THE CAUSE AND TREATMENT OF POST-POLIO FATIGUE.

From: Healthy Partnerships. Ontario: March of Dimes, 1995
By: Richard L. Bruno, Ph.D., Nancy M. Frick, Lh.D., Susan J. Creange, M.A., Todd Lewis, Ph.D., and Terry Molzen, M.S.

Fatigue is the most commonly reported, most debilitating and least studied Post-Polio Sequelae (PPS) affecting the nearly 2 million North American polio survivors.Among polio survivors, 91% reported new or increased fatigue, 41% reported fatigue significantly interfering with performing or completing work and 25% reported fatigue interfering with self-care activities (1,2).Fatigue was reported to be triggered or increased by physical overexertion in 92% and by emotional stress in 61%. Importantly, polio survivors distinguish between the physical tiredness and decreased endurance they associate with new muscles weakness, and a 'brain fatigue' that is characterized by problems with attention and thinking. Between 70% and 96% of polio survivors reporting fatigue complained of problems with concentration, memory, attention, word-finding, maintaining wakefulness and thinking clearly, with 77% percent reporting moderate to severe difficulty with these functions (3).

Problems with attention, memory and thinking suggest that the symptoms of post-polio fatigue cannot be explained merely by the poliovirus damaging anterior horn motor neurons (4). Autopsies performed fifty years ago on people who died after having had polio, whether they had paralysis or not, showed that the poliovirus almost always damaged specific areas in the brain (Figure 1).These damaged areas include the brain's activating system that keeps you awake and allows you to focus your attention. The poliovirus also damaged neurons that produce neurotransmitters, including the enkephalins and endorphins (called the 'body's own morphine') as well as dopamine and ACTH which activate the brain.

With poliovirus damaging the brain's activating system, you would expect that the original polio infection should cause brain activating problems. And, reports written during the polio epidemics did describe 'drowsiness,' lethargy, prolonged sleeping and even coma during the acute polio infection (7,12,21,22).One-third of patients with acute spinal, spinal and bulbar and even non-paralytic polio showed 'disorientation, apathy, pronounced sleep disorder (and) irritability' (4).These mental changes were associated with the abnormal slowing of brain wave activity on the electroencephalogram (EEG).Further, a high percentage of children clinically recovered from poliomyelitis insofar as motor disability is concerned, had qualitative difficulties in mental functioning such as 'fatiguability and fleeting attention' for months after the acute polio (5).

These reports of persistent drowsiness, fatigue and fleeting attention following the acute poliovirus infection are similar to polio survivors' recent complaints of late-onset fatigue and impaired attention (25).  And, both acute and late-onset post-polio fatigue are reminiscent of nearly two dozen outbreaks during this century of post-viral fatigue syndromes (PFS) that are related clinically, historically or anatomically to poliovirus infections (26-28).These relationships and recent studies comparing post-polio fatigue and chronic fatigue syndrome will be described in an attempt to understand the cause and treatment of post-polio fatigue.

CAN THE POLIOVIRUS CAUSE FATIGUE?

Type II Poliovirus and Decreased Brain Activation.During the polio epidemics of the 1950's, there were several small outbreaks of patients having drowsiness, prolonged sleeping, slowing of brain waves, as well as some of the symptoms of both bulbar polio and Parkinson's disease (e.g., tremor and rigidity) (29-30).In 1952, Type II poliovirus was isolated from one group of patients having these symptoms and it was found that the neurons in their brain activating system had been damaged.

The association of decreased brain activation and Parkinson's disease symptoms remind Dr. Oliver Sacks of the 'sleeping sickness' patients with Parkinson's disease he described in his book Awakenings.The relationship between 'sleeping sickness,' Parkinson's disease and polio may be important for understanding post-polio fatigue, since all of these have conditions are associated with damage to a part of the brain activating system called the basal ganglia.For example, Parkinson's disease (PD) patients have severe damage to one of the basal ganglia, the substantia nigra (sub-STAN-sha NYE-gra), which produces the neurotransmitter dopamine (doe-PAH-mean).  PD patients often describe fatigue.'Excessive fatigue' was reported by 48% of PD patients in one study (40) while nearly one-third of PD patients reported that fatigue was their 'most disabling symptom' (39).As a matter of fact, one of the first descriptions of Parkinson's disease (41) could serve as a definition of post-polio fatigue, i.e., a syndrome 'characterized by a diminution of voluntary attention, spontaneous interest, initiative and the capacity for effort and work, with significant and objective fatiguability, and a slight diminution of memory' (38).

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).

'Atypical Poliomyelitis' and Chronic Fatigue.Beginning in Los Angeles in 1934 and continuing for more than twenty years, there were over a dozen outbreaks of a disease that was at first thought to be poliomyelitis, was then called "abortive" or "atypical" poliomyelitis and finally named 'Myalgic Encephalomyelitis' (ME) (6).Like poliomyelitis, initial symptoms of ME included headache, neck pain, low-grade fever and muscle pain that were often followed by muscle weakness.Patients were excessively sleepy and had "conspicuous changes in their levels of concentration" that lasted for months after the initial illness.Slowing of the EEG similar to that seen inacute polio was also noted.

Unlike poliomyelitis, there were frequent complaints of numbness or tingling, usually no breathing problems, paralysis or muscle wasting and almost invariably no deaths.Also unlike poliomyelitis, recovery from the initial symptoms of ME sometimes required months with most patients being left with a marked "exhaustion and fatiguability" that were "always made worse by exercise (and) emotional stress.'Patients continued to have fatigue, excessive sleepiness, trouble concentrating, difficulty with word finding, memory and thinking for years after the acute episode.

Despite the differences between poliomyelitis and ME, an association with the poliovirus was suggested by the fact that, of the more than one dozen ME outbreaks before the introduction of the Salk vaccine, nine occurred during or immediately after outbreaks of polio and several involved hospital staff who cared for polio patients (7).

Type III Poliovirus and Chronic Fatigue in Iceland.A more direct association between the poliovirus and ME was seen in 1948 in Akureyri, Iceland.Patients there presented with fever, muscle pain and weakness and were at first diagnosed as having poliomyelitis.After about a month, this diagnosis was discarded as patients reported additional symptoms not typical of polio, including tingling, numbness, "nervousness" and "general tiredness."Also unlike poliomyelitis, no deaths were reported and poliovirus was never isolated from any of these patients.When patients were reexamined six years after their original illness, 72% still had chronic "nervousness and general tiredness' and 21% reported a of "loss of memory.'

