Bruno RL,Sapolsky R, Zimmerman JR, Frick NM.
The pathophysiology of a central cause of post-polio fatigue. Annals of the
New York Academy of Sciences, 1995; 753: 257-275.
And then!!! The article itself.............
PATHOPHYSIOLOGY OF POST-POLIO FATIGUE:
A Role for the Basal Ganglia in the Generation of Fatigue.
Fatigue is the most commonly
reported, most debilitating and least
studied Post-Polio Sequelae (PPS) affecting the more than 1.63 million
American polio survivors with 91% reporting new or increased fatigue, 41%
reporting fatigue significantly interfering with performing or completing work
and 25% reporting fatigue interfering with self-care activities (1,2).
Fatigue was reported to be triggered or exacerbated by physical over-exertion
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 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 and cognition suggest that the symptoms of
post-polio fatigue cannot be explained merely by poliovirus-induced damaged to
anterior horn 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), with the midbrain reticular formation always
severely altered (6) being heavily peppered throughout (7-11) with lesions
that were very common and often severe (7). The hypothalamus, thalamic and
caudate nuclei, 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 the poliovirus (5, 8-11).
These findings indicate that poliovirus consistently and often
severely damaged the brain areas responsible for cortical activation, the
reticular formation (13,14), hypothalamus (15), thalamus (16), locus ceruleus
(17-20), i.e., the reticular activating system (RAS). And, clinical reports
written during the polio epidemics corroborate the pathological evidence of
poliovirus damage to the RAS since drowsiness, lethargy, prolonged somnolence
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) (i.e., 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.
These reports of persistent drowsiness, fatigue and fleeting
attention following the acute poliovirus infection are similar to polio
survivorsÕ 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 empirical
comparisons between post-polio fatigue and chronic fatigue will be described
in an attempt to understand the pathophysiology of post-polio fatigue.
POLIOVIRUS AND FATIGUE
Attenuated Type II Poliovirus Infection and Impaired Cortical
During the polio
epidemics of the 1950's, 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 a 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 patients were described having an
encephalitis whose dominant features were again somnolence and extrapyramidal
symptoms (30). Type II poliovirus was isolated from half of the patients, and
the two fatal cases that came to autopsy had lesions in the reticular
formation, hypothalamus and substantia nigra.
Magoun (31) stated it was surprising that parkinsonism was not a
more common sequelae of all poliovirus infections because of the frequent and
severe injuries to the brain stem. Magoun explained what he called this
paradox by invoking the correlation Bodian reported between the severity of
poliovirus lesions in the reticular formation and basal ganglia: If the
injury to the lower brain stem reticular formation is intense, some of the
vital centers are destroyed and the patient does not survive long enough for
extrapyramidal symptoms to become displayed. If reticular injury is less
intense, it may be below the threshold necessary to evoke (extrapyramidal)
signs (page 250). This correlation of lesion severity may explain why nearly
all of the reported cases of post-polio parkinsonism have been rapidly fatal
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 in maintaining cortical
activation and attention. The basal ganglia are thought to gate sensory
input to the thalamus (33) with the putamen said to control the mechanisms
that contribute to selective attention (34). Putamen lesioned animals are
Òinsensitive to quite gross visual stimuli and Òclearly (demonstrate)
difficulty transferring attention from one object to another (35). In
humans, basal ganglia lesions and impairment of dopaminergic input to the
striatum decrease both the diffuse activation of the cortex (36) and the
ability to Òmaintain targeted attention (37).
For example, ParkinsonÕs disease (PD) patients demonstrate not only
an impaired ability to Òtransfer attention but also marked fatigue (38,39).
ÒExcessive fatigue was reported by 48% of PD patients (40) while nearly
one-third reported that fatigue was their Òmost disabling symptom (39). It
is noteworthy that one of the first descriptions of cognitive dysfunction in
PD (41) could serve as a description of post-polio fatigue, i.e., a syndrome
Òcharacterized 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 diagnosed as poliomyelitis,
then as "abortive" or "atypical" poliomyelitis and finally
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 also 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).
