By: R. L.
Bruno
ABSTRACT
Fatigue is the
most commonly reported and most debilitating Post-Polio Sequelae (PPS)
affecting
the more than
1.8 million North American polio survivors. Post-polio fatigue is
characterized
by subjective
reports of difficulty with attention, cognition and maintaining
wakefulness,
symptoms reminiscent
of nearly two dozen outbreaks during this century of post-viral fatigue
syndromes (PVFS)
that are related clinically, historically, anatomically or
physiologically
to poliovirus infections.
Recent studies that relate the symptoms of post-polio fatigue and
Chronic
Fatigue Syndrome
(CFS) to clinically significant deficits on neuropsychologic tests of
attention,
histopathologic and neuroradiologic evidence of brain lesions, impaired
activation of the hypothalamic-pituitary-adrenal axis, increased
prolactin
secretion and EEG slow wave activity are reviewed.
Described will be a possible common pathophysiology for post-polio
fatigue
and CFS, based
on the Brain Fatigue Generator Model of PVFS, and a possibility
pharmacotherapy
for PVFS based on the replacement of brain dopamine.
Fatigue is the
most commonly reported and most debilitating Post-Polio Sequelae (PPS)
affecting the
more than 1.8 million North American polio survivors. In two national
surveys,
91% of polio survivors
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 exacerbated by physical overexertion in
92% and by emotional stress in 61%.
Importantly,
polio survivors differentiate 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 cognition. Between
70% and 96% of polio survivors reporting fatigue complained of
difficulty
with concentration, memory, attention, word-finding, maintaining
wakefulness
and thinking clearly, with 77% percent reporting moderate to severe
difficulty
with these symptoms (3).
These reports
are reminiscent of the symptoms associated with nearly two dozen
outbreaks
during this
century of Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome
(CFS), conditions that
can be related historically, clinically, anatomically or
physiologically
to poliovirus infections. These relationships will be described in an
attempt
to suggest a possible common pathophysiology for all post-viral fatigue
syndromes (PVFS).
POLIOENCEPHALITIS
AND FATIGUE
Neither the acute
nor late-onset problems with attention and cognition in polio survivors
can be explained
by poliovirus-induced damaged to spinal motor neurons (4). Postmortem
histopathology
performed fifty years ago demonstrated the consistent presence of
poliovirus
lesions in specific brain areas (Figure 1). Brain stem centers were
found
to be involved in even mild cases' of polio (5). The midbrain reticular
formation was always severely altered' (6), being heavily peppered
throughout'
(7-11) with lesions that were very common and often severe' (7).
Hypothalamic,
thalamic and caudate nuclei, the putamen and globus pallidus were also
lesioned by the poliovirus (11,12). Neurons in the periaquiductal gray,
locus ceruleus, median raphe nuclei and especially the substantia nigra
were also damaged or destroyed by poliovirus infection (5, 8-11).
These findings
indicate that poliovirus consistently and often severely damaged the
brain
areas responsible
for cortical activation, the reticular formation, hypothalamus,
thalamus,
substantia nigra
and locus ceruleus , i.e., the reticular activating system (RAS)
(13-20).
And, clinical reports written
during the polio epidemics corroborate the pathological evidence of
poliovirus
damage to the
RAS since drowsiness,' lethargy, prolonged somnolence, rousable stupor
and even coma were described as sequelae of the acute poliovirus
infection
(7,12,21,22). Holmgren (23) reported that
34% of 258 patients with acute spinal, spinal/bulbar and non-paralytic
poliomyelitis demonstrated
mental changes' such as 'disorientation, apathy, pronounced sleep
disorder (and) irritability.'
These changes were significantly correlated with abnormal slowing of
the electroencephalogram
(EEG) (the emergence of theta and some delta activity') in 42% of those
with spinal or spinal
and bulbar symptoms as well as in 33% of those with non-paralytic
poliomyelitis. Meyer
(24) reported that a high percentage of children clinically recovered
from poliomyelitis insofar
as motor disability is concerned, reveal qualitative difficulties in
mental functioning (such
as) fatigability (sic) and fleeting attention' for months after the
acute
episode.
