.
The
Committee for Justice
and
Recognition of Myalgic Encephalomyelitis
===============================================================================
Poliomyelitis and Myalgic
Encephalomyelitis
Conditions irrevocably
linked together by their history and
more importantly by
extensive neurological similarities.
=====================================================================
THE AMERICAN
JOURNAL OF MEDICINE.
September 28, 1998, Volume 105 (3A).
Parallels Between Post-Polio Fatigue and Chronic
Fatigue
Syndrome: A Common Pathophysiology ?
Richard L. Bruno,
PhD, Susan J. Creange, PhD, Nancy M. Frick, LhD
Fatigue
is the most commonly reported and most debilitating of post-polio sequelae
affecting the >1.8 million North American polio survivors. Post-polio fatigue is characterized by
subjective reports of difficulty with attention, cognition, and maintaining
wakefulness. These symptoms resemble
those reported in nearly 2 dozen outbreaks of post-viral fatigue syndromes
(PVFS) that have recurred during this century and that are related clinically,
historically, anatomically, or physiologically to poliovirus infections. This article reviews 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 electroencephalogram (EEG) slow-wave activity. A possible common pathophysiology for
post-polio fatigue and CFS, based on the Brain Fatigue Generator Model of PVFS,
and a possible pharmacotherapy for PVFS based on replacement of depleted brain
dopamine, will be described.
Am
J Med. 1998;105(3A):66S-73S.
©1998 by Excerpta Medica, Inc.
________________________________________________________________________
Fatigue is the most commonly
reported and most debilitating of post-polio sequelae affecting the >1.8
million North American polio survivors.
In 2 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 muscle 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% reporting moderate-to-severe difficulty with these symptoms.[3]
These reports are reminiscent of
the symptoms associated with nearly 2 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 relations 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 damage to spinal motor neurons.[4] Post-mortem
histopathology performed 50 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 the globus
pallidus were also lesioned by the poliovirus.[11,12] Neurons in the
periaqueductal gray, locus ceruleus, 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.[13-20] Moreover, clinical reports written during
the polio epidemics corroborate the pathologic evidence of poliovirus damage to
the reticular-activating system, 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 ³34%
of patients with acute paralytic or nonparalytic 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) in 33% of those with paralytic or nonparalytic
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, myalgic encephalomyelitis, and CFS can now be compared
using techniques that were unavailable during the 1950s.[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
empiric data can more meaningfully be interpreted.
HISTORICAL
PARALLELS
"Attenuated"
Type II Poliovirus Infection
During the polio epidemics of the
1950s, a syndrome of impaired cortical activation and parkinsonism was
attributed to the poliovirus. In 1951,
3 cases of "drowsiness" and rousable stupor with marked slowing of
the EEG, "bulbar signs," and parkinsonism were reported.[29] Although 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 investigators to suggest that the syndrome might be caused by a poliovirus
with "attenuated virulence."
In 1952, 8 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 2 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 in maintaining cortical activation.[31,32] The basal ganglia 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.[34]
In
humans, basal ganglia 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,
Parkinson's disease patients demonstrate not only an impaired ability to
"transfer attention,"[37] but
also marked fatigue.[38,39] "Excessive fatigue" was reported
in another study by 48% of Parkinson's disease 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
Parkinson's disease [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 >20 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 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,[22] and even a few cases of
post-acute parkinsonism [42] were seen. 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.[23,43-45]
Unlike
poliomyelitis, there were frequent complaints of numbness or parasthesias,
usually no respiratory involvement, infrequent paralysis or muscle atrophy, and
almost invariably no fatalities.
Poliovirus was never isolated from ME patients. Also unlike poliomyelitis, recovery from the
acute symptoms of ME sometimes required months or years.[46] 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" and anomia 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 >12 ME outbreaks before
the introduction of the Salk vaccine, 9 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 after 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 6 years after the original outbreak, 72% reported
chronic "nervousness and general tiredness," and 21% reported
"loss of memory."[55]
Sigurdsson
et al [54] suggested 2 alternatives for the
cause of this constellation of symptoms, which has been called Iceland Disease:
"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."