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 (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 Chronic Fatigue in Iceland. A more direct
association between the poliovirus and ME was seen following a 1948 epidemic
in Akureyri, Iceland. Patients presented with fever, myalgia and paresis and
were at first diagnosed as having poliomyelitis. This diagnosis was quickly
discarded as patients reported additional 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 re-examined 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 ÒAkureyri Disease but was 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, on the other hand, some unknown
neurotropic virus has been present." Support for an "unusual"
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 ID-affected cities 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 Òdangerously rising titre to Type III poliovirus was documented
in a patient who did not have polio but had been diagnosed with ME (59).
Post-Polio Fatigue and Chronic
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) reported subjective memory
impairment and word finding difficulty, while 85% of patients with CFS
demonstrated Òan excess of irregular slow wave activity on EEG (61) similar
to that seen following ME and polio (cf.44-46). And, although polio survivors
are on average at least ten years older than patients with CFS, the level of
education, sex distribution, incidence of subjective difficulty with
concentration and concomitant psychological symptoms are nearly identical in
the two groups (2,27).
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 and neuroendocrine comparisons
between this most recent PFS and post-polio fatigue.
EMPIRICAL 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
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 1). 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 (25).
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. and have higher
than average levels of educational and 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). However, polio survivors have twice been shown to have a
clinical impairment of delayed recall of visual information whether or not
they report fatigue (25).
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 in both patients with CFS and
polio survivors. Given the histopathological documentation of frequent and
severe poliovirus lesions in the brainÕs activating system, it was
hypothesized that damage to the RAS and basal ganglia is responsible for both
fatigue and impaired attention in polio survivors.
Neuroanatomic Studies. To test this hypothesis, magnetic resonance
imaging (MRI) of the brain was performed in hope of documenting evidence of
poliovirus lesions in the RAS and basal ganglia. In a first study, small
discrete and multiple punctate areas of hyperintense signal (HS) on MRI were
imaged in the thalamus, caudate nucleus, centrum semiovale, deep and
periventricular white matter in eleven of twelve polio survivors (3). These
areas of HS were interpreted as evidence of poliovirus damage to the basal
ganglia, RAS and its associated corticofugal white matter tracts. However, no
attempt was made in this study to correlate HS with fatigue severity.
In a second study, 22 carefully selected polio survivors who had
unequivocal histories of polio and were free from comorbidities that could
have caused fatigue or cognitive problems underwent MRI of the brain (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
imaged in any of the subjects reporting mild daily fatigue (Figure 2). Small
discrete areas of HS were imaged in the putamen, the rostral reticular
formation and in the right medial leminiscus. 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 5.0 mm2 to 24.0 mm2 in area
(Figure 3). 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 2). The presence of HS
was also significantly correlated with the frequency or severity of
subjective problems 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
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. HS imaged in the putamen and reticular formation most
likely indicate areas where astroglia have replaced neurons destroyed during
the acute poliovirus infection, since gliosis has been correlated with HS in
postmortem examinations of the brains of healthy elderly adults (68). 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
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. 68,72) 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
a number of studies that have documented a relationship between HS, impaired
attention and fatigue. Notably, periventricular and deep white (but not gray)
matter HS have been imaged in between 27% and 100% of CFS patients and have
been suggested to represent either enlarged, fluid-filled spaces around
arterioles or demyelination (27,68,72,73). White matter HS imaged in both
demented (74,75) and non-demented (76-79) 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
Neuroendocrine Studies. 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 in polio survivors. The
documentation of hypothalamic lesions on autopsy following polio suggested
that neuroendocrine abnormalities may also be post-polio sequelae. In 1992,
Gupta, et al. reported a marked decrease in growth hormone secretion in polio
survivors reporting muscle weakness (80). Since poliovirus lesions have been
described in the arcuate nucleus (81) it is possible that damage to these
neurons could result in decreased secretion of growth hormone releasing
hormone with aging of the hypothalamus and thereby cause a decrease in GH
release in mid-life (82).