Late-onset post-polio
fatigue, ME and CFS are now compared using techniques that were
unavailable
during the the 1950Õs (25-28). However, the historical
parallels
between the poliovirus and chronic fatigue should not be overlooked,
since
history provides its own lessons as well as a context in which new
empirical
data can more meaningfully be interpreted.
HISTORICAL PARALLELS
Attenuated' Type
II Poliovirus Infection and Impaired Cortical Activation. During the
polio
epidemics of the 1950Õs, a syndrome of impaired cortical
activation
and parkinsonism was attributed to the poliovirus. In 1951, three cases
of drowsiness' and rousable stupor with marked slowing of the EEG,
bulbar
signs' and parkinsonism were reported (29). While these symptoms were
atypical
of polio, their occurrence in an area where poliomyelitis had become a
serious problem,' and the pathologic evidence that the main brunt of
the
disorder was borne by the midbrain,' prompted the authors to suggest
that
the syndrome might be caused by a poliovirus with attenuated
virulence.'
In 1952 eight additional patients were described having an encephalitis
whose dominant features were again somnolence and extrapyramidal
symptoms
(30). Type II poliovirus was isolated from half of these patients, and
the two fatal cases that came to autopsy had lesions in the reticular
formation,
hypothalamus and substantia nigra.
The association
of poliovirus-induced somnolence with extrapyramidal symptoms
highlights
the prominence of poliovirus lesions in the basal ganglia and
importance
of the basal ganglia (BG) in maintaining
cortical activation (31,32). The BG are thought to gate sensory input'
to the thalamus (32) with the putamen said to control the mechanisms
that
contribute to selective attention' (33). Putamen lesioned animals are
insensitive
to quite gross visual stimuli' and clearly (demonstrate) difficulty
transferring
attention from one object to another' (34). In humans, BG lesions and
impairment
of dopaminergic input to the striatum decrease both the diffuse
activation
of the cortex (35) and the ability to maintain targeted attention'
(36).
For example,
ParkinsonÕs disease (PD) patients demonstrate not only an
impaired
ability to transfer
attention' (37) but also marked fatigue (38). In one survey 33% of PD
patients
reported that
fatigue was their most disabling symptom' (39). Excessive fatigue' was
reported in another study by 48% of PD patients (40), fatigue that was
associated with abnormal glucose metabolism or blood flow in the
putamen
and supplementary motor area (cf. the Brain Fatigue Generator Model,
below).
It is noteworthy that one of the first descriptions of cognitive
dysfunction
in PD (41) could serve as a definition for PVFS, i.e., syndromes
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.'
"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 diagnosed as poliomyelitis, then as "abortive" or
"atypical"
poliomyelitis and finally named Myalgic Encephalomyelitis'
(ME) (26,42).
Like poliomyelitis, initial symptoms of ME included headache, neck
pain,
low-grade fever and myalgia that were often followed by paresis.
Irritability
and anxiety, symptoms typical of the encephalitis accompanying bulbar
polio
(cf. 22), and even a few cases of post-acute parkinsonism (42) were
noted.
Patients demonstrated hypersomnolence and "conspicuous changes in their
levels of concentration" that persisted for months after the acute
illness
(26). Slowing of the EEG with the emergence of theta activity, similar
to that documented in polio survivors, was also noted (44-46, cf. 23).
Unlike poliomyelitis,
there were frequent complaints of numbness or parasthesias, usually no
respiratory involvement, infrequent paralysis or muscle atrophy and
almost
invariably no fatalities. CSF protein was usually normal and poliovirus
was never isolated from ME patients. Also unlike poliomyelitis,
recovery
from the acute symptoms of ME sometimes required months or years (43).
