"Non-paralytic" Polio as Prelude to Post-Polio Sequelae.


Dr. Richard L. Bruno
Chairperson
International Post-Polio Task Force
and
Director
The Post-Polio Institute
Englewood Hospital and Medical Center
Englewood, New Jersey 07631
Phone: (201) 894-3724 Toll Free: 1-877-POST-POLIO
PPSENG@AOL.COM

 

Cincinnati, 1947. The Summer arrives bringing heat, humidity . . . and fear. Polio is coming again and the terror has never been greater. 1946 had brought America's worst epidemic ever, the death rate rising to an all-time high. But as July became August and then September, there was an eerie calm. While there had been 167 cases of polio during a previous Cincinnati summer, only 40 cases were reported by the end of August. Why were there so few cases of polio? Had the "The Summer Plague" miraculously come to an end? No, the poliovirus had not disappeared. It was attacking Cincinnati wearing a disguise.

For at least four weeks during August and early September, pediatricians saw a new illness they called the "Summer Grippe." It's symptoms -- headache, fever, stomach pain, nausea, sore throat, and generalized aching -- came on suddenly in children between one and ten years old. The kids were not sick enough to go to the hospital and saw their doctor once if at all. Albert Sabin, a doctor at The Children's Hospital of Cincinnati in 1947 and developer of the oral polio vaccine a decade later, reported that there were at least 10,000 cases of "Summer Grippe" in Cincinnati and that "in some parts of the city hardly a child escaped." 1

Why was Sabin, a preeminent polio researcher, interested in the "Summer Grippe?" Because many of the children had a stiff neck, the "red flag" symptom that would require immediate hospitalization and the terrifying diagnosis "rule out poliomyelitis." However, since "Summer Grippe" symptoms did not lead to paralysis and disappeared within a week, pediatricians were not interested in hospitalizing children. But Sabin was. He remembered that there had been an unusually mild polio outbreak in Denmark in 1934 when, although only 27 patients were paralyzed, 600 more reported a "slight fever." Sabin also recalled the unusual increase in influenza in Copenhagen during August and September, 1934, and the 100 cases of polio that came with it. He wondered if a mild form of the poliovirus could have caused the "slight fever" and flu in Denmark in 1934 and the "Summer Grippe" in Cincinnati in 1947. 2 Sabin decided to find out.

A Medical Detective Story

From August 22 to September 9, Sabin admitted 13 children to The Children's Hospital with "Summer Grippe" symptoms. The children had fevers of around 103, almost all were listless and had headaches, many had sore throats and most had stomach pain. These fluish, feverish, and sometimes fussy children had spinal taps and bodily fluid specimens taken. Eight were diagnosed with "Summer Grippe." Two had a stiff neck and were diagnosed with "non-paralytic polio;" one had "dysentery," another had a sinus infection and a third had pneumonia. None of the children was seriously ill and they all left the hospital in about nine days.

With the children gone, Sabin returned to his laboratory to see if a poliovirus caused the "Summer Grippe." Remarkably, Sabin found antibodies (cells produced by the immune system that render a virus harmless) to the Lansing (or Type II) poliovirus in the blood of five of the eight children with "Summer Grippe," in the child with the sinus infection and in one of the two children who had non-paralytic polio. But Sabin knew that antibodies could have been present because the children had been exposed to poliovirus during the epidemic of 1946. So he followed the accepted procedure to prove that the Type II poliovirus had indeed been present in the children: Sabin exposed monkeys to specimens collected from his patients and watched the monkeys for about a month to see if weakness or paralysis developed.

Then, Sabin performed autopsies on the animals to look for damage to the spinal cord and brain that was the unique "calling card" of the poliovirus. Specimens from "Summer Grippe" patients did indeed damage monkeys: specimens from one patient paralyzed a monkey, specimens from three damaged motor neurons in the spinal cord, and specimens from four damaged the brain stem neurons responsible for keeping the brain awake. Specimens from only one of the children who had non-paralytic polio paralyzed a monkey in spite of her lack of Type II antibodies. However, when Sabin exposed monkeys to specimens from seven different patients diagnosed during August with non-paralytic polio, only one monkey became paralyzed while the other animals had no evidence of nerve damage.