In addition, lesions in the paraventricular nucleus (PVN) were
frequently documented following poliovirus infection (70) and are of special
interest with regard to the symptoms of post-polio fatigue. PVN lesions could
impair its ability to secrete corticotrophin releasing hormone (CRH) (83) and
thereby decrease ACTH and cortisol release (see 84).
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 cortisol and ACTH measured by a commercial laboratory using
radioimmunoassay following a mild stressor (fasting) which is known to
stimulate the HPA axis (85). Venous blood was drawn from an antecubital vein
immediately upon subjectsÕ 11:00 AM arrival at the Institute, after they has
fasted for eleven hours, but preceding neuropsychological testing. Not
surprisingly, mean plasma ACTH was elevated outside of the normal range (7.2
to 26.0 ng/ml) in the mild fatigue subjects (26.7 ± 3.2 ng/ml). In contrast,
there was no ACTH elevation in subjects reporting severe daily fatigue (14.3
± 0.6 ng/ml). Also, there was no difference in mean plasma cortisol levels
between subjects reporting mild (11.5 ± 4.0 ug/dl) and severe (10.8 ± 1.2 ug/dl)
fatigue, which were within the normal range (6.2 to 19.4 ug/dl) for 11:00 AM.
These findings suggested that the HPA axis had been activated by the fasting
stress 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 neuropsychological testing (25).
These pilot data lead to the measurement of plasma cortisol and ACTH
in 44 patients evaluated by the Post-Polio Service following a similar
fasting stressor: Venous blood was drawn from an antecubital vein immediately
upon patientsÕ 11:00 AM arrival at the Institute after they has fasted for
eleven hours and preceding their first meeting with the post-polio treatment
team. Patients with conditions that could have altered HPA axis activity
(e.g., diabetes, hypothyroidism, administration of hormones) 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 high (i.e., 3 moderate) fatigue (19.7±10.7 ng/ml) (t=2.02;
p<0.05). Further, plasma ACTH was significantly positively correlated with
the number of years since polio and significantly negatively correlated with
the daily fatigue severity rating (Figure 4), 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. Plasma cortisol levels
were neither elevated nor different between subjects reporting mild (14.8 ±
5.7 ug/dl) and high daily fatigue (12.6 ±5.2 ug/dl), nor were cortisol levels
correlated with demographic data or polio severity (Table 2). However, plasma
cortisol was significantly negatively correlated with the frequency of word
finding difficulty and the severity of problems with recent memory.
The severity of depressive symptoms as measured by the Beck Depression
Inventory was not correlated with plasma cortisol or ACTH.
These preliminary data suggest that the HPA axis response to a
fasting stressor is blunted in polio survivors reporting fatigue. This
finding, coupled with histopathological evidence of poliovirus lesions in the
PVN, suggest 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. 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" (84,86). 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 brain activating system but also in the PVN which reduce the
secretion of neuromodulators that stimulate this system.
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). Poteliakhoff (92)
suggests that symptoms of chronic fatigue occur when "exhaustion of cells
in the hypothalamus (leads) to decreased stimulation of the pituitary-adrenal
Such "exhaustion" could conceivably occur more easily in a
whose aging PVN (and arcuate nucleus) neurons may have been lesioned and
reduced in number by a previous viral infection.
It may be of importance to note that a reduction in CRH release would
reduce plasma concentrations of not only ACTH but also b-endorphin via a
decrease in the secretion of their precursor, pro-opiomelanocortin (POMC).
In addition, enkephalin secretion may also be reduced as a result of
documented poliovirus damage to the periaquiductal gray (5,8). A reduction in
b-endorphin and enkephalin production might help to explain polio survivorsÕ
nearly doubled sensitivity to pain (3) as well as contribute to their impaired
attention, since opioid peptides are thought to stimulate the effort (to) pay
attention in animals with experimentally-induced attentional impairments (17).