Most patients were left with a marked "exhaustion and fatiguability"
that
were "always made worse by exercise (and) emotional stress' (26).
Patients
continued to demonstrate fatigue, hypersomnolence, impaired
concentration,
and reported "an inordinate desire to sleep," anomia, that they were
"not
as quick or incisive in thought as before, (had) a decreased ability to
learn and a decline in their short-term memory' for years after the
acute
episode (26).
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
(42,47-53).
Type III Poliovirus
and Iceland Disease. A more direct association between the poliovirus
and
ME was seen following a 1948 epidemic in Akureyri, Iceland. Two
patients
presented with fever, myalgia and paresis and were at first diagnosed
as
having poliomyelitis. This diagnosis was quickly discarded as many more
patients reported symptoms atypical of polio, including parasthesias,
numbness,
"nervousness" and "general tiredness" both acutely and for months after
the acute episode. Also unlike poliomyelitis, there was a
case fatality
ratio of zero versus a minimum of 2.0% for polio in Iceland (54) and
poliovirus
was never isolated from any of these patients. When patients were
reexamined
six years after the original outbreak, 72% reported chronic
"nervousness
and general tiredness' and 21% complained of "loss of memory" (55).
Sigurdsson, et
al (54) suggested two alternatives for the cause of this constellation
of symptoms that
he called Akureyri Disease' but has been more commonly referred to as
Iceland
Disease' (ID): 'Either a strain of poliomyelitis virus with unusual
pathologic
properties and of low virulence was responsible for this epidemic or .
. . some unknown neurotropic virus has been present." Support for an
"unusual"
poliovirus as the cause came from Sigurdsson himself (56). There was an
"extensive epidemic" of poliomyelitis caused by Type I poliovirus in
Iceland
during 1955 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 cities
newly-affected
by ID and only 13% of the children in Akureyri, showed 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, respectively,
than
titers in a city where ID had not been reported. The authors concluded
that Type I poliovirus was not related to the occurrence of ID but that
inhabitants of the ID-affected areas had previously been exposed to an
agent 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 (57,58). 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 who had been diagnosed with ME (59).
Post-Polio Fatigue
and Chronic Fatigue Syndrome. A constellation of symptoms resembling ME
was termed Chronic Fatigue Syndrome' (CFS) following a Nevada outbreak
in 1984 (27). Like ME and post-polio fatigue, CFS is characterized by
complaints
of chronic fatigue and impaired concentration that are triggered or
exacerbated
by physical exertion and emotional stress (59). Both CFS patients
(59,60)
and polio survivors (3) report subjective memory impairment and word
finding
difficulty, while 85% of patients with CFS demonstrated an excess of
irregular
slow wave activity' on EEG (61) similar to that seen following ME and
polio
(cf. 23,44-46). And although polio survivors are different from CFS
patients,
being on average 16 years older and having had more years of schooling,
subjective difficulty with concentration is marked in both groups and
the
incidence of fatigue, physical and psychological symptoms are elevated
and significantly higher than in the general population (2,27) (Table
1).
The recent emergence
of CFS has allowed it to be studied using techniques that were
unavailable during the polio,
ME and ID epidemics and that now allow neuropsychologic, neuroanatomic,
neuroendocrine and electrophysiological comparisons between this most
recent
putative PVFS and post-polio fatigue.
EMPIRICAL PARALLELS
Neuropsychologic
Parallels. Some of the subjective difficulties with attention and
cognition
in CFS patients and polio survivors have been corroborated by the
documentation
of clinical abnormalities on neuropsychologic testing. CFS patients
(62,63)
and polio survivors with severe fatigue (25) have been shown to have
clinical
impairments of attention and information processing speed (Table 2). In
spite of these marked impairments of attention, CFS patients (60) and
polio
survivors (2,25,64) have been shown to be within the high normal or
superior
range on measures of higher-level cognitive processes and I.Q., as well
as having higher than average levels of professional achievement.