Unbeknownst to Sigurdsson, the existence of a "low virulence"
nonparalytic poliovirus, capable of lesioning the anterior cord and/or the
medulla, midbrain, vagal and vestibular nuclei, reticular formation, substantia
nigra, thalamus, and hypothalamus, had been demonstrated in the United States
in 1947.[56]
Support
for an "unusual" poliovirus as the cause of Icelandic Disease came 10
years later from Sigurdsson himself.[57] 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
Iceland Disease. Remarkably, 2 cities
in which Iceland Disease 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 2 cities newly affected by Iceland Disease, 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, after poliovirus immunization, children in one of the
Iceland-Disease-affected cities demonstrated antibody titres to Type II and
Type III poliovirus that were 4 and 25 times higher, respectively, than titers
in a city where Iceland Disease had not been reported. The investigators concluded that Type I
poliovirus was not related to the occurrence of Iceland Disease but that
inhabitants of the Iceland-Disease-affected areas had previously been exposed
to an agent immunologically similar to Type III poliovirus.
Post-Polio
Fatigue and Chronic Fatigue Syndrome (CFS)
A constellation of symptoms
resembling ME was termed CFS after 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.[58]
Both CFS patients [58,59]
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
[60] similar to that seen after ME and polio.[23,43-45] In both polio survivors
and CFS patients the incidence of fatigue and physical and psychological
symptoms is significantly higher than in the general population (Table 1).[2,27]
The
recent emergence of CFS has allowed it to be studied using techniques that were
unavailable during the polio, ME, and Iceland Disease epidemics and that now
allow physiologic comparisons between this most recent putative PVFS and
post-polio fatigue.
Table 1. Demographic Data, Signs, and Symptoms in Polio Survivors
with Fatigue,
Patients
with Chronic Fatigue Syndrome (CFS), and Non-disabled Controls
Polio CFS
Survivors Patients Controls
n 373 259 145
Age 54(±11)*
38(±11)*$ 47(±14)
Female/male ratio 1.5 2.1
1.5
Working full time 40%$ 43%
$ 59%
Fatigue 91%$ 100%*$ 15%
Difficulty concentrating 96% 82%* n/a
Muscle pain 72%$ 85%*$
15%
Anxiety 69%$ 71%
$ 36%
Depressed mood 57%$ 68%*$
41%
Headaches 32%$ 58%*$
15%
Diarrhea 10%$ 36%*$ 2%
n/a = not ascertained.
Significantly different (p <0.01) as compared to polio survivors (*) or controls ($) by independent-groups t test or chi-square. CFS data from Ann Intern Med [27]; polio
survivors' and control data from Research and Clinical Aspects of the Late
Effects of Poliomyelitis [2] and Orthopedics. [3]
Table 2. Demographic and Neuropsychologic Data (mean ± standard deviation) in Polio Survivors Reporting Low and High Fatigue and in
Patients with Chronic Fatigue Syndrome (CFS)
. Polio Survivors A .
Low
High CFS
Fatigue Fatigue
Patients
Age (years) 51 (12) 44
(4) 37
(9) C
Years of education 15 (3) 14
(4) 16
(2) C
Beck Depression Inventory Score 13
(7) 14
(2) 15
(3) B
I.Q. 111
(2) 111
(1) 111
(4) B
Memory tests
WMS-R Logical Memory:
Immediate
Recall 23 (3) 32
(6) 26
(7) C
Delayed
Recall 14 (9)
28 (8) 21
(8) C
WMS-R Visual
Reproduction:
Immediate
Recall 32 (7) 34
(7) 34
(4) C
Delayed
Recall 16 (3)F 16 (9)F 29
(6) C
Attention tests
Trail Making Test:
A (seconds) 21
(3) 35
(13)F 34 (12) D
B (seconds) 48
(9) 62
(6) 76
(35) D
Paced Auditory Serial
Addition
Test (%
correct):
2.4/second 88
(11) 55
(29)F 39 (5) B,F
2.0/second 73
(6) 56
(23)F 32 (5) B,F
1.6/second 67
(17) 45
(27)F 28 (4) B,F
Word fluency (no.
words/60 seconds)
Animal
Naming 23
(4) 18
(6) 19
(5) E
FAS 43
(11) 40
(11) 41
(14) E
A
- Data from Arch Phys Med
Rehabil [25] and Bruno [103]
B
- Data from Arch Nerurol [61]
C
- Data from J Neurol Neurosurg
Psychiatry [64]
D
- Data from Biol Psychiatry [62]
E - Data from Biol
Psychiatry.[104]
F
- Clinical impaired score.
