symptoms of fatigue.
It is also possible that
damage to the basal ganglia and a lack of dopamine may be related to other PPS
symptoms.Word finding difficulties, reported by 82% of polio survivors with
fatigue, appear similar both to word finding problems reported by CFS patients
and the 'tip-of-the-tongue' phenomena seen in PD patients (Table 1)(1,7).And,
in a study we have just completed, polio survivors with severe fatigue had low
scores on a test of word finding ability - scores that were identical to those
in Parkinson' patients.
In addition, 63% of polio
survivors report Generalized Random Myoclonus (GRM), the slow contraction or
rapid twitching of hand, arm, trunk and leg muscles at night that disturb sleep
in 33% of polio survivors (2). GRM may provide more evidence that polio
survivors have a brain dopamine shortage, since GRM are similar to 'periodic
movements in sleep' seen in PD patients.
We continue to examine the
possible role of the basal ganglia and dopamine in PPS to help identify the
cause and treatment of not only post-polio fatigue, but also other PPS, CFS and
to understand the neurophysiology of fatigue itself. ACKNOWLEDGEMENTS
The authors gratefully
acknowledge the participation of the subjects, the support of the Joel Leff
Charitable Trust and Deluxe Corporation, the continued support of the George
Ohl, Jr. Foundation, and the efforts and expertise of Mary Ann Solimine, R.N.,
M.L.S., without whom this work would not have been possible. We also thank Drs.
Leonard Kurland and Oliver Sacks for their criticisms of the manuscript and
Esther Carlton of Nichols Institute who provided the 11:00 AM norms for
cortisol and ACTH.
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Please
address all correspondence and reprint requests to: Dr. Richard L. Bruno,
Director Post-Polio Rehabilitation and Research Service, Kessler Institute for
Rehabilitation, 300 Market Street, Saddle Brook, New Jersey 07663. 1 (800)
648-0296 (x6057).
Post Polio Litaff, Association A.C _APPLAC Mexico