Taken together, the historical, clinical and empirical findings
presented above suggest a model for the pathophysiology of post-polio fatigue
Poliovirus primarily and sometimes exclusively causes lesions in
the reticular formation, basal ganglia and substantia
nigra that have been associated with acute, post-acute and possibly chronic
impairment of cortical activation, attention and subjective
fatigue; Recent neuropsychologic data have documented impaired
while neuroradiologic and neuroendocrine data have
indicated damage to brain areas responsible for cortical activation and
attention in polio survivors and others with chronic
fatigue; Therefore, poliovirus-induced damage to the brainÕs activating
system may be responsible for decreasing cortical activation,
impairing attention and generating the symptoms of post-polio
While it is explicable that a poliovirus-lesioned brain activating
system could cause acute impairment of cortical activation, inattention and
fatigue, it is the recrudescence or seeming de novo appearance of these
symptoms decades after the acute infection that require explanation. The
emergence of late-onset post-polio fatigue may result from the age-related
attrition of and changes in neurons that had survived the original polio
infection. There is an age-related decrease in the number of substantia
nigra neurons in human brain, with a mean loss of 33% of nigral neurons by
age 50 (93). This age-related loss of nigral neurons, combining with an
already diminished neuronal pool, is thought to be responsible for the
emergence of post-encephalitic parkinsonism (94). In addition, the cell
bodies of animal reticular formation neurons distort and loose dendritic
shafts with aging, abnormalities that resemble degenerative changes in the
aging human cortex (95). Thus, the age-related attrition of substantia nigra
neurons and possible degeneration of reticular formation neurons, combining
with an already decreased number of these neurons as a result of the original
poliovirus infection, may impair the brainÕs activating system sufficiently
to decrease cortical activation and produce impaired attention and fatigue as
polio survivors reach mid-life (3).
A Role for the Basal Ganglia in Post-Polio Fatigue. The findings
presented above suggest an integral relationship between poliovirus lesions
in brain, impaired attention and fatigue (96). However, subjective
difficulty with attention is neither the only nor even the most prominent
symptom of fatigue. Polio survivors report that they are the most distressed
and disabled by the visceral symptoms of fatigue: feelings of exhaustion,
passivity and an aversion to continued effort (97) that generate an
antipathy toward both mental and physical activity. However unpleasant and
purposeless in polio survivors, feelings of passivity and aversion to
activity have clear survival value, especially in organisms without conscious
awareness that their attention and information processing 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 render
the animal unaware of dangers in its environment (e.g., a predator stalking
the animal in search of its food). Thus, there would be survival value in a
brain mechanism that monitors cortical activation and biases the organism
toward cessation of motor behavior and promotes rest when attention and
information processing ability are impaired. The basal ganglia are uniquely
situated to monitor the level of cortical activation and stop an organism when
its attention is inadequate to allow efficient and safe motor behavior. All
parts of the cortex project to the dorsal striatum (the putamen and caudate
nucleus) (16) which is said to accumulate samples of ongoing cortical
projected activity (34) (Figure 5).
This cortical activity stimulates the striatum, whose discharge suppresses
the chronic inhibition by the globus pallidus of the thalamus and, through
it, cortical motor areas (98,99). It appears that the natural function (of
the dorsal striatum) is the facilitation of movement (34) via disinhibiting
the automatic execution of learned motor plans (99,100). A decrease in
cortical activation could decrease stimulation of the putamen, reduce its
facilitory input to the thalamus, and thereby impair directed attention and
prevent the cortical execution of learned motor behavior (101-103). This
inhibition of the motor activating set may be subjectively perceived as the
aversion to effort and passivity that accompany fatigue (33,34). Further, a
reduction in the motor activating set might also generate two of the
peripheral signs of central fatigue - the relaxation and lack of recruitment
of motor units - that might underlie the visceral feeling of exhaustion that
accompanies fatigue (104). In addition, the relaxation and reduced
recruitment of motor units that may result from a decrease in the motor
activating set would be accentuated by poliovirus-induced damage to the
descending reticular activating system, since it is responsible for
maintaining muscle tone in preparation for motor activity (17).