It was suggested that either an 'unusual' and mild poliovirus or some unknown virus caused these symptoms that were called 'Akureyri Disease' but are more commonly referred to as 'Iceland Disease' (ID).Support for an "unusual" poliovirus as the cause came in 1955 (10).There was an extensive epidemic of poliomyelitis in Iceland caused by Type I poliovirus that coincided with and was followed by outbreaks of ID.Remarkably, two cities in which ID outbreaks were reported in 1955, as well as the area affected by the 1948 'Akureyri Disease' epidemic, were untouched by poliomyelitis.None of the children tested in the two ID-affected cities and only 13% of the children in Akureyri had antibodies to Type I poliovirus as opposed to 86% of the children tested in the polio epidemic areas.Further, following poliovirus immunization, children in one of the ID-affected cities demonstrated antibody titres to Type II and Type III poliovirus that were four and twenty-five times higher than titres in a city where ID had not been reported.It was concluded that Type I poliovirus was not the cause of ID, but the citizens of the ID-affected areas had previously been exposed to something that was immunologically similar to Type III poliovirus.

An interesting coda to these findings is the report that when an American airman who had contracted polio in the 1955 Iceland epidemic returned to Massachusetts, a small outbreak of ID and polio occurred (11).More recent support for a relationship between poliovirus and ME came in 1989 when a 'dangerously rising titre' to Type III poliovirus was documented in a patient who did not have polio but had been diagnosed with ME (12).

Post-Polio Fatigue and Chronic Fatigue Syndrome.A group of symptoms resembling ME was termed 'Chronic Fatigue Syndrome' (CFS) following a Nevada outbreak in 1984 (13).Like ME and post-polio fatigue, CFS is characterized by complaints of chronic fatigue and trouble with concentration, memory and word finding that are triggered or exacerbated by physical exertion and emotional stress.And, although polio survivors are on average at least ten years older than patients with CFS, the years of education, sex distribution, frequency of difficulty with concentration and psychological symptoms are nearly identical in the two groups (Table 1)(17,18,19).  However, unlike ME and PPS, CFS patients report recurring sore throat, swollen glands and fever, suggesting to some that CFS is caused by a recurring or chronic viral infection.It is important to keep in mind that there is no evidence that PPS is caused by a persistent infection by any virus, including poliovirus (14,15).

Polio Survivors CFS Patients

	Polio Survivors		CFS Patients
Sample Size	276	¥	259
Age	54 (±11)	¥	39 (±12)
College Graduates	40%	¥	40%
% Female	73%	¥	68%
I.Q.	111 (± 2)	#	111 (± 4)
Difficulty with:
Concentration	85%	¥	82%
Word Finding	82%	¥
Fatigue
does not impair functioning	21%	¤	0%
limits only social activities	13%	¤	43%
impairs work or self-care ability	66%	¤	57%
Depressive Symptoms	61%	¥	68%
Anxiety	74%	¥	71%

Table 1. Comparison of demographic data and symptom frequency in polio survivors reporting fatigue and in patients with Chronic Fatigue Syndrome (CFS).
* : Bruno and Frick, 1987; ¥ : Bruno, et al., 1991; ¤: Bruno, et al., 1993; # : Buchwald, et al., 1992.

The recent occurrence of CFS has allowed it to be studied using techniques that were not available during the polio, ME and ID epidemics and now allow neuropsychologic, neuroanatomic and neuroendocrine comparisons between this newest PFS and post-polio fatigue.

COMPARISONS OF POST-POLIO FATIGUE AND CFS

Neuropsychologic Studies.Some of the subjective difficulties with attention and cognition in CFS patients and polio survivors have been confirmed with neuropsychologic testing. CFS patients and polio survivors with severe fatigue have been shown to have clinical impairments of attention and information processing speed (Table 1)(16,19).Polio survivors reporting severe fatigue required 23% to 67% more time to complete tasks requiring sustained attention and vigilance than did polio survivors with no or mild fatigue.In spite of these marked impairments of attention, CFS patients and polio survivors have been shown to have I.Q.s within the high normal or superior range and have higher than average levels of educational and professional achievement (Table 1)(17).Further, despite the high frequency of subjective complaints of memory impairment in CFS patients and in 87% of polio survivors reporting fatigue, verbal memory has been shown to be intact on testing in both groups (16,19,20).However, polio survivors have twice been shown to have trouble recalling visual information whether or not they report fatigue (7,16).

These findings indicate that fatigue in CFS patients and polio survivors is associated with impairment of attention and information processing speed but not of memory or thinking ability.Given the findings of frequent and severe poliovirus lesions in the brain's activating system, it was hypothesized that damage to the brain's activating system is responsible for both fatigue and impaired attention in polio survivors.

Brain Scan Studies.

To test this hypothesis, magnetic resonance imaging (MRI) of the brain was performed to look for evidence of poliovirus lesions in the brain's activating system.In a first study, small areas of hyperintense signal (which look like white spots) on MRI were seen in the brain's activating system and in the myelinated (insulated) neurons that connect the brain stem (at the bottom of the brain) to the cortex (the 'supercomputer' at the very top of the brain) in eleven of twelve polio survivors (1).In a second study, white spots were seen in 55% of polio survivors with fatigue but were not seen in any of the subjects without fatigue (Figure 2)(21).The presence of the white spots were not only related to increased fatigue severity, but also to problems with memory, thinking clearly, mind wandering, attention and concentration.

Finding white spots on MRI supports the theory that fatigue and problems with attention in polio survivors may be related to damage the poliovirus did to the brain activating system.This conclusions is supported by a number of other studies that have shown a relationship between white spots on MRI, fatigue and problems with attention.Notably, white spots have been seen in between 40% and 100% of CFS patients (13) and even in healthy elderly adults who have problems with attention similar to those seen in CFS patients and polio survivors (22).

The figure is unavailable from the source document

Figure 2. A 24 mm2 focus of hyperintense signal (arrow) in the centrum semiovale in a 50 year old female polio survivor reporting moderate daily fatigue and frequent problems with concentration, thinking clearly, short term memory and staying awake (putamen lesion not seen in this view).

Hormonal Studies.The association of white spots in the brain activating system with the symptoms of post-polio fatigue suggested that the effects of poliovirus on other brain areas might also be evident in polio survivors.  For example, poliovirus lesions were often seen on autopsy in the hypothalamus (hypo-THAL-ah-mus), the brain area that automatically controls the body's internal environment and its response to stress.

To test the functioning of the hypothalamus, we measured polio survivors' blood concentrations of ACTH (a-DRE-no cor-ti-co-TRO-pick hormone), one of the body's stress hormones whose release is triggered by the hypothalamus. ACTH was measured following an an overnight fast, which is a mild stress known to cause the release of ACTH (7).ACTH was increased  outside of the normal range (as it should be following stress) in polio survivors who reported mild fatigue. However, there was noACTH increase in subjects reporting severe daily fatigue.Further, the higher the ACTH level, the lower the subjects' reported fatigue and the less the difficulty with memory, word finding, muscle weakness and staying awake during the day.

These findings indicate that the hypothalamus had not been activated in the subjects with post-polio fatigue and that ACTH production is reduced in these individuals.This conclusion is interesting for two reasons.  First, ACTH has been found in humans to promote alertness, increase attention and decrease fatigue by directly stimulating the brain activating system. Thus, a decrease in ACTH production may prevent brain activation and contribute to the symptoms of post-polio fatigue.Decreased activation of the hypothalamus has already been found in patients with CFS and a decrease in ACTH stimulation of the brain has been suggested as a cause of CFS (23).