EMPIRIC
PARALLELS
Neuropsychoiogical
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
neuropsychological testing. CFS patients
[61,62] and polio survivors with severe
fatigue [25] have clinical impairments of
attention and information processing speed (Table 2). Despite these marked impairments of attention, CFS patients
[59] and polio survivors [2,25,63] have been shown to be within the high normal or superior range
on measures of higher-level cognitive processes and intelligence quotient (IQ),
as well as having higher-than-average levels of professional achievement.
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 poliovirus lesions in the brain's activating system, it was
hypothesized that reticular-activating system and basal ganglia damage are
responsible for 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 reticular-activating system and basal ganglia.[65] 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 hyperintensities were not seen in any
of the subjects reporting no or mild daily fatigue. Small discrete areas of hyperintense signal were imaged in the
putamen and rostral reticular formation.
Multiple punctate areas of hyperintense signal were imaged in the
periventricular and deep white matter and discrete areas of hyperintense signal
were seen in the centrum semiovale. The
presence of hyperintense signal 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. The presence of hyperintense signal was also significantly
correlated with the frequency or severity of subjective difficulty with recent
memory, thinking clearly, mind wandering, attention, and concentration.
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 [16-18] and especially the reticular
formation [66] has been shown in other
populations to cause deficits in attention.
The hyperintense signal imaged in the reticular formation and basal
ganglia 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 hyperintense signal in the midbrain and medulla on antemortem MRI
corresponded with histopathologic findings of necrosis in the substantia nigra
and reticular formation.[67]
Hyperintense
signals imaged along white matter tracts that have been implicated in the
centrifugal spread of the poliovirus [68,69] may have resulted from damage to the brain parenchyma by a
local tissue toxic effect of the poliovirus causing enlarged, fluid-filled
spaces around arterioles,[7] local
neuronal atrophy,[69,70] 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
relation between hyperintense signal, impaired attention, and fatigue. First, periventricular and deep white (but
not gray) matter hyperintense signals have been imaged in 27-100% of CFS
patients and have been suggested to represent either enlarged, fluid-filled
spaces around arterioles or demyelination.[17,70,71] Second, white matter
hyperintense signal imaged in both demented [72,73] and non-demented [74-76]
elderly adults has 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 hyperintense signal as well as
decreased glucose metabolism on positron emission tomography (PET) in cortical
premotor and supplementary motor areas and in the putamen
[77] --findings similar to abnormalities in the supplementary motor
area and putamen in Parkinson's disease patients with fatigue
[40] (see the Brain Fatigue Generator [BFG] Model, below). These finding implicate both damage to the
reticular activating system and basal ganglia, as well as a partial
disconnection between the reticular activating system, basal ganglia, thalamus,
and cortex, as underlying symptoms of fatigue (Figures 2 and 3).
Neuroendocrine
Parallels
The correlation of hyperintense
signal 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 after poliovirus infection suggested that neuroendocrine abnormalities
may also be present.
For
example, lesions in the paraventricular nucleus were frequently documented
after poliovirus infection [68] and
could impair this nucleus' ability to secrete corticotropin-releasing hormone,[78] thereby decreasing adrenocorticotropic hormone (ACTH) release.[79]
To
examine the relation between hypothalamic-pituitary-adrenal axis activity and
the symptoms of post-polio fatigue, polio survivors had their plasma
concentrations of ACTH measured using radioimmunoassay after a mild stressor
(an overnight fast) that is known to stimulate the
hypothalamic-pituitary-adrenal axis.[80,81] Mean plasma ACTH was
significantly elevated and outside of the normal range, as it should be after
an overnight fast, in subjects reporting mild daily fatigue (28.5 ± 17.7 ng/mL)
but not in those reporting moderate or higher 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.