Implications for the Pharmacological Treatment of PPS. This putative
role for the basal ganglia in the generation of fatigue suggests that
stimulation of the basal ganglia via its dopaminergic afferents might
increase cortical activation, counter attentional impairments, release the
motor activating set and reduce both the cognitive and visceral symptoms of
fatigue. Impairment of cortical activation and attention, disabling fatigue,
as well as the bradykinesia and even akinesia that result from damage to
dopaminergic afferents to the striatum in humans (36), can be reversed to
some extent by the administration of L-Dopa or dopamine receptor agonists
(103). A dopamimetic agent chosen to treat post-polio fatigue should not
stimulate (as does amphetamine) or require the functioning of (as do L-Dopa,
reuptake blockers and MAOIs) the remaining, poliovirus-damaged dopaminergic
neurons. We are currently studying the use of a post-synaptic dopamine
receptor agonist to treat post-polio patients whose fatigue has been been
refractory to the current treatments of choice, i.e., adequate rest, energy
conservation, the pacing of activities and reducing physical and emotional
stress (3,105). However, there is the real danger that the pharmacological
treatment of fatigue will allow polio survivors to resume their hyperactive
Type A lifestyles, as they do now when their symptoms respond to current
treatments, and further stress poliovirus-damaged, Òmetabolically vulnerable
neurons in the brain stem and anterior horn (105). Post-polio fatigue and all
PPS must be treated holistically, with both physical and psychological factors
being carefully considered when formulating a treatment strategy. It is also
possible that basal ganglia lesions may be related to other symptoms reported
by polio survivors. Word finding difficulties are reported by 82% of polio
survivors with fatigue (3) and appear similar both to word finding problems
reported by CFS patients (60) and the tip-of-the-tongue phenomena in PD
patients (106). In addition, 66% of polio survivors report generalized random
myoclonus (GRM), the slow contraction or rapid twitching of hand, arm, trunk
and leg muscles during sleep (2; cf. 21).
GRM in polio survivors is reminiscent of the periodic movements in sleep
seen in PD (107) that have responded to treatment with dopamimetic agents
We continue to study the possibility of basal ganglia abnormalities
in polio survivors in an effort to understand the pathophysiology of
post-polio fatigue and identify treatments for PPS.
The authors gratefully
acknowledge the participation of the subjects, 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. Jordan Grafman, Leonard Kurland, Kaup
Shetty and Oliver Sachs for their criticisms of the manuscript, Carol
Greentree for her educational efforts on behalf of those with CFS, and Esther
Carlton of Nichols Institute who provided the 11:00 AM norms for cortisol and
Figure 1. Brain areas lesioned
by the polio virus as seen in 158 human
autopsies. Severe lesions: Reticular formation (RF); vestibular nuclei (V);
cerebellar roof nuclei (R); periaquiductal gray (PG). Moderate lesions:
Paraventricular hypothalamic nucleus (PV); posterior hypothalamic nuclei (P);
substantia nigra (SN). Mild lesions: Globus pallidus and putamen (GP); locus
ceruleus (LC); median raphe nuclei (MR); preoptic hypothalamic nuclei (PO);
thalamic nuclei (T).
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.
Figure 3. Location of
hyperintense signal (HS) on MRI in polio survivors
reporting fatigue. Arrows represent white matter tracts of the ascending
reticular activating system. Diamonds contain the number of subjects having
HS in various brain areas (e.g., 2: Lesions of the putamen in two subjects).
Medial leminiscus (ML); Rostral reticular formation (RF); Thalamus (T).
Figure 4. Linear regression of
plasma ACTH following fasting stress on daily fatigue severity rating. Normal
control mean ACTH (± 95th percentile) at 11:00 AM provided by the reference
laboratory performing the radioimmunoassay.
Figure 5. A putative role for
the basal ganglia in the generation of
fatigue. Fatigue symptoms could be produced by viral lesions of the RAS, GP,
putamen and substantia nigra (SN) reducing the firing of RAS and putamen
neurons. A reduction in reticular activating system (RAS) activity would
decrease cortical activation, impair attention and cognition and also prevent
the firing of putamen neurons (dark lines). The lack of putamen activity
(stippled lines) would allow the unopposed inhibition of the thalamus by the
globus pallidus (GP), which would impair directed attention and inhibit
release of the motor activating set to produce the visceral feelings of
Òexhaustion and aversion to effort that accompany fatigue (stippled lines).
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