Second, a decrease in ACTH production may be caused by a decrease in production of its parent molecule, POMC.POMC also produces beta-endorphin (BAY-ta en-DOOR-fin) which along with the enkephalins (en-KEF-ah-lins) are 'the body's own morphine.'Since poliovirus also damaged the brain area that produces enkephalins, both beta-endorphin and enkephalin production may be reduced in polio survivors.A reduction in the body's own morphine would help to explain why polio survivors have a nearly doubled sensitivity to pain (1).

A MODEL FOR POST-POLIO AND CHRONIC FATIGUE

Taken together, these findings suggest a model for the cause of post-polio fatigue:

•               Poliovirus damaged the brain activating system;

•               MRI and hormonal findings suggest that damage to the brain activating system is present today in polio survivors;

•               Neuropsychological testing shows impaired attention in patients with post-polio fatigue;

•               Therefore, poliovirus damage to the brain's activating system may cause decreased brain activation, impair attention and generate the symptoms of post-polio fatigue.

While poliovirus damage to the brain activating system would be expected to causethe sleepiness, inattention and fatigue reported during the original polio infection, it is the recurrence of these symptoms, or their appearance decades after the acute infection, that are more difficult to explain.The emergence of fatigue decades after the acute polio may result from normal age-related changes in and loss of brain activating system neurons that had survived the acute polio infection, combined with an already decreased number of neurons as a result of the original poliovirus infection.Eventually, the loss of brain activating system neurons would decrease cortical activation, reduce attention and produce the symptoms of fatigue as polio survivors reach mid-life (1).The occurrence of these symptoms during physical or emotional stress in polio survivors may reflect the ability of stressors to uncover otherwise unseen damage in the brain activating system.

IS FATIGUE 'HARD WIRED' INTO THE BRAIN?

The findings presented above describe an intimate relationship between impaired attention and fatigue.However, difficulty with attention is not fatigue's only symptom.Even more disabling is the physical experience of fatigue: feelings of exhaustion, 'passivity and an aversion to continued effort' that generate an aversion to both mental and physical activity. However unpleasant these feelings are in man, passivity and aversion to activity have clear survival value, especially in organisms without conscious awareness that their attention and thinking speed are impaired. For example, an animal that continues to explore its environment even though its attention is impaired would be less able to direct attention on the goal of its exploration (e.g., searching for food) and would thereby waste already diminishing energy stores.More importantly, impaired attention could also render the animal unaware of dangers in its environment (e.g., a predator stalking the animal in search of itsfood). Thus, there would be survival value in a brain mechanism that monitors cortical activation, biases an animal toward stopping motor behavior and promotes rest when attention and thinking speed are impaired.

The Brain 'Listens' to Itself.Groups of neurons near the bottom of brain called the basal ganglia are in an ideal location to monitor the level of brain activation and stop an animal when it has too little attention to allow efficient and safe activity in its environment.All parts of the cortex connect to one of the basal ganglia, called the putamen (pew-TAY-men), which 'listens' to the activity level of the brain (24).If the brain is awake enough, the putamen allows us to focus attention, to move and to act.When the brain activating system turns down, the putamen stops the cortex from allowing us to move.Damage to the putamen in animals has been shown to slow movement, while damage to another of the basal ganglia, the substantia nigra, decreases or even stops movement and prevents us from focusing attention (7).

The importance of the basal ganglia - and especially the neurotransmitter dopamine - in focusing attention and allowing us to move is most evident in patients with Parkinson's disease (PD).PD patients, whose damaged substantia nigra neurons produce too little dopamine, show not only slowed movement and an inability to focus attention but also excessive and disabling fatigue (7, 38-41).And, remember Oliver Sacks' Awakenings patients whose damaged basal ganglia caused both Parkinson's disease and 'sleeping sickness.'

The Brain Fatigue Generator.It appears that the basal ganglia could produce the mental and physical symptoms of both normal and pathological fatigue.In normal fatigue, a long and hard day of work would slow the firing of brain activating system neurons.This decreased activity would impair attention and information processing ability recognized by humans as symptoms of fatigue) and produce a decrease in cortical activation that would slow the firing of putamen neurons, prevent the release learned motor behaviors and slow or stop activity (Figure 3).Humans would notice problems with focusing attention, feel an aversion to activity and would be able to move only with significant conscious effort.Animals would slow or even stop their activity.In both man and animals, rest or sleep would increase the firing of brain activating system neurons, restore cortical activation, increase the firing of putamen neurons and once again allow the release of motor behavior.

The figure is unavailable from the source document

Figure 3. A model for the brain fatigue generator.Fatigue would be produced by a reduction inreticular activating system (RAS) activity that would directly decrease cortical activation, impair attention and cognition and prevent the firing of putamen neurons (dark lines).The reduction in putamen activity would then inhibit the release of motor behavior, further decrease attention and produce the visceral feelings of 'exhaustion' and aversion to effort that accompany fatigue (stippled lines).

Pathological states such as chronic fatigue syndromes could be produced by viral damage to the brain activating system, putamen and/or dopamine-producing neurons.This damage would chronically reduce the firing of brain activating system and putamen neurons, decrease cortical activation and produce the symptoms of fatigue.Poliovirus would be expected to cause fatigue, impaired cortical activation and decreased attention since it damages all of these brain areas.

CLINICAL IMPLICATIONS

This description of the basal ganglia as the brain fatigue generator suggests that increasing brain levels of dopamine (the neurotransmitter that stimulates the basal ganglia) might 'turn on' the brain activating system, increase cortical activation and attention, release motor behaviors and reduce the symptoms of chronic fatigue.We are currently studying the use of a drug that stimulates dopamine receptors on brain neurons to treat post-polio patients whose fatigue has not responded to the current treatments of choice, i.e., adequate rest, energy conservation, the pacing of activities and reducing physical and emotional stress (2,17,27,28). Preliminary results show that fatigue, impaired attention and difficulty staying awake during the day decrease as the dose of the drug increases.

However, there is the very real danger that taking a drug that reduces fatigue will allow polio survivors to resume their hyperactive, Type A lifestyles (as they do now when they feel better following physical, occupational and psychological therapy for PPS) and further stress poliovirus-damaged, 'metabolically vulnerable' neurons in the brain and spinal cord.  Decreasing 'overuse abuse' will always be necessary to treat PPS, regardless of whether a drug is found that decreases the symptoms of fatigue.

It is also possible that damage to the basal ganglia and a lack of dopamine may be related to other PPS symptoms.Word finding difficulties, reported by 82% of polio survivors with fatigue, appear similar both to word finding problems reported by CFS patients and the 'tip-of-the-tongue' phenomena seen in PD patients (Table 1)(1,7).And, in a study we have just completed, polio survivors with severe fatigue had low scores on a test of word finding ability - scores that were identical to those in Parkinson' patients.