Further,
despite the high frequency of subjective complaints of memory
impairment
in CFS patients (65) and in 87% of polio survivors reporting fatigue
(25),
verbal memory has been shown to be intact on testing in both groups
(25,63,66).
These findings
indicate that chronic fatigue is associated with impairments of
attention
and information
processing speed but not of verbal memory or higher-level cognitive
processes
both in patients
with CFS and in polio survivors. Given the histopathologic
documentation
of frequent and severe poliovirus lesions in the brainÕs
activating
system, it was hypothesized that damage to the RAS and BG is
responsible
for both fatigue and impaired attention in polio survivors.
Neuroanatomic
Parallels. To test this hypothesis, magnetic resonance imaging (MRI) of
the brain was performed in hope of documenting poliovirus lesions in
the
RAS and BG. Carefully selected polio survivors who had unequivocal
histories
of polio and were free from comorbidities that could have caused
fatigue
or cognitive problems were imaged (67). Areas of hyperintense signal in
gray and white matter were imaged in 55% of subjects who rated their
daily
fatigue as moderate or higher but were not seen in any of the subjects
reporting no or mild daily fatigue (Figure 2). Small discrete areas of
HS were imaged in the putamen and rostral reticular formation. Multiple
punctate areas of HS were imaged in the periventricular and deep white
matter and discrete areas of HS were seen in the centrum semiovale that
were as large as 24.0 mm2. Subjects with and without HS were equal in
terms
of age, years of education, age at polio and the severity of acute
polio.
The presence of HS was significantly correlated with fatigue
severity,
year of acute polio and years since polio, but not with depressive
symptoms,
new respiratory problems or difficulty sleeping (Table 3). The presence
of HS was also significantly correlated with the frequency or severity
of subjective difficulty with recent memory, thinking clearly, mind
wandering,
attention and concentration. The daily fatigue severity rating was
significantly
correlated with the frequency and severity of all of these cognitive
symptoms
(Table 3).
These data support
the hypothesis that areas of hyperintense signal are associated with
late-onset fatigue and subjective
problems with attention in polio survivors and may represent poliovirus
damage within the
brain activating system. Damage to the putamen and caudate nucleus
(16,17,18) and especially
the reticular formation (69) has been shown in other populations to
cause deficits in attention.
The HS imaged in the reticular formation and BG most likely indicate
areas of necrosis where
neurons were destroyed by the acute poliovirus infection. This
conclusion
is supported by a recent case of vaccine-related poliomyelitis in which
HS in the midbrain and medulla on antemortem MRI corresponded with
histopathological
findings of necrosis in the substantia nigra and reticular formation
(68).
HS imaged along
white matter tracts that have been implicated in the centrifugal spread
of the poliovirus
(70,71) may have resulted from damage to the brain parenchma by a
local,
tissue toxic effect
of the poliovirus causing enlarged, fluid-filled spaces around
arterioles
(7), local neuronal atrophy
(71; cf. 72) and possibly axonal demyelination (10,11). Diffuse atrophy
and demyelination of
axons within corticofugal white matter tracts could conceivably impair
transmission, decrease cortical
activation and cause attention deficits and other symptoms of fatigue.
This notion is
supported by studies that have documented a relationship between HS,
impaired
attention and fatigue. First, periventricular and deep white (but not
gray)
matter HS have been imaged
in 27% to 100% of CFS patients and have been suggested to represent
either
enlarged, fluid-filled spaces around arterioles or demyelination
(27,72,73).
Second, white matter HS imaged in both demented (74,75) and
non-demented
(76-78) elderly adults have also been associated with impairments of
attention
and information processing speed similar to those documented in CFS
patients
and polio survivors with fatigue. Third, patients with fatigue
secondary
to multiple sclerosis have been found to have more brain stem and
midbrain
white matter HS as well as decreased glucose metabolism on PET in
cortical
premotor and supplementary motor areas and in the putamen (79),
findings
are similar to abnormalities in the supplementary motor area and
putamen
in PD patients with fatigue (40) (see the Brain Fatigue Generator
Model,
below). Taken together, these finding implicate both damage to the RAS
and BG, as well as a partial disconnection between the RAS, BG,
thalamus
and cortex, underlying the symptoms of fatigue.