A Kinder, Gentler Poliovirus?

Sabin concluded that a mild or "low virulence" Type II poliovirus caused the flu-like symptoms of the "Summer Grippe." Although Sabin's "mild" poliovirus did not cause even muscle weakness in humans, it did more than twice the damage to monkeys' nervous systems than did the virus causing non-paralytic polio in Cincinnati that Summer. What's more, Sabin's low virulence poliovirus did something even the most virulent paralytic poliovirus did not do: sicken at least 10,000 kids. At it's worst the paralytic poliovirus in Cincinnati felled only 167. Some mild virus!

Yet not everyone agreed that a kinder, gentler poliovirus caused the "Summer Grippe," not even the editor of the journal that published Sabin's findings. David Bodian, editor of The American Journal of Hygiene, told Sabin in a letter that the evidence supporting Sabin's conclusion was "very far from being satisfactory" and that the paper would be "subject to serious criticisms." 3 Bodian, a Johns Hopkins pathologist, is the unsung hero of the polio vaccine. It was Bodian who discovered that damage to neurons in the brain stem and spinal cord was the calling card of the poliovirus and that as many as 60% of spinal cord motor neurons had to be killed by the poliovirus for any muscle weakness, let alone paralysis, to occur. Bodian should have been the one scientist to readily accept Sabin's claim that a low virulence poliovirus not only caused "Summer Grippe" symptoms but also killed neurons,  although not enough neurons to cause weakness or even a stiff neck. Bodian did not.

Bodian wrote to Sabin that a "causal relationship" between the poliovirus and the "Summer Grippe" had not been proved saying, "it is equally plausible to assume that the (polio) virus was found in accidental relationship with the illness." Sabin wrote back that bodily fluid collected "during the same period" from 24 additional patients with non-paralytic poliomyelitis did not cause nerve damage in monkeys, supporting his claim that he had "caught" a poliovirus unique in that it caused "Summer Grippe" symptoms and damaged neurons in monkeys at a much higher rate than did the non-paralytic poliovirus floating around Cincinnati that Summer. But Sabin could not actually prove a causal relationship between a his "stealth" poliovirus and the "Summer Grippe," admitting to Bodian, "It is, in fact (a) matter of probable guilt by association." Sabin was missing two important cards if his claim that two different polioviruses were circulating simultaneously were to trump Bodian's criticisms: one card Sabin wouldn't hold until 1952; the final card wouldn't be dealt until 1955.

In 1949, David Bodian himself discovered that it was not just the Type II poliovirus that damaged human neurons, but that there were three types of poliovirus that caused illness in humans, each requiring a unique antibody to render it harmless. 4 So in 1952, Sabin tested bodily fluid saved from his 1947 paralytic and non-paralytic polio patients (but, unfortunately, not from the "Summer Grippe" kids) for the other types of poliovirus. He discovered Type I antibodies and concluded that the Type I poliovirus -- not Type II -- was responsible for paralytic and non-paralytic polio in 1947. 5 So Sabin was right: there were two different types of poliovirus circulating simultaneously in Cincinnati that Summer. But did the "high virulence" Type I poliovirus cause "typical polio" while a "low virulence" Type II virus caused the "Summer Grippe?" That answer would come years later and from thousands of miles away.

To Iceland From The Heartland

In September, 1948, three cases of paralytic polio were diagnosed in Akureyri, Iceland. 6 And although not another case of polio was reported, over the next few months more than 1100 Icelanders reported typical polio symptoms (fever, neck pain, muscle weakness and even some paralysis) as well as symptoms not associated with polio (tingling, numbness and "general tiredness"). Although fluid samples from four patients were sent to Bodian's laboratory for testing, neither poliovirus nor antibodies were found. Yet, doctors in Iceland concluded that there were only two possible causes for what has come to be called Iceland Disease: "Either a strain of polio (virus) of low virulence was responsible for this epidemic" or "some unknown (neuron-damaging) virus has been present."

