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. In the 1985 National Survey of 676 polio survivors, 91 percent reported new or increased fatigue, 41 percent reported fatigue significantly interfering with performing or completing work and 25 percent reported fatigue interfering with self-care activities. Fatigue was reported to be triggered or exacerbated by physical overexertion in 92 percent and by emotional stress in 61 percent. In the 1990 National Survey of 373 polio survivors, between 70 percent and 96 percent of respondents reported that fatigue was accompanied by problems with concentration, memory, attention, word-finding, maintaining wakefulness and thinking clearly, with 77 percent reporting moderate to severe difficulty with these functions.
These problems with attention and cognition suggest that the symptoms of post-polio fatigue cannot be explained merely by the poliovirus damaging the spinal cord motor neurons and causing muscle paralysis. And autopsies performed 50 years ago on people who died after having had polio did show that poliovirus not only damaged the spinal cord but almost always damaged specific areas of the brain. Those brain areas include the reticular formation (also called the reticular activating system or RAS ), hypothalamus and putamen-all parts of the brain's "activating system" that turns on the cortex (the brain's super computer), keeps you awake and allows you to focus attention. Poliovirus also damaged the neurons that produce the neurotransmitters dopamine and ACTH, which themselves activate the brain and stimulate the cortex to focus attention and process information.
Since poliovirus damages the brain's activating system, one would expect that a poliovirus infection should cause brain activating problems, such as trouble with concentrating and staying awake. Articles written about polio 430 years ago describe problems with brain activation. Drowsiness, lethargy, prolonged sleepiness and even coma were described during the acute poliovirus infection. Holmgren reported that 34 percent of patients with paralytic and non-paralytic polio demonstrated "mental changes" such as "disorientation, apathy, pronounced sleep disorder (and) irritability." These changes were related to abnormal slowing of brain wave activity on the electroencephalogram (EEG) in those with paralytic and non-paralytic polio. Further, Meyer 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 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 survivors' recent complaints of late-onset fatigue and impaired attention. These symptoms are also reminiscent of nearly two dozen outbreaks during this century of a seemingly viral illness that was termed myalgic encephalomyelitis (M.E.) in the 1950's and has been called chronic fatigue syndrome (CFS) in the United States since a Nevada outbreak in 1984. Like post-polio fatigue, both M.E. and CFS are characterized by chronic fatigue and impaired attention that are triggered or made worse by physical exertion and emotional stress. There are a number of other clinical, historical, anatomical and physiological parallels between polio and these post-viral fatigue syndromes (PFS) that may help us to understand the cause of and identify treatments for chronic fatigue.
HISTORICAL AND CLINICAL PARALLELS
Myalgic Encephalomyelitis:Beginning in Los Angeles in 1934 and continuing for more than 20 years, there were over a dozen outbreaks of a disease that was at first diagnoses as poliomyelitis, then as "abortive" or "atypical" poliomyelitis and finally named M.E. Like poliomyelitis, initial symptoms of M.E. included headache, neck pain, low-grade fever and muscle pain that were often followed by muscle weakness. Patients were chronically sleepy and had "conspicuous changes in their levels of concentration" that persisted for months after the acute illness. Slowing of the EEG similar to that seen in polio survivors was also noted.
Unlike poliomyelitis, there were frequent complaints of numbness or tingling, usually no respiratory involvement, infrequent muscle paralysis and, almost invariably, no fatalities. Also unlike poliomyelitis, recovery from the acute symptoms of M.E. sometimes required months and most patients were left with a marked "exhaustion and fatigability" that were "always made worse by exercise (and) emotional stress." Patients continued to demonstrate fatigue, chronic sleepiness and impaired concentration and reported "an inordinate desire to sleep," difficulty finding words and 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.
Despite the differences between poliomyelitis and M.E., some association with the poliovirus was suggested by the fact that, of the more than one dozen M.E. outbreaks before the introduction of the Salk polio vaccine in 1954, nine occurred during or immediately after outbreaks of polio and several involved hospital staff who cared for polio patients.
Iceland Disease:The most intriguing M.E. epidemic occurred in Akureyri, Iceland in 1948 and was described by Sigurdsson. following the diagnosis of two clear cases of poliomyelitis, dozens of patients began presenting with fever, muscle pain and weakness and were at first diagnosed as having poliomyelitis. After about a month, this diagnosis was discarded as patients reported additional symptoms not typical of polio, including tingling, numbness, "nervousness" and "general tiredness." Importantly, poliovirus was never isolated from any of these patients.