(see Figures 3 and 4)
Neuroendocrine
Parallels. The correlation of HS on MRI with the symptoms of post-polio
fatigue suggested
that the effects of poliovirus on other brain centers might also be
evident.
The documentation of hypothalamic lesions on autopsy following
poliovirus
infection suggested that neuroendocrine
abnormalities may also be present. Gupta, et al. (80) reported a marked
decrease in
growth hormone (GH) secretion in polio survivors reporting late-onset
muscle
weakness. Since poliovirus
lesions have been described in the growth hormone releasing hormone-
(GHRH)
and dopamine-secreting neurons of the arcuate nucleus it is possible
that
damage to these neurons could result in a GHRH-induced GH menopause'
with
aging in polio survivors (81).
In addition,
lesions in the paraventricular nucleus (PVN) were frequently documented
following poliovirus infection (70) and could impair the
PVNÕs ability
to secrete corticotropin releasing hormone
(CRH) (82) and thereby decrease ACTH release (see 83).
To examine the
relationship between hypothalamic-pituitary-adrenal (HPA) axis activity
and the symptoms of post-polio fatigue, polio survivors who underwent
neuropsychological
testing (25) had their plasma concentrations of ACTH measured using
radioimmunoassay
following a mild stressor (an overnight fast) which is known to
stimulate
the HPA axis (84). Mean plasma ACTH was elevated and outside of the
normal
range in the mild fatigue subjects (26.7 ± 3.2 ng/ml) as it
should
be following a fast. In contrast, there was no ACTH elevation in
subjects
reporting severe daily fatigue (14.3 ± 0.6 ng/ml). These
findings
suggested that the HPA axis had been activated by the fasting stressor
in the mild fatigue subjects but not in those with severe daily fatigue
who subsequently were found to have clinical impairments of attention
and
information processing speed on neuropsychologic testing (25).
These pilot data
lead to the measurement of plasma ACTH in polio survivors following an
overnight fast (85). Patients with conditions that could have altered
HPA
axis activity were excluded. Again, mean plasma ACTH was significantly
elevated and outside of the normal range in subjects reporting mild
daily
fatigue (28.5 ±17.7 ng/ml) but not in those reporting
moderate or
greater fatigue (19.7±10.7 ng/ml) (t=2.02; p<0.05).
Further,
plasma ACTH was significantly negatively correlated with the daily
fatigue
severity rating, the frequency of problems with recent memory, word
finding
and muscle weakness and the severity of problems with recent memory and
staying awake during the day, but not with the Beck Depression
Inventory
score (Table 3).
These data suggest
that the HPA axis response to a fasting stressor is blunted in polio
survivors reporting fatigue.
This finding, coupled with histopathologic evidence of poliovirus
lesions
in the PVN,
suggested that the hyposecretion of ACTH may be secondary to decreased
production of the hypothalamic secretalogs CRH and vasopressin whose
cell
bodies are located in the PVN (82). Further, the significant negative
correlations
between ACTH level and fatigue severity, cognitive problems and
difficulty
staying awake suggest that a diminution in HPA hormones may contribute
to the symptoms of post-polio fatigue. An existing literature
demonstrates
that reduced levels of CRH and ACTH are associated with fatigue and
impaired
attention, since both peptides exert "stimulatory effects on
biochemical
and electrophysiological parameters of the brain" (83,86). In man,
administration
of ACTH fragments lacking adrenal stimulating activity were associated
with improved memory and alertness, "EEG arousal response patterns,"
increased
sustained attention that was "resistant to attentional fatigue" (87)
and
a "statistically significant fall in fatigue" (88). These results were
attributed to the direct activation of ACTH receptors on neurons in the
hypothalamus, midbrain (89) and "the brain stem, particularly the
non-specific
reticular-thalamic system" (89,90). Thus, post-polio fatigue may be
attributable
to poliovirus lesions not only in the RAS and BG but also in the PVN
which
reduce the secretion of peptides that stimulate the cortex. Decreased
HPA
activity has already been documented in patients with CFS and the
reduced
secretion of "activating" peptides such as CRH and ACTH has been
implicated
in its pathophysiology (91,92).