Hard evidence for a low virulence poliovirus did not come for six more years. 1955 brought an extensive polio epidemic to Iceland caused by the Type I poliovirus, along with two new outbreaks of Iceland Disease. 7 Incredibly, not one case of polio was reported in towns with Iceland Disease in spite of the fact that only 7% of the children had antibodies to Type I poliovirus. Incredibly, 100% of children in the Iceland Disease towns had antibodies to Type II poliovirus. Just as Sabin thought happened in Cincinnati, children in Iceland had been exposed to a low virulence Type II poliovirus that damaged their nervous systems, caused symptoms of Iceland Disease, but prevented infection by a high virulence Type I poliovirus.

How could an infection by one type of poliovirus prevent infection by another without protective antibodies? That answer came during the 1959 Singapore study of Sabin's own oral polio vaccine. 8 Children were given all three live attenuated (totally non-virulent) polioviruses developed for the vaccine. Unexpectedly, the Type II poliovirus was found to be "dominant." Just as a flock of dominant blue jays blocks less aggressive robins from roosting in your back yard, the dominant Type II poliovirus blocks all other polioviruses -- even the naturally-occurring Type I poliovirus that was causing Singapore's 1959 polio epidemic -- from entering your blood stream. So children in Iceland and Singapore were protected from paralytic polio by a Type II poliovirus that blocked a high-virulence Type I poliovirus from entering their blood. And a Type II poliovirus protected the children of Cincinnati from paralysis by blocking a Type I poliovirus from entering their blood but at the price of the "Summer Grippe," a very much milder version of Iceland Disease. When the "Summer Grippe" epidemic was "at its peak by the end of August, there were not more than 40 reported cases of poliomyelitis." Only after the "Summer Grippe" had left town by mid-September did polio cases start to increase, reaching a total of 170, the highest number in Cincinnati history. (cf 9,10)

Polio By Any Other Name

Knowing that there are relatively "mild" polioviruses, that damage the spinal cord and brain without causing paralysis or even weakness, is important as we try to explain the cause of Post-Polio Sequelae (PPS) today. As early as 1941, Bodian cautioned that "the clinical diagnosis of a non-paralytic case (of polio) may rest on the failure to detect minimal degrees of muscle weakness," predicting the 1953 finding that at least 39% of those diagnosed with NPP in fact had demonstrable muscle weakness. 11-13 Bodian showed that paralytic and non-paralytic polio are not separate entities but a single process whose pathophysiology and clinical manifestations lie on a continuum. 15 He reported that the appearance of paralysis and its severity increased as the percentage of motor neurons killed increased; rhesus monkeys could have apparently normal muscle function with only 40% of their anterior horn cells remaining. 17, 18

In 1997 Canadian researcher Alan McComas supported this conclusion, finding the "limbs not considered to have been involved" in paralytic polio survivors had lost on average 40% of their motor units. 19 These findings contradict the common wisdom that the absence of paralysis is synonymous with the absence of CNS damage, and the notion that NPP survivors' motor neurons could not be experiencing metabolic failure and death to which late-onset muscle weakness has been attributed. 19

New fatigue and non-paralytic polio. The focus of PPS research during the past 15 years on new muscle weakness has ignored the most frequently reported and most disabling late-onset symptom, fatigue. 10 Certainly "brain fatigue," with its associated trouble with attention and staying awake, cannot be attributed to spinal motor neuron damage. 20