These
data suggest that the response of the hypothalamic-pituitary-adrenal axis to a
fasting stressor is blunted in polio survivors reporting fatigue. This finding, coupled with histopathologic
evidence of poliovirus lesions in the paraventricular nucleus, suggested that
the hyposecretion of ACTH may be secondary to decreased production of the
hypothalamic secretagogues corticotropin-releasing hormone and vasopressin,
whose cell bodies are located in the paraventricular nucleus.[78] Further, the
significant negative correlations between ACTH level and fatigue severity,
cognitive problems, and difficulty staying awake suggest that a diminution in
hypothalamic-pituitary-adrenal hormones may contribute to the symptoms of
post-polio fatigue. An existing study
demonstrated that decreased levels of corticotropin-releasing hormone and ACTH
are associated with fatigue and impaired attention, since both peptides exert "stimulatory
effects on biochemical and electrophysiologic parameters of the brain."[79,82] In humans,
administration of ACTH fragments lacking adrenal-stimulating activity was
associated with improved memory and alertness, "EEG arousal response
patterns," increased sustained attention,[83] and a "statistically significant fall in fatigue."[84] These results were
attributed to the direct activation of ACTH receptors on neurons in the
hypothalamus, midbrain,[85] and
"the brain stem, particularly the nonspecific reticular-thalamic
system."[85,86]
Thus, post-polio fatigue may be attributable to poliovirus lesions not
only in the reticular activating system and basal ganglia but also in the
paraventricular nucleus, which decreases the secretion of peptides that cause
cortical stimulation. Decreased hypothalamic-pituitary-adrenal
activity has already been documented in patients with CFS, and the decreased
secretion of "activating" peptides such as corticotropin-releasing
hormone and ACTH has been implicated in its pathophysiology.[87,88]
THE
BRAIN FATIGUE GENERATOR MODEL OF PVFS
Taken together, the clinical,
historical, and empirical findings presented above suggested the BFG model of
post-polio fatigue and PVFS (Figure 2).
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,
decrease 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 (Figure 3).[89] The operation and survival value of a
hardwired, autonomic, and normal BFG that inhibits motor activity when cortical
activation, attention, and information processing speed are impaired is
described fully by Bruno et al.[89]
Recent
studies support the BFG model as an explanation for PVFS. Two studies using thallium-201 single-photon
emission computed tomography (SPECT) have documented that decreased brain stem
metabolism --and by inference decreased activity of reticular activating system
neurons-- was the only physiologic finding differentiating subjects with CFS
from healthy controls and subjects with depression or neurologic disease.[90,91]
Fainting
and Fatigue
Other studies have provided
additional support for the BFG model as an explanation for post-polio fatigue
as well as suggesting that decreased dopamine secretion may play a role in the
generation of fatigue symptoms.
Reports
of neurally mediated hypotension and symptomatic orthostatic tachycardia
syndrome in CFS patients suggest that there may be an association between
fainting and chronic fatigue.[92-94] The brain fatigue generator 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 polio-virus and other viral
encephalitides was the reticular formation, 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.[95,96]
Near the reticular formation in the brain stem lie other cardiovascular
control centers, all of which were also damaged by the polio-virus: 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.[22,97]
To
test the hypothesis that fatigue is associated with fainting, the 1995
International Post-Polio Survey asked 1,047 polio survivors and 419 nondisabled
control subjects about the frequency and cause of faints during their lifetimes
and to rate their current typical daily fatigue severity.[95] Fatigue severity was
not only significantly higher in polio survivors as compared with controls, but
also higher in polio survivors and controls who had fainted even once, as
compared with those who had never fainted.
Daily fatigue severity also increased in both groups as the number of
lifetime faints increased. These findings
suggest a physiologic relation between fatigue and fainting, possibly attributable
to the close proximity of cardiovascular regulation and brain activation
centers within the brain stem.
Therefore, fatigue and hypotension in patients with CFS and in polio
survivors with late onset fatigue may be a symptom of damage to reticular formation
neurons and not a primary cause of fatigue.
Hypothalamic
abnormalities in polio survivors and CFS patients may also contribute to a
relation between fatigue and fainting.
Corticotropin-releasing hormone release may be impaired secondary to
paraventricular nucleus damage in polio survivors and CFS patients.[81,88] Since the
paraventricular nucleus also produces vasopressin, the secretion of which is
impaired in CFS,[98] paraventricular nucleus damage
in polio survivors and CFS patients may decrease both brain-activating and
blood pressure-regulating hormones, thereby reinforcing reticular formation and
BFG abnormalities and predisposing these patients to both fatigue and fainting.