THE BRAIN FATIGUE
GENERATOR MODEL OF PVFS
Taken together,
the clinical, historical and empirical findings presented above
suggested
the Brain Fatigue Generator (BFG) model of post-polio fatigue and PVFS
(Figure 3). The BFG model postulates that viral damage to the reticular
formation, lenticular, hypothalamic and thalamic nuclei, cortical motor
areas -- and especially dopaminergic neurons in the substantia nigra
and
arcuate nucleus -- decreases cortical activation, not only impairing
attention
and slowing information processing speed, but also inhibiting motor
activity
and generating the disabling visceral' feelings of fatigue: exhaustion,
passivity and an aversion to effort (93) (Figure 4). (The operation and
survival value of a hard-wired, autonomous and normal' Brain Fatigue
Generator
that inhibits motor activity when cortical activation, attention and
information
processing speed are impaired is described fully in 93).
Recent studies
have lent support to the BFG model as an explanation for PVFS. Two
studies
using
SPECT have documented
that decreased brain stem metabolism, and by inference decreased
activity
of RAS neurons, was the only physiological finding differentiating
subjects
with CFS from healthy controls and subjects with depression or
neurological
disease. (94,95) Other studies have provided additional support for the
BFG model as an explanation for post-polio fatigue well as suggesting
that
reduced dopamine secretion may play an important role in the generation
of fatigue symptoms.
Fainting and
Fatigue. Reports of neurally mediated hypotension (NMH) and symptomatic
orthostatic tachycardia syndrome (SOTS) in CFS patients suggest that
there
may be an association between fainting and chronic fatigue. (96-98) The
BFG model predicts such an association, not just in CFS patients but
especially
in polio survivors. The brain stem area most frequently and severely
lesioned
by the poliovirus and other viral encephalitides was the reticular
formation
(RF), which is not only responsible for cortical activation, waking and
focusing attention, but also contains the cardiodepressor center whose
outflow slows the heart via stimulation of the vagus nerve. (99,100)
(Figure
5). Near the RF in the brain stem lie other cardiovascular control
centers,
all of which were also damaged by the poliovirus: the dorsal vagal
nucleus,
responsible for slowing the heart and activating the gut, and the
nucleus
ambiguus and solitary tract nuclei which regulate blood pressure.
Acutely,
patients with bulbar polio,' in which damage to brain stem neurons was
most severe, demonstrated not only respiratory impairment, rousable
stupor,
somnolence and even coma, but also cardiovascular abnormalities.
Cardiodepressor
center abnormalities were the more frequent symptoms, with 73%
demonstrating
hypertension and tachycardia which led to cardiovascular collapse and
death
in 6% (22, 101).
To test the hypothesis
that fatigue is associated with fainting, the 1995 International
Post-Polio Survey asked 1,047
polio survivors and 419 non-disabled control subjects about the
frequency
and cause
of faints during their lifetimes and to rate their current typical
daily
fatigue severity (99). Fatigue
severity was not only significantly higher in polio survivors as
compared
to controls, but also
in polio survivors and controls who had fainted even once, as compared
to those who had never fainted. Daily fatigue severity also increased
in
both groups as the number of lifetime faints increased. Fatigue was
significantly
higher in controls who fainted one time and three times as compared to
controls
who had never fainted. Daily fatigue severity was significantly higher
in polio
survivors who had fainted three, four and five times as compared to
those
who had never fainted.