In addition, 63% of polio survivors report Generalized Random Myoclonus (GRM), the slow contraction or rapid twitching of hand, arm, trunk and leg muscles at night that disturb sleep in 33% of polio survivors (2).  GRM may provide more evidence that polio survivors have a brain dopamine shortage, since GRM are similar to 'periodic movements in sleep' seen in PD patients.

We continue to examine the possible role of the basal ganglia and dopamine in PPS to help identify the cause and treatment of not only post-polio fatigue, but also other PPS, CFS and to understand the neurophysiology of fatigue itself. ACKNOWLEDGEMENTS

The authors gratefully acknowledge the participation of the subjects, the support of the Joel Leff Charitable Trust and Deluxe Corporation, the continued support of the George Ohl, Jr. Foundation, and the efforts and expertise of Mary Ann Solimine, R.N., M.L.S., without whom this work would not have been possible. We also thank Drs. Leonard Kurland and Oliver Sacks for their criticisms of the manuscript and Esther Carlton of Nichols Institute who provided the 11:00 AM norms for cortisol and ACTH.

REFERENCES

1.              Bruno, R.L., N.M. Frick ∓ J. Cohen.1991.Polioencephalitis, stress and the etiology of post-polio sequelae. Orthopedics. 14:1185-93.

2.              Bruno, R.L. ∓ N.M. Frick. 1987.Stress and 'Type A' behavior as precipitants of Post-Polio Sequelae.In Research and Clinical Aspects of the Late Effects of Poliomyelitis.L.S. Halstead and D.O. Wiechers, Eds. March of Dimes.White Plains, NY.

3.              Bodian, D.1949.Histopathological basis of clinical findings in poliomyelitis.Am. J. Med. 6: 563-578.

4.              Holmgren, B.E. 1952. Electro-encephalography in poliomyelitis.In Poliomyelitis. Lippincott.Philadelphia, PA.

5.              Meyer, E. 1947.Psychological considerations in a group of children with poliomyelitis.J. Pediatrics.31: 34-48.

6.              Gilliam, A.G. 1938.Epidemiological study of an epidemic, diagnosed as poliomyelitis, occurring among the personnel of the Los Angeles County General Hospital during the summer of 1934.U.S. Public Health Bull. (No. 240): 1-90.

7.              Bruno, R.L., Sapolsky, R., Zimmerman, J.R., ∓ N.M. Frick.1995.  The pathophysiology of central post-polio fatigue: A role for the basal ganglia in the generation of fatigue. Ann. NY Academy of Sciences. 753: 257 - 275.

8.              Sigurdsson, B., J. Sigurjonsson, H.J. Sigurdsson, et al.1950.  A disease epidemic in Iceland simulating poliomyelitis.Am. J. Hyg. 52:222-238.

9.              Sigurdsson, B. and K.R. Gudmundsson.Clinical findings six years after outbreak of Akureyri Disease. Lancet.i: 766-767.

10.           Sigurdsson, B., M. Gudnadotti ∓ G. Petursson.1958.Response to poliomyelitis vaccination.Lancet. i: 370-371.

11.           Hart, R.H.1969.Epidemic neuromyesthenia.N. Eng. J. Med.281:797.

12.           Hyde, B.M., J. Goldstein∓ P. Levine, Eds.1992. The Clinical and Scientific Basis of ME/CFS.The Nightingale Research Foundation.  Ottawa, Ontario.

13.           Buchwald, D.P.R.,P.R. Cheney,D.L. Peterson, et al. 1992. A chronic illness characterized by fatigue, neurologic and immunologic disorders and active human herpesvirus type 6 infection.Ann. Int. Med. 116:103-113.

14.           Bruno, R.L. 1991. Post-Polio Sequelae.Orthopedics. 14: 1169-1170.

15.           Melchers, W., M. De Visser, P. Jongen, et al.1992.The postpolio syndrome:No evidence for poliovirus persistence.Ann. Neurol.  32:728-732.

16.           Bruno, R.L., T. Galski, J. DeLuca.1993.Neuropsychology of Post-Polio Fatigue.Arch. Phys. Med. Rehabil. 74: 1061-1065.

17.           Bruno, R.L. ∓ N.M. Frick. 1991. The psychology of polio as prelude to Post-Polio Sequelae. Orthopedics.14: 1185-1193.

18.           Bruno, R.L. 1991. Post-polio sequelae, chronic fatigue syndrome and chronic musculoskeletal pain:Coincidence or causal connections?N.J. Rehab. 5:4-8.

19.           DeLuca, J., S.K. Johnson ∓ B.H. Natelson.1993.Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. Arch. Neurol.50: 301-304.

20.           Sandman, C.A., J.L. Barron, K. Nackoul, et al.1993.Memory deficits associated with chronic fatigue immune dysfunction syndrome.  Biol. Psychiatry. 33: 618-623.

21.           Bruno, R.L., J. Cohen, T. Galski∓ N.M.Frick.1994.  The neuroanatomy of post-poliofatigue.Arch. Phys. Med. ∓ Rehabil. 75: 498-504.

22.           Junque, C., J. Pujol, P. Vendrell, et al.1990. Leuko-araiosis on magnetic resonance imaging and speed of mental processing.Arch Neurol.47:151-156.

23.           Demitrack, M.A., J.K. Dale, S.E. Straus, et al.1991.Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J. Clin. Endocrinology ∓ Metabolism.  73: 1224-1234.

24.           Denny-Brown, D. ∓ N. Yanagisawa. 1976.The role of the basal ganglia in the initiation of movement.In The Basal Ganglia.  M.D. Yahr, Ed. Raven. New York, NY.

25.           Friedman, J. ∓ H. Friedman.1993.Fatigue in Parkinson's disease. Neurology.43:2016-2018.

26.           Naville, F. 1922.Encephale.17:369-375.

27.           Young, G. 1991. Energy conservation, occupational therapy and the treatment of Post-Polio Sequelae.Orthopedics. 14:1233-39.

28.           Agree, J.C. ∓ A.A. Rodriguez.1991.Neuromuscular function in polio survivors.Orthopedics. 14:1343-1347.

Please address all correspondence and reprint requests to: Dr. Richard L. Bruno, Director Post-Polio Rehabilitation and Research Service, Kessler Institute for Rehabilitation, 300 Market Street, Saddle Brook, New Jersey 07663. 1 (800) 648-0296 (x6057).

Post Polio Litaff, Association A.C _APPLAC Mexico

POLIOENCEPHALITIS AND A BRAIN FATIGUE GENERATOR Dr. Richard. Bruno

By: Dr. Richard. Bruno
Director, Post-Polio Rehabilitation and Research Service
Kessler Institute for Rehabilitation
Saddle Brook,Copy Right to publish you need author permission or write to litaffac@prodigy.net.mx

JOURNAL OF CHRONIC FATIGUE SYNDROME, 1996; 2 (in press)
Polioencephalitis and the Brain Fatigue Generator Model of Post-Viral Fatigue Syndromes.