Bodian made scores of comparisons at autopsy between poliovirus-induced spinal cord and brain lesions. In animals without paralysis, he found that "lesions in the brain are more extensive and numerous than in some monkeys which did develop paralysis" and that some "animals with non-paralytic poliomyelitis do not have any lesions in the spinal cord but have a characteristic distribution of lesions in the brain ." 21, 22  (Notably, the brain lesions Bodian found were in the same areas damaged in monkeys injected with specimens from Sabin's "Summer Grippe" patients.) Bodian stated that "although non-paralytic infection may be associated with severe neuronal damage in the spinal cord," the poliovirus "is capable of producing an encephalitis, with or without associated clinical symptoms, in the absence of any pathological change in the spinal cord" (italics Bodian's). 17 Bodian also found that the "degree of involvement of brain centers" in humans having paralytic polio is comparable to the brain lesions in animals with non-paralytic polio 18. Bodian concluded that "all available evidence shows conclusively that every case of poliomyelitis, human or experimental, exhibits lesions of the brain," and that, "As far as the pathologist is concerned all cases of poliomyelitis are 'encephalitic'." 22

The finding that lesions in the brain activating system can be the only damage resulting from poliovirus infection may explain 1) why fatigue is reported more frequently than muscle weakness in both paralytic and non-paralytic polio survivors, 2) the lack of correlation between the severity of late-onset fatigue and the number of limbs paralyzed, hospital admission or length of hospital stay, impaired breathing or use or respirator during the acute polio episode, and 3) the neuropsychologic, neuroendocrine, neuroanatomic, and EEG abnormalities associated with post-polio fatigue and the occurrence of central sleep apnea and abnormalities of sleep architecture in polio survivors. 16,20,23-28 With the occurrence of late-onset fatigue, we are seeing today what Bodian predicted in 1949: that symptoms resulting from "lesions in the central gray of the mid-brain and hind-brain and in the mid-brain tegmentum and reticular formation" would be more often observed if they were not overshadowed by "paralysis of skeletal muscles." 10

Prevalence of poliovirus-induced illness. Unfortunately, it is impossible to know how many Americans had their CNS damaged by the poliovirus, damage that set the stage for PPS. Although infectious disease texts state there is a 1:10:50 ratio of paralytic polio, non-paralytic polio, and a "minor illness" with symptoms identical to the "Summer Grippe," the data do not support this claim. 12,29 In Cincinnati during 1947, the ratio of paralytic to non-paralytic cases was 1:1.2 while the ratio of paralytic polio patients to "Summer Grippe" cases was at least 1:106 1, 2 Across the U.S., the incidence of reported NPP cases varied widely depending on location and year, ranging from 0% to 80% of cases during the 1940's (mean ratio of paralytic to non-paralytic cases: 7:3) to 25% - 65% during the 1950's (mean ratio of paralytic to non-paralytic cases: 1:1). 2,11 (R. Bruce, C.D.C., personal communication.)

There are a several of factors that caused the marked variability in reported cases of paralytic and non-paralytic polio: Patients did not present for diagnosis. Failure to present for diagnosis may have resulted from symptoms being very mild or not seen as indicative of poliovirus infection (especially in infants) and patients, especially those who were poor, not having access to or having to travel for medical care. A study of polio diagnoses in a San Francisco city hospital from 1950 to 1953, and the reported cases of polio in Cincinnati during 1947, show that 15% more paralytic and 121% more non-paralytic polio cases were diagnosed among patients living in the city versus those living in outlying areas. 2,11 * Urban patients were thought to be more likely to present for diagnosis, being nearer to hospitals, versus those living in areas where they had to travel for medical care. Those with mild symptoms -- as in the "Summer Grippe," non-paralytic polio or even mild paralytic polio, especially in infants and young children -- may never have been diagnosed. Although diagnosis may have been more accurate and reporting to public health authorities more likely at city hospitals, and especially at university medical centers such as Sabin's in Cincinnati, the number of cases of both paralytic and non-paralytic polio reported by rural hospitals would have been underestimates of the true incidence;