Sigurdsson returned to Akureyri in 1955 to follow up on the epidemic. Six years after the original infection, 87 percent of patients re-examined still had symptoms, the majority of which were again atypical of polio. The most frequent symptoms were "nervousness and general tiredness" in 72 percent, "muscle pains" in 62 percent and "loss of memory" in 21 percent.
Sigurdsson suggested two alternatives for the cause of these varied symptoms that he called Akureyri 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...some unknown... virus has been present." Support for an "unusual" poliovirus as the cause of ID came from Sigurdsson himself. There was an "extensive epidemic "in Iceland during 1955 of poliomyelitis caused by Type I poliovirus that coincided with and was followed by outbreaks of ID. Remarkably, two cities in which ID outbreaks were reported in 1955, as well as the area affected by the 1948 "Akureyri Disease" epidemics, were untouched by poliomyelitis. None of the children tested in the ID-affected cities showed any antibodies to Type I poliovirus. Following poliovirus immunization, children in one of the ID-affected cities showed antibody titers to Type II and Type III poliovirus that were 4 and 25 times higher, respectively, than titers in a city where ID had not been reported. Sigurdsson concluded that Type I poliovirus did not cause ID but that inhabitants of the ID-affected areas had at some earlier time 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. More recent support for a relationship between poliovirus and M.E. came 1989 when a "dangerously rising titer" to Type III poliovirus was documented in a patient who did not have polio but had been diagnosed with M.E. Taken together, these reports suggest that there may be an association between an agent immunologically similar to Type III poliovirus and the symptoms if ID and M.E.
Chronic Fatigue Syndrome:A constellation of symptoms resembling M.E. was termed chronic fatigue syndrome (CFS) following a Nevada outbreak in 1984. Like M.E. and post-polio fatigue, CFS is characterized by complaints of chronic fatigue and impaired concentration that are triggered or made worse by physical exertion and emotional stress. Unlike M.E. or post-polio fatigue, CFS patients report recurring sore throat, swollen glands and fever. These symptoms have prompted the suggestion that CFS may by caused by an as-yet unidentified persistent viral infection that is not one of the three types of poliovirus. Importantly, it should be noted that there is no support for the hypothesis that post-polio fatigue (or any PPS) is caused by a persistent infection by any virus, including poliovirus.
Another similarity between polio, M.E. and CFS is the report that all three groups have shown slowing of the EEG. Further, both CFS patients and polio survivors report subjective impairment of memory and difficulty with word finding. And, although polio survivors are, on average, at least 10 years older and significantly less disabled by fatigue than are patients with CFS, the level of education, sex distribution, incidence of difficulty with concentration and psychological symptoms are nearly identical in the two groups.
The recent emergence of CFS has allowed it to be studied using techniques that were unavailable during the polio, M.E. and ID epidemics and that now allow other parallels between this most recent PFS and post-polio fatigue to be explored.
Some of the subjective difficulties with attention and thinking in CFS patients and polio survivors have been confirmed by documenting clinical abnormalities on neuropsychological testing. CFS patients and polio survivors with severe fatigue have been shown to have clinical impairments of attention and information processing speed. Polio survivors reporting severe fatigue required 23 to 67 percent more time to complete tasks requiring sustained attention and vigilance than did polio survivors with no or mild fatigue. In spite of these marked impairments of attention, CFS patients and polio survivors have been shown to be within the high normal or superior range on measures of higher-level cognitive processes and IQ 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 and in 87 percent of polio survivors reporting fatigue, verbal memory has been shown to be intact on neuropsychological testing in both groups.
These findings indicate that fatigue in both CFS patients and polio survivors is associated with impairments of attention and information processing speed, but not of verbal memory or higher-level cognitive processes. Given the findings of frequent and severe poliovirus lesions in the brain, it was hypothesized that damage to the brain's activating system is responsible for both fatigue and impaired attention in polio survivors.