These findings suggest a physiological relationship between fatigue and
fainting, possibly attributable
to the close proximity of cardiovascular regulation and brain
activation
centers within the
brain stem. Fatigue and hypotension in patients with CFS and in polio
survivors
with late-onset fatigue may be a symptom of damage to RAS neurons and
not
a primary cause of fatigue.
Hypothalamic
abnormalities in polio survivors and CFS patients may also contribute
to
a relationship between fatigue and fainting. CRH release may be
impaired
secondary to PVN damage in polio survivors and CFS patients (85, 92).
Since
the PVN also produces vasopressin, the secretion of which is also
impaired
in CFS (102), PVN damage in polio survivors and CFS patients may reduce
both brain activating and blood pressure regulating hormones, thereby
reinforcing
RAS and BFG abnormalities and predisposing these patients to both
fatigue
and fainting.
EEG Slowing,
Prolactin and Fatigue. The postmortem documentation of RAS and
dopaminergic
neuron lesions in polio survivors, the recent SPECT findings of
decreased
brain stem neuron activation in CFS, and impaired attention in
post-polio
fatigue and CFS all suggest that decreased cortical activation and a
dopamine
deficiency should underlie the symptoms of chronic fatigue. If there is
a dopamine deficiency in polio survivors it should be physiologically
evidenced
by elevated levels of prolactin, since dopaminergic neurons in the
arcuate
nucleus were damaged by the poliovirus and arcuate dopamine secretion
inhibits
prolactin release via dopamine 2 (D2) receptor stimulation (103).
Therefore,
elevated prolactin should be associated with impaired cortical
activation
as evidenced by slowing of the electroencephalogram (EEG). Even in
healthy
subjects, EEG slowing is indicative of impaired cortical activation and
has been associated with decreased arousal, "drowsiness" and impaired
performance
on neuropsychologic tests of attention (104-105). As many as 85% of CFS
patients have been shown to have an excess of irregular slow wave
activity'
on EEG (44-46,61), similar to the theta and delta activity seen in
patients
with acute paralytic and non-paralytic polio (23).
To test the hypothesis
that fatigue, plasma prolactin and EEG slowing are associated with
post-polio
fatigue, polio survivors without medical or psychologic comorbidities
were
studied (106). Subjects were administered the Post-Polio Fatigue
Questionnaire
(PFQ), which asked about cognitive symptoms of fatigue, and had resting
measurements of plasma prolactin and power across the EEG frequency
spectrum
using bilateral temporal-occipital electrode placements. Plasma
prolactin
levels were within the normal range and EEG power was equal between the
two hemispheres across all frequency bands. However, EEG slow wave
power
in the right hemisphere was significantly correlated with daily fatigue
severity and prolactin level (r=.37; p<.05), and prolactin was
significantly
correlated (r=.39; p<.05) with daily fatigue severity.
These data suggest
that EEG slowing is related to the severity of post-polio fatigue
symptoms,
findings similar to those in patients with acute polio and CFS. An
important
role is also suggested for
a dopamine deficiency, implied by the correlation of EEG power and
fatigue
symptoms with prolactin. A recent study further supported the putative
relationship between decreased dopamine secretion,
impaired attention and symptoms of post-polio fatigue. An objective
measure
of word finding
difficulty (animal naming) was significantly correlated not only with
subjective
word finding
difficulty on the PFQ (r=-.41; p<.05) but also with plasma
prolactin
(r=-.36; p<.05) and scores on four
neuropsychologic tests of attention (107). Notably, the animal naming
score
in polio
survivors with fatigue was nearly identical to that measured in
patients
with CFS (108) (Table
3).