Richard L. Bruno, Ph.D.1,2, Nancy M. Frick, Lh.D., 3 Susan Creange, M.A., 1 Jerald R. Zimmerman, M.D.1,2, and Todd Lewis, Ph.D.1

Polioencephalitis and the Brain Fatigue Generator Model of Post-Viral Fatigue Syndromes.

ABSTRACT

Fatigue is the most commonly reported and most debilitating Post-Polio Sequelae (PPS) affecting millions of polio survivors world-wide. Post-polio fatigue is associated with:
1) subjective reports of difficulty with attention, cognition, word-finding and maintaining wakefulness;
2) clinically significant deficits on neuropsychological tests of information processing speed and attention;
3) gray and white matter hyperintensities in the reticular activating system on magnetic resonance imaging of the brain;
4) neuroendocrine evidence of impaired activation of the HPA axis.
Many of these findings are identical to those documented following a variety of viral encephalitides, including acute polio-virus infection, lethargic encephalitis, Iceland Disease, myalgic encephalomyelitis, and, most recently, Chronic Fatigue Syndrome. The clinical, historic, neuropsychologic, neuroanatomic and physiologic parallels between polio-virus infection, post-polio fatigue and post-viral fatigue syndromes (PVFS) will be explored in an attempt to describe the pathophysiology of PVFS. The disinhibition of a putative Brain Fatigue Generator will be implicated as a cause of the subjective symptoms and objective signs that accompany PVFS. The results of a pilot placebo-controlled study of a dopamine 2-receptor agonist to treat post-polio fatigue will also be described.

Fatigue is the most commonly reported, most debilitating and least studied Post-Polio Sequelae (PPS) affecting millions of polio survivors throughout the world. In two national surveys of American polio survivors, 91% reported new or increased fatigue, 41% reported fatigue significantly interfering with performing or completing work and 25% reported fatigue interfering with self-care activities.(1) Fatigue was reported to be triggered or exacerbated by physical overexertion in 92% and by emotional stress in 61%.

Importantly, polio survivors differentiate between the physical tiredness and decreased endurance they associate with new muscles weakness, and a "brain fatigue" that is characterized by problems with attention and cognition. Between 70% and 96% of American polio survivors reported that fatigue was accompanied by problems with concentration, memory, attention, word-finding, maintaining wakefulness and thinking clearly, with 77% percent reporting at least moderate to severe difficulty with these problems. (2)

These reports of late-onset "brain fatigue" are reminiscent of the persistent drowsiness; fatigue and fleeting attention that frequently followed the acute polio-virus infection. Clinical reports written during the polio epidemics documented "drowsiness," lethargy, apathy, slowing of the EEG, prolonged somnolence, fatigability and fleeting attention" for months after the acute episode of paralytic and even non-paralytic polio. (3-8) Such symptoms should have been expected since polio-virus produced an encephalitis, whether paralysis was present or not, consistently and often severely damaging brain areas responsible for cortical activation - the midbrain reticular formation, thalamus, locus ceruleus, posterior and paraventricular hypothalamus (i.e., the reticular activating system (RAS) - and for directed attention, i.e., the putamen, globus pallidus and the substantia nigra. (5-17)

POST-POLIO FATIGUE AND POST-VIRAL FATIGUE SYNDROMES

Both acute and late-onset post-polio fatigue are also reminiscent of Myalgic Encephalomyelitis (ME), celand Disease and Chronic Fatigue Syndrome (CFS). 18-19 There are a number of clinical, historical, anatomical and physiological parallels between polio and these putative post-viral fatigue syndromes (PVFS).

Myalgic Encephalomyelitis. Between 1934 and 1954 there were over a dozen outbreaks of a syndrome that was at first diagnosed as poliomyelitis, then as "abortive" or "atypical" poliomyelitis and finally as Myalgic Encephalomyelitis (ME). 18 Like poliomyelitis, initial symptoms of ME included headache, neck pain, low-grade fever and myalgia that were often followed by paresis. Patients also demonstrated hypersomnolence, slowing of the EEG and "conspicuous changes in their levels of concentration" that persisted for months after the acute illness. 18 Unlike poliomyelitis, there were frequent complaints of numbness or parasthesias, usually no respiratory involvement, infrequent paralysis or muscle atrophy and almost invariably no fatalities. Also unlike poliomyelitis, recovery from the acute symptoms of ME sometimes required months and most patients were left with a marked "exhaustion and fatiguability" that were "always made worse by exercise [and] emotional stress."18-20 Patients continued to demonstrate fatigue, hypersomnolence and 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. (18)

Despite the differences between poliomyelitis and ME, and the fact that polio-virus was never isolated from ME patients, some association with the polio-virus was suggested. 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. (21-28)

Iceland Disease. The PVFS epidemic most intimately linked with polio occurred in Akureyri, Iceland in 1948. Following the diagnosis of two unequivocal cases of poliomyelitis, patients began presenting with fever, myalgia and paresis and were at first diagnosed as having poliomyelitis. (29) This diagnosis was 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. Six years after the original infection, 72% complained of "nervousness and general tiredness" while 21% reported "loss of memory." As in ME, polio-virus was never isolated from any of these patients.

Two alternatives were suggested for the cause of this constellation of symptoms that Sigurdsson called Akureyri Disease but has been more commonly referred to as Iceland Disease (ID): "Either a strain of poliomyelitis virus with unusual pathologic properties and of low virulence was responsible for this epidemic or . . . some unknown neurotropic virus has been present." (30) Support for an "unusual" polio-virus as the cause came in 1955 with an "extensive epidemic" of poliomyelitis, caused by Type I polio-virus, that coincided with and was followed by outbreaks of ID. (31) Remarkably, two Icelandic 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 new ID-affected cities, and only 13% of the children in Akureyri, showed antibodies to Type I polio-virus as opposed to 86% of the children tested in the polio epidemic areas. Further, following polio-virus immunization, children in one of the ID-affected cities demonstrated antibody titres to Type II and Type III polio-virus 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 polio-virus 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 polio-virus.