Paralytic polio was under diagnosed. Studies document the underdiagnosis of paralytic polio. 11,12 Shaw and Levin reported that "mild degrees of muscle weakness may be easily overlooked" if manual muscle testing were employed without a functional assessment of strength: "Many patients who are eager for activity, who can readily walk out of the hospital, and who are persuasively non-paralytic will thus be found to have very definite muscle weakness which cannot be detected while they are recumbent in bed." 11 The failure to detect muscle weakness was also attributed to "too short a period of observation without opportunity for follow-up;" eighteen months to 6 years after having been diagnosed with non-paralytic polio, 39% of patients were found to have weakness in at least one muscle group; 11,12

Polio cases were not reported. The number and severity of polio cases during the epidemics may also have prevented overwhelmed physicians from reporting the occurrence of polio, especially NPP, to local public heath authorities. This occurred even at Sabin's Children's Hospital in Cincinnati. (Dr. J. Englert, personal communication.) Even if polio cases were reported locally, between 1915 to 1934 a varying number of states failed to report cases to the federal government, thereby preventing documentation of the true incidence of polio and even the extent of large polio outbreaks, such as the 1916 epidemic. 2 What is more, the C.D.C. did not separately tabulate non-paralytic and paralytic polio cases until 1951, and did not itself require the reporting of polio cases until the late 1950's. (R. Bruce, C.D.C., personal communication.)

These factors have not only caused inaccuracies in archival polio incidence and prevalence data, but also they have impaired the ability of recent surveys to accurately estimate the actual number of living polio survivors. For example, the 1987 National Health Interview Survey (N.H.I.S.) relied on respondents to report whether they had had polio and if they had paralytic or NPP. 30 The N.H.I.S. estimated that there are 641,416 living American paralytic polio survivors, 832,852 NPP survivors and 159,919 who reported they had had polio but did not know whether that had been paralyzed. This survey documented 1 paralytic case for 1.3 non-paralytic cases, a ratio similar to that reported during the 1950's but much lower than the 7:3 ratio of paralytic to non-paralytic cases reported during the 1940's. The fact that 10% of the N.H.I.S. respondents did not know whether they had been paralyzed makes clear that retrospective surveys, which rely on patient reports of early-life symptoms and diagnoses, may not be able to accurately determine the prevalence of paralytic polio, let alone the prevalence of NPP or a "minor illness" such as the "Summer Grippe."

"Polio suspects" and PPS. It may be possible to control for the sources of diagnostic and reporting error described above and approximately estimate the number of living Americans who did have a "minor illness" and thereby estimate the total number of polio survivors who had CNS damage and therefore are at risk for PPS today.

As early as 1935, the Mayo Clinic's centralized records-linkage system recorded not only cases of paralytic and non-paralytic polio, but also what were called polio "suspects . . ."

". . . a term used by the physicians in polio epidemic years to describe persons with an acute fibrile illness suspiciously similar to polio but without paresis or evidence of central nervous system involvement from clinical history and/or cerebrospinal fluid examination. Many of these persons were family members and contacts of cases. Some may have had abortive polio and may constitute the 'tip of the iceberg,' since so many cases of polio never came to the attention of the physician." 31

Although the population-based Mayo data are not representative of polio incidence in other regions of the country, especially in urban centers, they do significantly reduce, if not eliminate, errors resulting from improper diagnosis and underreporting. Between 1935 and 1955, for each paralytic polio patient, 0.65 polio "suspects" were recorded in the Mayo system. Applying this ratio to the N.H.I.S. estimate of 641,416 paralytic polio survivors, there would be at least 416,920 living polio "suspects" having had symptoms similar to those of the "Summer Grippe." Since 38% of Sabin's "Summer Grippe" patients had pleocytosis, indicating CNS involvement, 158,430 Americans would be at risk for PPS in addition to the estimated 1.63 million paralytic and non-paralytic polio survivors.