Bromocriptine
and Fatigue. To test the hypothesis that treating the putative dopamine
deficiency will
decrease the symptoms of post-polio fatigue, a double-blind,
placeboÐcontrolled
pilot study of
bromocriptine mesylate, a directÐacting, postÐsynaptic
D2 receptor
agonist, was performed in polio
survivors disabled by severe, chronic fatigue. (109) Patients were
placed
on placebo for 28 days
and then on an increasing dose of bromocriptine (from 1.25 to 12.5
mg/day)
for 28 days. Days
on bromocriptine, but not days on placebo, were significantly
negatively
correlated with subjective
difficulty with fatigue on awakening, attention, cognition, word
finding,
memory and staying awake
during the day. It is notable that bromocriptine was effective only in
the most neurophysiologically
impaired subjects, i.e., those with more than twice as many lesions on
MRI, a
blunted ACTH response to an overnight fast and a baseline plasma
prolactin
level nearly double that
of the drug non-responders.
That reduced
dopamine secretion contributes to the symptoms of chronic fatigue is
supported
by a placebo-controlled
study of healthy subjects who were administered remoxipride, a potent
and selective D2 receptor
antagonist. (110) The most frequently reported effects of D2 receptor
blockade were "moderate
fatigue," "mild somnolence" and "difficulty concentrating."
Statistically
significant, dose-related increases in subjective "drowsiness" and
impairment
on neuropsychologic tests of auditory vigilance, continuous attention
and
critical flicker fusion were also found following D2 receptor blockade.
CONCLUSION
These data suggest
that the polioviruses may be the prototypes for chronic
fatigue-producing
agents, since they routinely and often preferentially damage neurons
responsible
for brain activation and the BFG. Post-polio fatigue may provide a
complete
model for a post-viral fatigue syndrome, since the causative agent is
know,
the damage done by the agent to the brain has been
demonstrated histopathologically,
and the signs of that damage -- neuroanatomic, neuropsychologic,
neuroendocrinologic
and electroencephalographic -- have been documented and correlated with
the symptoms of fatigue.
However, polioviruses
are not the only agents for which the brain's activating system is the
"favourite location."
Lesions in the reticular formation, putamen, thalamus, hypothalamus and
white matter have
been associated with a variety of viral encephalitides whose symptoms
include markedly impaired
cortical activation and fatigue (e.g., Australian X, Coxsackie B1-6,
Equine, Enterovirus 71, Japanese
B and St. Louis infections) (26-28,111-114). Some viral encephalitides
are histopathologically
and clinically similar to, or actually indistinguishable from,
poliovirus infection (e.g.,
Central European Encephalomyelitis and Coxsackie A9, Coxsackie B1-6,
ECHO, Enteroviruses
70 and 71 infections), the Coxsackie A7 virus producing a paralytic
syndrome
so similar
to that caused by the polioviruses it has been named Poliovirus IV'
(26-28,111-117)
So, while post-polio
fatigue may present a neat and complete' pathophysiological model for
PVFS,
clinicians and researchers must remember that the polioviruses are
neither
alone nor unique in their ability to damage the spinal cord and brain,
impair the RAS and BG, disrupt the BFG and generate chronic fatigue
symptoms.
Given the ubiquity of viruses that can impair brain activation the
existence
of PVFS should be expected. Yet, clinicians and researchers often
refuse
to believe' that there could be a syndrome with a physiological basis
that
has fatigue as its principal symptom. Those of us in the disparate
disciplines
who are studying PVFS should focus less on who is right' about the
etiology
of chronic fatigue and focus both ourselves and front line clinicians
on
what may be wrong' in the brain, and how brain abnormalities causing
fatigue
symptoms may be able to be treated.
ACKNOWLEDGEMENTS
This
paper is dedicated to the memory of Dr. David Bodian, whose pioneering
work describing the pathophysiology of polioencephalitis appeared in
this
journal in 1949. The authors gratefully acknowledge the participation
of
the subjects, the continued support of the George Ohl, Jr., Infantile
Paralysis
Foundation, the generosity and expertise of Dr. E.G. Dowsett and the
efforts
of Mary Ann Solimine, R.N., M.L.S., without whom this work would not
have
been possible.
REFERENCES