To test this hypothesis, magnetic resonance imaging (MRI) of the brain was performed in hope of documenting evidence of poliovirus lesions in the brain's activating system. Small area of hyperintense signal (which look like white spots) on MRI were seen in the brain's activating system (reticular formation and putamen) and in the myelinated (insulated) neurons that connect the brain stem to the cortex in 55 percent of subjects with post-polio fatigue but none of the subjects without fatigue. These findings are interesting since hyperintense signal on MRI is associated with damage to brain neurons and their supporting tissues. The presence of hyperintense signal was significantly correlated with fatigue severity but not with depressive symptoms or difficulty sleeping. The presence of hyperintense signal was also significantly correlated with the frequency or severity of subjective problems with recent memory, clear thinking, mind wandering, attention and concentration.
These findings support the hypothesis that areas of hyperintense signal in the brain activating system are associated with late-onset fatigue and subjective problems with attention in polio survivors. This notion is supported by a number of other studies that have documented a relationship between hyperintense signal on MRI, impaired attention and fatigue. Notably, hyperintense signal in myelinated neurons had been seen in 40 to 100 percent of CFS patients and has also been associated with impairment of attention and information processing speed in elderly adults similar to those documented in polio survivors and CFS patients.
The association of hyperintense signal in the brain activating system with the symptoms of post-polio fatigue suggested that the effects of poliovirus on other brain areas might also be evident in polio survivors. For example, poliovirus lesions were often seen on autopsy in the hypothalamus, which automatically controls the body's internal environment and response to stress. To test the functioning of the hypothalamus, polio survivors' blood concentrations of ACTH (one of the body's stress hormones whose release is triggered by the hypothalamus) were measured following an overnight fast (a mild stressor known to cause ACTH release).
Not surprisingly, ACTH was increased outside of the normal range following the fasting stress in the mild fatigue subjects. In contrast, there was no ACTH increase in subjects reporting severe daily fatigue. Further, the higher the level of ACTH, the lower the severity or frequency of problems with recent memory, work finding and staying awake during the day.
These findings indicate that the hypothalamus had not been activated in the subjects with post-polio fatigue and suggests that ACTH production is reduced in these individuals. This conclusion is interesting for two reasons. First, ACTH has been found in humans to stimulate alertness, increase attention and decrease fatigue by directly stimulating the brain activating system. Thus, a decrease in ACTH production may reduce brain activation and contribute to the symptoms of post-polio fatigue. Second, decreased activation of the hypothalamus has already been seen in patients with CFS and a decrease in ACTH stimulation of the brains has been suggested as a possible cause of CFS.
A MODEL FOR POST-VIRAL FATIGUE SYNDROMES
Taken together, the findings presented above suggest a model for the mechanism of PFS:
Poliovirus may be the prototype for a fatigue-producing agent since it routinely and often preferentially damaged the brain activating system. But, poliovirus is not the only virus that attacks the brain activating system. Lesions in the brain activating system are caused by a variety of viral infection (e.g., equine encephalitis, Central European Encephalomyelitis, Coxsackie, echo and herpes viruses) whose symptoms include markedly impaired cortical activation and symptoms of chronic fatigue.
While a virus-damaged brain activating system could cause an acute impairment of cortical activation, inattention and fatigue, it is the chronic nature and recurrence of these symptoms, or their appearance decades after the acute infection, that are more difficult to explain. The persistence of impaired attention in M.E. and ID long after the acute illness may simply reflect the persistence of damage to brain areas responsible for cortical activation. The absence and then recurrence of these symptoms during physical or emotional stress in M.E. and PPS may reflect the ability of these stressors to uncover otherwise unseen damage to the brain activating system. However, the recurrence of fatigue and impaired attention coupled with sore throat, swollen lymph glands and fever in CFS have suggested the as-yet unproven hypothesis that a persistent or recurrent infection may be responsible for this most recent PFS. Finally, the emergence of late-onset fatigue in polio survivors decades after the acute illness may result from normal age-related changes in and the loss of brains activating system neurons that had survived the acute viral infection--combining with and already decreased number of these neurons as a result of the original poliovirus infection, impairing the brain's activating system sufficiently to decrease cortical activation and produce impaired attention and fatigue as polio survivors reach mid-life.
IS FATIGUE "HARD WIRED" INTO THE BRAIN?