Clinical Implications

"Non-paralytic" polio and "Post-Polio Syndrome." The diagnostic criteria for "Post-Polio Syndrome" reflect the principal clinical concerns of the 1950's and the 1980's: acute paralysis and new muscle weakness, respectively. Post-Polio Syndrome criteria require the "onset of new weakness" in an individual with a "prior episode of paralytic polio confirmed by history, physical exam," as well as EMG changes "consistent with prior anterior horn cell disease." 32 Unfortunately, these criteria do not take into account the studies described above which make clear that non-paralytic polio -- and even a "minor illness" such as the "Summer Grippe" -- can be associated with the death of neurons in the spinal cord and brain that sets the stage for late-onset symptoms.

Recent studies make clear that NPP survivors do have late-onset symptoms. A population-based study of 828 polio survivors found that new muscle weakness and fatigue were reported, respectively, in 38% and 34% of those who had been paralyzed, and in 14% and 21% of those who had had NPP. 23 A study of 34 sets of twins found PPS symptoms in 71% of the twins who had had paralytic polio and "PPS-like symptoms" in 42% who had had no symptoms of paralysis. 33 The presence of PPS-like symptoms, as well as muscle biopsies "showing long-standing signs of denervation" in some of the non-paralyzed twins, caused the authors to conclude that the acutely non-paralyzed twin "had also suffered subclinical nonparalytic polio (and that) symptoms of PPS might also be sequelae of nonparalytic polio." Indeed, 13% of the non-paralyzed twins had been acutely diagnosed as having "non-paralytic polio." 34

Further, the 1987 N.H.I.S. found that 28% of NPP survivors reported new health problems related to polio. 30 45% more paralytic polio survivors reported limitations as compared to those who had had NPP, while NPP polio survivors reported 46% more limitation in life activities than did the general population.

EMG changes indicative of denervation may not be present in those who had "Summer Grippe," NPP or even in those who had acute transient paralysis. Sabin stated that "transitory" and reversible paralysis may be seen because "not all nerve cells attacked by the poliomyelitis virus are irreversibly damaged." 35 Bodian documented that motor neurons did recover function after poliovirus infection even if all of the intracellular organelles, except for the nucleus, had been destroyed. 17 Thus, an individual could have been acutely paralyzed without neuronal death or axonal degeneration, the poliovirus-infected neurons recovering and restoring muscle function without EMG evidence of chronic denervation. Such a scenario would be more likely in those who had been weakened or mildly paralyzed acutely and especially in those who had NPP or "Summer Grippe."

However, it is important to note that neurons which recovered from poliovirus infection were internally damaged, their cellular machinery for metabolism, protein manufacturing, neurochemical packaging transportation likely having been significantly impaired. 36,37 Bodian suggested that such poliovirus-damaged neurons "may be vulnerable for life to metabolic factors such as changes of senescence;" this vulnerability and eventual metabolic failure are thought to be the likely causes of late-onset muscle weakness and fatigue in polio survivors with or without acute evidence of paralysis or EMG evidence of denervation. 19,26,38-40.

Therefore, "Post-Polio Syndrome" should not be used as the generic descriptor for late-onset problems in polio survivors, since its diagnostic criteria exclude those without a history of paralysis, EMG evidence of denervation and new muscle weakness. The Post-Polio Syndrome definition should either be modified to include other frequently reported and disabling symptoms, especially fatigue, or its name should be changed to "Post-Polio Muscle Weakness Syndrome." In either case, the requirement of a history of paralytic polio and EMG evidence of denervation should be removed.

So the story of the poliovirus and its effects on the body may be like the fable of the elephant and the blind men: everyone infected by the poliovirus may be left holding a slightly different piece of the "animal." Doctors must remember that polio survivors' symptoms today depend, not on a diagnosis given 40 years ago, but on how many neurons were killed by the poliovirus in any given area of the spinal cord and brain. The one to six million North Americans who had "non-paralytic" polio must be assertive and advocate for themselves, showing doctors the research describing the varied effects of poliovirus on the nervous system and making clear that non-paralytic polio survivors do develop PPS. And "non-paralytic" polio survivors must follow the same prescription as survivors of paralytic polio to manage their PPS: listen to your body, stop activities before symptoms start and discard the "use it or lose it" philosophy and begin to "conserve to preserve" your remaining, poliovirus-damaged neurons. 41-45
 

References

  1. Sabin AB, Steigman AJ. Poliomyelitis virus of low virulence in patients with epidemic "Summer Grippe or Sore Throat." Am. J Hyg 1949; 49:176-193

  2. Sabin AB. Epidemiologic patterns of poliomyelitis in different parts of the world. In Poliomyelitis.
    Lippincott:Philadelphia, 1949.