EEG
Slowing, Prolactin, and Fatigue
The postmortem documentation of
reticular activating system and dopaminergic neuron lesions in polio survivors,
the recent SPECT findings of decreased brain stem neuron activation in CFS
patients, and impaired attention in post-polio fatigue and CFS, all suggest
that decreased cortical activation and a dopamine deficiency may 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.[99] Therefore, elevated
prolactin should be associated with impaired cortical activation as evidenced
by slowing of the EEG, since even in healthy subjects, EEG slowing is
indicative of impaired cortical activation and has been associated with
decreased arousal, "drowsiness," and impaired performance on
neuropsychological tests of attention.[100,101] Furthermore, as many as
85% of CFS patients have been shown to have an excess of irregular slow wave
activity on EEG,[43-45,60] similar to the theta and delta
activity seen in patients with acute paralytic and nonparalytic polio.[23]
To
test the hypothesis that fatigue, prolactin, and EEG slowing are associated
with post-polio fatigue, polio survivors had resting measurements of plasma
prolactin and power across the EEG frequency spectrum.[102] Prolactin levels were
within the normal range and EEG power was equal between the 2 hemispheres
across all frequency bands. However,
EEG slow-wave power in the right hemisphere (measured with eyes open) was
significantly correlated with daily fatigue severity and prolactin level (r =
0.37; P <0.05), and prolactin was significantly correlated (r = 0.39; P
<0.05) 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
severity with prolactin. A recent study
further supports the putative relation between decreased dopamine secretion,
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 (r = -0.41; P
<0.05) but also with plasma prolactin (r = -0.36; P <0.05) and scores on
2 neuropsychologic tests of attention.[103] Notably, the
animal-naming score in polio survivors with fatigue was nearly identical to
that in patients with CFS (Table 2).[104]
Bromocriptine
and Fatigue
To test the hypothesis that
treating the putative dopamine deficiency will decrease the symptoms of post-polio
fatigue, a double-blind, placebo-controlled pilot study of bromocriptine
mesylate, a direct-acting, postsynaptic D2 receptor agonist, was performed in
polio survivors disabled by severe, chronic fatigue.[105] Patients were placed on
placebo for 28 days and then on an increasing dose of bromocriptine (1.25-12.5
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.
That
decreased 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.[106] 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
neuro-psychological tests of auditory vigilance, continuous attention, and
critical flicker fusion were also found after D2 receptor blockade.
CONCLUSIONS
These data suggest that
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 postviral fatigue syndrome, since
the causative agent is known, the damage done by the agent to the brain has
been demonstrated, and the signs of that damage -- neuroanatomic, neuropsychologic, neuro-endocrinologic, 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 "favorite 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, Equine,
Japanese B, and St. Louis infections).[26-28,107-110]
Some CNS viral infections are histopathologically and clinically similar
to, or actually indistinguishable from, poliovirus infection (e.g., Central
European encephalomyelitis and Coxsackie A9, Coxsackie B1-6, ECHO, Enterovirus
70 and 71 infections). The Coxsackie A7
virus produces a paralytic syndrome so similar to that caused by the
polioviruses it has been named poliovirus IV.[26-28,107-113]
So,
whereas post-polio fatigue may present a neat and complete pathophysiologic
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
reticular activating system and basal ganglia, 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 often refuse to believe that there
could be a syndrome with a physiologic basis that has fatigue as its principal
symptom. However, the research reviewed
in this article suggests that the practitioners in the disparate disciplines
who are studying PVFS should focus less on who is right about the etiology of
chronic fatigue, and focus instead on what may be wrong in the brain and how
brain abnormalities causing fatigue symptoms can be treated.
_____________________________________________
From the Kids' Fatigue
Management Program and The Post-Polio Institute, Englewood Hospital and Medical
Center, Englewood, New Jersey; and
Harvest Center, Hackensack, New Jersey.
ACKNOWLEDGMENT
This article is dedicated to the memory
of Dr. David Bodian, whose pioneering work describing the pathophysiology of
polioencephalitis appeared in this Journal in 1949.
This research
was supported by grants from the George A. Ohl, Jr, Infantile Paralysis
Foundation.
Requests for reprints should be addressed to Richard L. Bruno, PhD, The
Post-Polio Institute, Englewood Hospital and Medical Center, 350 Engle Street,
Englewood, NJ 07631
--------------------------
REFERENCES --------------------------
THE AMERICAN
JOURNAL OF MEDICINE.
Recent
Developments in Chronic Fatigue Syndrome
======================================================================
The Committee for
Justice
and Recognition of Myalgic Encephalomyelitis
Visit these pages
ME: The Record of Epidemics =>
http://www.oocities.org/tcjrme/CurrentTopics3.html
The Neurology of ME => http://www.oocities.org/tcjrme/fundamentals6.html
The Fundamentals Library => http://www.oocities.org/tcjrme/fundamentals.html
Diagnosis, Metabolism, Immunology
TCJRME
Home Page; http://www.oocities.org/tcjrme
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Poliomyelitis
and Myalgic Encephalomyelitis
TCJRME F - 11
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