The findings presented above indicate that there is an intimate relationship between impaired attention and fatigue. However, difficulty with attention is not fatigue's only symptom. Even more disabling is the physical experience of fatigue: feelings of exhaustion, "passivity and an aversion to continued effort" that generate an avoidance of both mental and physical activity. However unpleasant and disabling these feelings are in man, 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 also render the animal unaware of dangers in its environment (e.g., a predator stalking the animal). Thus, there would be survival value in a brain mechanism that monitors cortical activation and biases the organism toward stopping motor behavior and promoting rest when attention and information processing ability are impaired.
Motor Behavior, Attention and the Basal Ganglia:Groups of neurons near the bottom of the brain called the basal ganglia are uniquely situated to monitor the level of cortical activation and stop an organism from moving when its attention is inadequate to allow efficient and safe motor behavior. All parts of the cortex connect to one of the basal ganglia, called the putamen, which is said to "listen" to the cortex and "accumulate samples" of cortical activity. Cortical activity stimulates the putamen and turns off the normal inhibition of cortical areas where learned motor behaviors are stored. A decrease in cortical activation could decrease stimulation of the putamen and thereby prevent the release of learned motor behavior. Damage to the putamen in animals has been shown to decrease motor behavior. Damage to another of the basal ganglia, the substantia nigra (which produces the neurotransmitter dopamine), decreases or even stops movement in both animals and man. Damage to the putamen and the substantia nigra also impairs cortical activation and attention in both animals and humans.
The importance of the basal ganglia and especially dopamine in releasing motor behavior and focusing attention is evident in patients with Parkinson's disease (PD). PD patients, who have damaged substantia nigra neurons that produce too little dopamine, show both decreased motor behavior and an impaired ability to focus their attention. Importantly, fatigue is also a prominent symptom of PD. "Excessive fatigue" was reported by 48 percent of PD patients while nearly one-third reported that fatigue was their "most disabling symptom." It is noteworthy that one of the first descriptions of PD could serve as a definition of post-viral fatigue, i.e., a syndrome "characterized by a diminution of voluntary attention, spontaneous interest, initiative and the capacity for effort and work, with significant and objective fatigability and a slight diminution of memory.
Basal Ganglia as the Brain Fatigue Generator:Taken together, these data suggest that the basal ganglia are in a position to generate the mental and physical symptoms of fatigue in both normal and pathological states. "Normal fatigue" would result from a long, hard day at work tiring (that is, slowing the firing of) the neurons of the brain activating system, especially in the reticular formation. This decrease in the firing of activating neurons would decrease cortical activation and impair attention and information processing speed. The decrease in cortical activation would also slow the firing of putamen neurons and thereby inhibit the release of motor behavior. Under these conditions, animals would decrease or even stop their activity. Humans would notice problems with focusing attention, feel an aversion to physical activity and be able to move only with significant conscious effort. In both man and animals, rest or sleep would increase the firing of brain activating system neurons, restore cortical activation, increase the firing of putamen neurons and once again allow motor behavior.
Pathological states, such as chronic fatigue, could be produced by damage to the brain activating system, especially to the reticular formation, putamen and dopamine-producing neurons. This damage would chronically reduce the firing of reticular formation and putamen neurons, decrease cortical activation and produce the symptoms of fatigue.
This description of the basal ganglia as the brain fatigue generator suggests that increasing brain levels of dopamine (the neurotransmitter that stimulates the basal ganglia) might "turn on" the brain activating system, increase cortical activation, increase attention, release motor behavior and reduce the symptoms of chronic fatigue. We are currently studying the use of a drug that stimulated dopamine receptors i the basal ganglia to treat post-polio patients whose fatigue has not responded to the current treatments of choice (adequate rest, energy conservation, the pacing of activities and reducing physical and emotional stress). Preliminary results show that fatigue and difficulty staying awake during the day decrease as the dose of the drug increases. If dopamine receptor stimulating drugs are found to be effective in polio survivors, they may also be of use in the treatment of CFS.
It is also possible that damage to the basal ganglia may be related to other symptoms reported by polio survivors and patients with CFS. Word finding difficulties are reported by 82 percent of polio survivors with fatigue and appear similar both to word finding problems reported by CFS patients and the "tip-of-the-tongue" phenomena seen in Parkinson's patients. We continue to study the basal ganglia to help identify the cause and treatment of post-polio fatigue and other post-viral chronic fatigue syndromes and to understand the physiology of fatigue itself.
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