  3. Papers from the The Hauck Center for the Albert B. Sabin Archives, Cincinnati Medical Heritage Center, University of Cincinnati Medical Center.

  4. The committee on typing of the National Foundation for Infantile Paralysis. Immunologic classification of poliomyelitis viruses. Am. J Hyg 1951; 54:191-204.

  5. Sabin AB. Transitory appearance of Type 2 neutralizing antibody in patients infected with Type 1 poliomyelitis virus. J Exp Med 1952; 96:99-106.

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

  7. Sigurdsson B, Gudnadottir M, Petursson G. Response to poliomyelitis vaccination. Lancet 1958; i:370-371.

  8. Hale JH, Lee LH, Gardner PS. Interference patterns encountered when using attenuated poliovirus vaccines Brit. Med J 1961; 2:278-732.

  9. Weinstein L, Shelokov A, Seltzer R, Winchell GD. A comparison of the clinical features of poliomyelitis in adults and children. N.E.J.M 1952; 246:296-302.

  10. C.D.C. Update. Outbreak of Influenza A Infection -- Alaska and the Yukon Territory, July-August 1998. M.M.W.R. 1998; 47:685-688.

  11. Moskowitz E, Kaplan LI. Follow-up study in seventy-five cases of nonparalytic poliomyelitis. JAMA 1953; 152:1505-1506.

  12. Shaw EB, Levin M. The Infrequent Incidence of Nonparalytic Poliomyelitis. J Pediatrics 1954; 44:237-243.

  13. Bodian D, Howe HA. The pathology of early arrested and non-paralytic poliomyelitis. Bull Johns Hopkins Hosp 1941; 69:135-147.

  14. Hoepich PD, Jordan MC. Infectious Diseases. Philadelphia:Lippincott, 1989.

  15. Bodian D, Howe HA. The pathology of early arrested and non-paralytic poliomyelitis. Bull Johns Hopkins Hosp 1941; 69:135-147.

  16. Bruno RL, Frick NM. Stress and "Type A" behavior as precipitants of Post-Polio Sequelae. In LS Halstead and DO Wiechers (Eds.):Research and Clinical Aspects of the Late Effects of Poliomyelitis. White Plains: March of Dimes Research Foundation, 1987.

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

  18. Bodian D. Poliomyelitis: Pathologic anatomy. In Poliomyelitis. Lippincott: Philadelphia, 1949.

  19. McComas AJ, Quartly C, Griggs RC. Early and late losses of motor units after poliomyelitis. Brain 1997; 120:1415-1412.

  20. Bruno RL, Creange SJ, Frick NM. Parallels between post-polio fatigue and chronic fatigue syndrome: A Common pathophysiology? Am J Med 1998, 105 (3A):66-73.

  21. Bodian D, Howe HA. Experimental nonparalytic poliomyelitis: Frequency and range of pathological involvement. Bull Johns Hopkins Hosp 1945; 76:1-17.

  22. Bodian D. Poliomyelitis: Neuropathologic observations in relation to motor symptoms. JAMA 1947 134, 1148-1154.

  23. Ramlow J, Alexander M, LaPorte R, et al. Epidemiology of the Post-Polio Syndrome. Am J Epidemiology 1992, 136:769-786.

  24. Bruno RL, Creange SJ, Zimmerman JR, Frick NM. Elevated plasma prolactin and EEG slow wave power in post-polio fatigue: Implications for a dopamine deficiency underlying chronic fatigue syndromes. J CFS 1998; 4:61-76.