Chronic Fatigue Syndrome (CFS). Like post-polio fatigue, ME, and ID, CFS is associated with complaints of chronic fatigue, triggered or exacerbated by physical exertion and emotional stress, that have been associated with impaired concentration, memory and word finding ability, and an excess of irregular slow wave activity on EEG. (cf. 3; 2, 32-36)

Subjective difficulties with attention in CFS patients and polio survivors with fatigue have been corroborated by the documentation of clinical abnormalities on neuropsychological testing. CFS patients and polio survivors with severe fatigue demonstrated clinically significant impairments of attention and information processing speed. (17, 37-40) In spite of these marked impairments of attention, polio survivors and CFS patients in several studies have been shown to be within the high normal on measures of higher-level cognitive processes and I.Q. 1,33,40 Further, despite the high frequency of subjective complaints of memory impairment in CFS patients and in 87% of polio survivors reporting fatigue, verbal memory has been shown to be intact on testing in both groups. (2, 38-40)

In some studies, magnetic resonance imaging (MRI) of the brain has also shown similarities between CFS and post-polio fatigue. Areas of hyperintense signal in gray and white matter were imaged in 55% of polio survivors reporting at least moderate daily fatigue but were not imaged in any subjects reporting mild fatigue. (42) Small discrete or multiple punctuate areas of HS were imaged in the putamen, the rostral reticular formation, centrum semiovale, periventricular and deep white matter. The presence of HS was significantly correlated with the severity of fatigue, subjective difficulty with thinking clearly, mind wandering, attention, recent memory and concentration, but not with depressive symptoms or difficulty sleeping. These areas of HS were interpreted as evidence of polio-virus damage to the basal ganglia, RAS and its associated corticofugal white matter tracts. (2) This conclusion is supported by a recent case of poliomyelitis, in which HS in the midbrain and medulla on antemortem MRI corresponded with histopathological findings of necrosis in the substantia nigra and reticular formation on autopsy. (43)

Periventricular and deep white (but not gray) matter HS have also been imaged in 27% to 100% of CFS patients. (44-45) White matter HS imaged in both demented and non-demented elderly adults have also been associated with impairments of attention and information processing speed similar to those documented in CFS patients and polio survivors. (46; cf. 52)

Neuroendocrine data also show similarities between CFS and post-polio fatigue. (17) Plasma ACTH was significantly elevated and outside of the normal range following an overnight fast in polio survivors reporting mild daily fatigue (28.5 ± 17.7 ng/ml) but not in those reporting high (>moderate) fatigue (19.7 ± 10.7 ng/ml) (t=2.02; p<0.05). Plasma ACTH was also significantly negatively correlated with the frequency of problems with recent memory, word finding and muscle weakness, the severity of daily fatigue, recent memory and staying awake during the day, but not with the severity of depressive symptoms. 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).

These data suggest that the HPA axis response to stress is blunted in polio survivors reporting fatigue. 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. (53-54)

POLIOENCEPHALITIS AS A PROTOTYPE FOR PVFS

These data suggest that polio-virus may be the prototype for a chronic fatigue-producing agent since it routinely and often preferentially damaged areas responsible for brain activation and attention and has been so often associated during this century with symptoms of acute and chronic fatigue. Certainly, polio-virus is not the only agent for which the brain's activating system is its "favorite location." Both gray and white matter lesions have been demonstrated with a variety of viral encephalitides whose symptoms include markedly impaired cortical activation, e.g., St. Louis, Japanese B, Equine and Australian X encephalitis and Central European Encephalomyelitis. (55-56) Still other agents (e.g., Coxsackie, echo and herpes viruses) have been associated with symptoms of chronic fatigue. (18-20) And, although there is no convincing clinical or immunological evidence that post-polio fatigue or CFS is caused by a persistent polio-virus infection, only polio-virus has been directly or indirectly associated so often throughout this century with acute and chronic impairment of cortical activation, decreased attention and symptoms of fatigue. (57-58) (Explanations for the recrudescence, de novo and stress-induced appearance of post-polio fatigue are presented elsewhere. 2,17)

POLIOENCEPHALITIS AND THE BRAIN FATIGUE GENERATOR

The findings presented above describe an integral relationship between polioencephalitis, decreased cortical activation and impaired attention. However, impaired attention is not fatigue's only symptom. Even more disabling is the "visceral" experience of fatigue: feelings of exhaustion, "passivity and an aversion to continued effort" that generate an antipathy toward both mental and physical activity. (59,60) However unpleasant and disabling these feelings are in humans, passivity and aversion to activity have clear survival value, especially in animals without conscious awareness that attention and information processing speed are impaired. An animal that continues to explore its environment even though its attention is impaired would be less able to direct and sustain attention on the goal of its exploration (e.g., searching for food) and would waste already diminishing energy stores. More importantly, impaired attention and information processing speed could also render an animal unaware of or slow to respond to 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 Fatigue Generator" that monitors cortical activation and biases the organism toward cessation of motor behavior and promotes sleep when attention and information processing ability are impaired. To explain pathological fatigue, some agent would have to impair the putative Brain Fatigue Generator by damaging brain areas responsible not only for cortical activation and attention, but also for behavioral activation and intentioned movement.

Putamen as Cortical Monitor. The lenticular nuclei are uniquely situated to act as the Brain Fatigue Generator (BFG), which monitors the level of cortical activation, stops an organism from moving and promotes sleep when its attention is inadequate to allow efficient and safe motor behavior. (Fig. 2) All cortical areas project to the dorsal striatum, especially the putamen which receives 33% of its innervation from the cortex. (61) The dorsal striatum is said to 'accumulate samples of ongoing cortical projected activity' via glutaminergic cortical efferents that synapse with the distal dendritic spines of putamenal GABAergic medium spiny neurons (MSN). (62-66) The putamen also sends excitatory efferents to the descending reticular formation (dRF) that increase tonic motor unit activity and muscle tone. (61,65,67) Muscle tone is important not only in preparing an animal for movement, but also in activating the cortex via muscle spindle afferents that stimulate the ascending reticular formation (aRF). (61,68,69) Decreased muscle tone, induced by curarization, has been shown to produce cortical synchronization and "drowsiness" and even induce a level of anesthesia sufficient to perform surgery. 

(70-72)

Animals with lesions of the putamen demonstrate "difficulty transferring attention from one object to apathy," "hypokinesia" and "insensitiv[ity] to quite gross visual stimuli." (62) Electrical stimulation at frequencies above 20 Hz. of single loci in the cat putamen causes cortical EEG desynchronization, opening of the eyelids and dilatation of the pupils.; However, stimulation of those same loci at frequencies below 9 Hz. causes cortical EEG synchronization, "closing of the eyelids accompanied by a narrowing of the pupils." 61 Repeated or long-term low frequency stimulation of the putamen causes motor inhibition where all spontaneous activity stops and the animal remains motionless. "In this sleep-like state the eyes will be closed or half-closed, even when the animal is not lying down." (61)

These findings suggest that the integrity of putamenal neurons and the rate at which corticostriatal efferents stimulate them regulate the state of activation of the animal in terms of its ability to direct attention, perform motor behavior and even maintain wakefulness. (73,74)

Pallidum as Phasic Moderator of Activation. 

The putamen's regulation of cortical and motor activation is accomplished directly through its inputs to the pallidum. Two types of putamenal medium spiny neurons (MSN) receive cortical efferents and project to the pallidum: Neurons expressing dopamine 1 (D1) receptors on their distal dendritic spines project to and inhibit the firing of the internal globus pallidus (GPi), while neurons expressing dopamine 2 (D2) receptors on their distal dendritic spines project to and inhibit the firing of the external globus pallidus (GPe). (61,64) Putamenal neurons projecting to the GPi are also thought to send inhibitory collaterals to the proximal dendritic shafts of putamenal GPe inhibitory neurons. (65,75) The lateral inhibition of GPe inhibitory neurons by MSN that inhibit the GPi is the simplest explanation for electrical stimulation of the putamen (but not the GPi) producing cortical and behavioral activation identical to that achieved by direct stimulation of GPe. (61)

Putamenal inhibition of the pallidum has two opposite effects. Inhibition of the GPi reduces the firing of its GABAergic efferents which tonically inhibit the ventral lateral and ventral anterior thalamic nuclei. (61-76) When disinhibited, these thalamic nuclei allow cortical desynchronization and send an "enabling" signal to the supplementary motor and premotor motor areas, allowing the initiation of intentional movement and the execution of "learned motor plans." (61-64,77-79)

Putamenal inhibition of the GPe reduces the tonic firing of its efferents which disinhibits the subthalamic nucleus (STN), allowing the STN to stimulate the GPi to inhibit the thalamus. Reduced GPe firing also decreases stimulation of the descending reticular formation (dRF) and reduces muscle tone. (61,65,67) The profound consequence of reduced GPe firing is seen in the akinetic mutism resulting from GPe lesions. (62)

Substantia Nigra as Tonic Moderator of Activation.

The release of dopamine from the substantia nigra pars compacta (SNc) increases the level of excitability of putamenal GPi inhibitory neurons via stimulation of D1 receptors, and inhibits putamenal GPe inhibitory neurons via D2 receptor stimulation. (64,65) The SNc also sends excitatory inputs to the dRF that enhance muscle tone. (61) Decreased dopaminergic input to the putamen in humans decreases the diffuse activation of the cortex and the ability to 'maintain targeted attention' and even produces akinesia - symptoms that can be reversed to some extent by the administration of L-Dopa or dopamine receptor agonists. (81,82) A reduction in dopaminergic input to the lenticular nucleus in Parkinson's disease (PD) has been implicated as the cause of hypokinesia, bradykinesia, and the impaired ability to "transfer attention." (81,82)

It is noteworthy that fatigue itself is also a prominent (albeit infrequently described) symptom of PD. (83) "Excessive fatigue" was reported by 48% of PD patients in one study, while nearly one-third of PD patients reported that fatigue was their "most disabling symptom." (83,84) One of the first descriptions of cognitive dysfunction in 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 fatiguability, and a slight diminution of memory.' (85)

Physiology of Non-Pathological Fatigue. Fatigue may occur normally when a reduction in the activation of the cortex decreases the firing of cortical efferents to the putamen. (Fig. 3) The resulting decrease in putamen MSN firing would decrease inhibition of the GPi, permit continued inhibition of the GPe and decrease stimulation of the dRF, allowing a reduction in muscle tone and reduced aRF stimulation of the cortex. Inhibition of the GPe would disinhibit the STN, allowing it to stimulate the GPi to inhibit thalamic nuclei, prevent release of the motor activating set, halt execution of learned motor plans, stop intentional movements, increase cortical synchronization and promote sleep in animals who have no conscious awareness of fatigue. Humans would subjectively perceive these events as the "aversion to effort," feelings of passivity and difficulty staying awake that are symptoms of fatigue. (86) Inhibition of the motor activating set and decreased dRF activity could also generate two of the peripheral signs of central fatigue - the relaxation and lack of recruitment of motor units - that may underlie the visceral feeling of "exhaustion" that accompanies fatigue. (86) In both humans and animals, rest or sleep would restore cortical activation and stimulation of the putamen, which would inhibit the GPi, disinhibit the GPe, release the motor activating set, and restore activity within the reticular formation to reinforce cortical activation, release learned motor behavior and allow intentional movement.

Pathophysiology of Post-Polio Fatigue.

Polio survivors' chronic fatigue, or the excessive fatigue that follows mild activity or emotional stress, may result from polio-virus lesions in brain biasing the BFG in favor of the fatigue generating process described above. A reduction cortical activation may result from polio-virus damage to neurons in the motor and premotor areas decreasing the firing of cortical efferents to the putamen. (Fig. 4) Polio-virus lesions in the putamen, globus pallidus, thalamus and midbrain reticular formation may also:
1) reduce putamenal inhibition of the GPi and prevent disinhibition of the GPe (allowing chronic STN stimulation of the GPi);
2) prevent thalamic nuclei from stimulating motor and prefrontal cortices; and
3) decrease stimulation of the dRF, reduce muscle tone and thereby decrease muscle spindle efferent activation of the aRF and the cortex.

These impairments of phasic activation of the brain may be superimposed on impairment of tonic activation of the putamen and dRF resulting from poliovirus lesion in the substantia nigra. A decrease in dopaminergic input could bias the putamen in favor of disinhibiting the GPi (as a result of decreased stimulation of excitatory D1 receptors on GPi inhibitory neurons) and maintaining inhibition of the GPe (as a result of decreased stimulation of inhibitory D2 receptors on GPe inhibitory neurons). Decreased SNc output would also reduce dRF stimulation, decrease muscle tone and aRF activity, as well as reduce direct dopaminergic stimulation of the cortex. (87) SPECT scans in patients with ME showing significantly decreased perfusion of the brain stem have provided the first evidence that a decrease in the activity of brain stem (possibly reticular formation) neurons is associated with chronic fatigue. (88)

These putative effects of polio-virus lesions in the motor cortex, basal ganglia, thalamus, and reticular formation may be reinforced by poliovirus-lesions in other areas of the CNS. White matter hyperintensities on MRI in polio survivors reporting fatigue may be evidence of damage to myelinated fibers, or their wallerian degeneration due to gray matter lesions, which may compromise transmission between or partially disconnect the thalamus and the cortex. (52,89,90) The decreased secretion of ACTH in polio survivors with fatigue, possibly resulting from poliovirus lesions within the paraventricular nucleus of the hypothalamus (PVN) or pallidal neurons projecting to the PVN, may also contribute to a generalized impairment of brain activation. (17,91) Polio survivors, regardless of their level of fatigue, have been shown in two separate studies to have an impairment of visual memory, a function ascribed to the right hemisphere (RH). (40) Since the RH is thought to play a central role in both cortical activation and preparation for movement, and right hemisphere lesions are associated with reduced cortical and behavioral activation, hypokinesia and even akinesia, polio survivors may have a hemispheric predisposition to decreased cortical activation and fatigue. (40,92,93) Finally, ubiquitous damage to anterior horn motor neurons may tonically reduce muscle tone, muscle spindle afferent stimulation of the aRF, predisposing polio survivors to decreased cortical activation and fatigue. (12)

TREATMENT OF POST-POLIO FATIGUE WITH A DOPAMINE RECEPTOR AGONIST

The central role of the basal ganglia in the putative Brain Fatigue Generator suggests that stimulation of its dopaminergic efferents might increase cortical activation, counter attentional impairments, release the
motor activating set and reduce the symptoms of fatigue. Therefore, bromocriptine mesylate (Parlodel; Sandoz), a direct-acting, post-synaptic dopamine 2 (D2) receptor agonist, was chosen for a placebo-controlled pilot study of a pharmacological treatment for postÐpolio fatigue.