  25. Bruno RL. Chronic fatigue, fainting and autonomic dysfunction: Further similarities between post-polio fatigue and Chronic Fatigue Syndrome? J CFS 1997; 3:107-117.

  26. Bruno RL, Frick NM, Creange SJ, Molzen T, Lewis T, Zimmerman JR. Polioencephalitis and the brain fatigue generator model of post-viral fatigue syndromes. J CFS 1996; 2:5-27.

  27. Siegel H, McCutchen C, Dalakas MC, et al. Physiologic events initiating REM sleep in patients with the postpolio syndrome. Neurol 1999; 52:516-522.

  28. Dean AC, Graham BA, Dalakas M, Sato S. Sleep apnea in patients with postpolio syndrome. Ann Neurol 1998; 43:661-664.

  29. Young NA. Poliovirus In GL Mandell, RG Douglas, JE Bennett (Eds.): Principles and Practice of Infectious Diseases. New York: John Wiley and Sons, 1979.

  30. Parsons PE. National Health Interview Survey. Hyattsville, Maryland: National Center for Health Statistics, 1989.

  31. Codd MB, Mulder DW, Kurland LT, et al. Poliomyelitis in Rochester, Minnesota, 1935-1955: Epidemiology and long-term sequelae. In LS Halstead and DO Wiechers (Eds.): Late Effects of Poliomyelitis. Miami: Symposia Foundation, 1985.

  32. Halstead LS. Assessment and differential diagnosis for post-Polio Syndrome. Orthopedics 1991; 14:1209-1217.

  33. Nee L, Dambrosia J, Bern R, et al. Post-Polio Syndrome in twins and their siblings: Evidence that Post-Polio Syndrome can develop in patients with nonparalytic polio. Ann NY Acad Sci 1995:378-380.

  34. Herndon CN, Jennings RG. A twin family study of susceptibility to poliomyelitis. Am J Human Genetics 1951; 3:17-46.

  35. Sabin AB, Ward R. Nature of non-paralytic and transitory paralytic poliomyelitis in rhesus monkeys inoculated with human virus. J Exp Med 1941; 73:757-770.

  36. Bodian D, Horstmann DM. Polioviruses. In Horsfall D (Ed.): Viral and Rickettsial Infections of Man. Philadelphia: Lippincott, 1965.

  37. Pezeshkpour GH, Dalakas MC. Long-term changes in the spinal cords of patients with old poliomyelitis. Arch Neurol 1988; 45:505-508.

  38. Bodian D. Motorneuron disease and recovery in experimental poliomyelitis. In LS Halstead, DO Wiechers (Eds.): Late Effects of Poliomyelitis. Miami, Symposia Foundation, 1985.

  39. Weichers DO. Acute and latent effect of poliomyelitis on the motor unit as revealed by electromyography. Orthopedics 1985; 8:872-872.

  40. Bruno RL, Frick NM, Cohen, J. Polioencephalitis, stress and the etiology of Post-Polio Sequelae. Orthopedics 1991; 14 (11):1269-1276.

  41. Young GR. Energy conservation, occupational therapy and the treatment of post-polio sequelae. Orthopedics 1991; 14:1233-1239.

  42. Agree JC, Rodriguez AA. Neuromuscular function in polio survivors. Orthopedics 1991;14:1343-47

  43. Bruno RL, Frick NM. The psychology of polio as prelude to Post-Polio Sequelae: Behavior modification and psychotherapy. Orthopedics 1991; 14:1185-1193.

  44. Creange SJ, Bruno RL. Compliance with treatment for Post-Polio Sequelae: Effect of Type A behavior, self-concept and loneliness. Am J PM&R 1997; 76:378-382.

  45. Peach PE, Olejnik S. Effect of treatment and noncompliance on Post-Polio Sequelae. Orthopedics 1991; 14:1199-1203.


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