Eighty-three polio survivors (who were without comorbidities that could cause fatigue or cognitive problems) completed treatment with the Kessler Post-Polio Service and complied with conservative therapies for fatigue (energy conservation, work simplification, pacing, daily rest periods.) Regardless of the severity of their fatigue before treatment, only 10 (12%) reported a typical daily fatigue level greater than moderate (the inclusion criterion for the study) after treatment. Two patients were diagnosed as having a major depressive episode and five of the remaining patients agreed to participate in the drug study. Four of those subjects rated their usual daily fatigue as severe and were on Social Security disability as a result of fatigue preventing continued employment. 

The remaining subject rated her daily fatigue as moderate but was only able to work part-time.

Subjects were given log forms and instructed to rate their fatigue upon awakening, at 12:00, 3:00, 6:00 and 9:00 PM. At 9:00 PM, subjects were instructed to describe any side effects experienced during the day and rate their overall difficulty with motivation, attention, mind wandering, thinking clearly, concentration, word finding, object naming, memory, staying awake during the day, and muscle weakness.

Subjects were given placebo for 28 days and then increasing doses of bromocriptine for 28 days up to a maximum of 12.75 mg/day. Three subjects reported a noticeable reduction in fatigue and related cognitive symptoms on bromocriptine as compared to placebo. These drug responders reported that they "felt awake" and "had a clear head" for the first time in many years; their daily symptoms logs documented decreased difficulty with attention and other cognitive symptoms, motivation and morning fatigue that were significantly correlated with days on bromocriptine, but not with days on placebo (Fig.5). Drug responders' fatigue decreased to below "moderate" at the highest dose of bromocriptine, with fatigue upon awakening decreasing 55%.

Drug responders had more severe CNS abnormalities at baseline than did non-responders; they had more than twice as many hyperintensities on MRI of the brain, a mean plasma ACTH that did not increase following an overnight fast, and clinically abnormal scores on neuropsychological tests of attention (Trail Making Test (Part A), information processing speed (Paced Auditory Serial Addition Test (2.4 numbers/second presentation speed)), distractibility and vigilance (Gordon Diagnostic System). (94) A resting mean prolactin level nearly double that of the non-responders suggested chronically reduced dopaminergic inhibition of prolactin secretion in the drug responders.

These preliminary findings support the BFG model that suggests inhibition of putamenal MSN that inhibit the GPe, via stimulation of their D2 receptors, may reduce symptoms of fatigue. This conclusion is also supported by a placebo- controlled study of healthy subjects who were administered remoxipride, a potent and selective D2 receptor antagonist. (95) The most frequently reported effects of D2 blockade were "moderate fatigue," "mild somnolence" and "difficulty concentrating." Statistically significant, dose-related increases in subjective "drowsiness" and scores on neuropsychological tests of auditory vigilance, continuous attention and critical flicker fusion were also found following D2 blockade.

We are continuing to test the Brain Fatigue Generator model by measuring attention, EEG power spectra, and plasma prolactin in polio survivors reporting chronic fatigue. We are just beginning studies of patients with CFS using this same protocol to determine if the BFG model is applicable to the pathophysiology of CFS.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the participation of the subjects, the support of the George Ohl, Jr. Infantile Paralysis Foundation, Sandoz Pharmaceuticals and the efforts and expertise of Mary Ann Solimine, R.N., M.L.S., Doris Sipos and Carol Diveny without whom this work would not have been possible. We also thank Drs. Peter Behan, Oliver Sacks and Jesse Kaysen for their review of the manuscript.

FIGURE LEGENDS

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 putative model of the brain fatigue generator. In the awake and moving animal, cortical activation would stimulate firing of putamen neurons. Putamenal efferent activity would inhibit the internal globus pallidus (GPi), decrease inhibition of the external globus pallidus (GPe), and maintain inhibition of the subthalamic nucleus (STN) to prevent its stimulation of the GPi. Lack of GPi inhibition of the ventral lateral (VL) and ventral anterior (VA) thalamus would allow activation of the frontal cortex (promoting wakefulness and allowing directed attention), release the motor activating set (allowing intentional movement), stimulate the descending reticular formation (dRF) (to increase tonic motor unit activity and muscle tone), and increase ascending reticular formation (aRF) inhibition of the reticular thalamic nucleus (RTN), thereby allowing a further increase in thalamic activity and cortical activation. (Solid lines: Excitatory neurons; Stippled lines: Inhibitory neurons. Width of lines indicates level of neuronal activity). SNc: Substantia nigra pars compacta; D1: Dopamine 1 receptors; D2: Dopamine 2 receptors. (Reciprocal connections between SNc, cortex, thalamus and putamen omitted for the sake of clarity.)

Figure 3.
The brain fatigue generator in non-pathological fatigue. Normally, symptoms of fatigue would result from a reduction in cortical activation that would reduce the firing of putamen neurons. A decrease in putamenal efferent activity would disinhibit the GPi, maintain inhibition of the GPe, and allow disinhibition of the STN stimulation of the GPi. The GPi would inhibit VL and VA thalamic stimulation of the cortex (impairing directed attention and wakefulness), inhibit release of the motor activating set (producing "aversion to effort"), reduce stimulation of the dRF, decrease tonic motor unit activity and muscle tone (producing feelings of "exhaustion"), and decrease aRF disinhibition of the RTN, thereby allowing a further reduction in cortical activation.

Figure 4.
The brain fatigue generator after poliovirus infection. Poliovirus lesions ( * ) would impair phasic activation of the putamen, GPe, reticular formation, thalamus, motor cortices and their myelinated connections. Lesions in the SNc would reduce dopaminergic stimulation of the putamen and bias the tonic activity of the lenticular nucleus in favor of GPi excitation and GPe inhibition, thereby inhibiting the thalamus, cortex and reticular formation, and producing symptoms of chronic fatigue.

Daily logged fatigue and symptom difficulty levels in the drug responders on placebo and at the highest dose of bromocriptine.

1.   Post-Polio Rehabilitation and Research Service; Kessler Institute for Rehabilitation, Saddle Brook, New Jersey

2.   Department of Physical Medicine and Rehabilitation; UMDNJ/New Jersey Medical School, Newark, New Jersey

3.   Harvest Center, Hackensack, New Jersey

Address all correspondence and reprint requests to: Dr. Richard L. Bruno, Post-Polio Rehabilitation and Research Service, Kessler Institute for Rehabilitation, 300 Market Street, Saddle Brook, New Jersey 07662. (201) 368-6057

This research was supported by grants from the George A. Ohl, Jr., Infantile Paralysis Foundation, the Joel Leff Charitable Trust, The Deluxe Corporation and Sandoz Pharmaceuticals.

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