Chapter 34.

Poliomyelitis and the Post-Polio Syndrome

Burk Jubelt and Judy Drucker.
Reprinted from Motor Disorders edited by David S. Younger.
Lippincott Williams & Wilkins, Philadelphia © 1999

Lincolnshire Post-Polio Library copy by kind permission of Dr. Jubelt.

B. Jubelt and J. Drucker:
Department of Neurology,
State University of New York Health Science Centre at Syracuse,
Syracuse
New York 13210.

In the first half of the this century, epidemics of poliomyelitis (polio) ravaged the world. In the epidemic of 1952, over 20,000 Americans developed paralytic polio. With the introduction of the Salk inactivated polio vaccine (IPV) in 1954 and the Sabin oral polio vaccine (OPV) in 1961, the number of paralytic cases decreased to a handful per year. Polio had vanished and no longer was on the consciousness of Americans. The elimination of polio was a tremendous achievement for science and American medicine. However, in the late 1970s, survivors of paralytic polio began to notice new health problems that included fatigue, pain, and new weakness, thought not to be "real" by the medical establishment. The term "post-polio syndrome" (PPS) was coined by these patients to emphasize their new health problems.

This chapter reviews acute poliomyelitis and the related PPS.

POLIOMYELTIS.

History.

Poliomyelitis has occurred sporadically from 1600 to 1300 BC (1); however, epidemic poliomyelitis is a modern disease related to improved sanitation and human hygiene of the Western world (2). The first epidemics occurred in Europe in the mid-1800s and in North America in the 1890s. In 1870, Charcot and Joffroy ascribed flaccid paralysis to anterior horn cell damage. In 1905, Wickman recognized that asymptomatic infection and transmission occurred via the gastrointestinal tract (3). In 1909, Landsteiner and Popper (4) transmitted poliomyelitis to monkeys by the intracerebral inoculation of human brain tissue homogenates. In 1949, Enders et al. (5) cultured poliovirus in nonneural tissues, eliminating animals for pathogenetic studies, and the three poliovirus serotypes were also recognized (6,7).

The most important development in the history of poliomyelitis was the introduction of polio vaccines. They decreased the incidence of paralytic poliomyelitis in the United States to fewer than 10 cases per year (8,9). Recent developments have included the cloning and sequencing of several strains of the three types of poliovirus (10-17) and the resolution of the viral structure to 29 nm by x-ray crystallography (18). These techniques have made it possible to determine the precise viral coat amino acids that induce antibody responses (19) and the location and the amino acid sequence of the site on the virus for cellular attachment (16,18,20). The poliovirus receptor on the cell membrane has been identified and is a member of the immunoglobulin superfamily (21).

Clinical Manifestations.

Definitions and Nomenclature.

Poliovirus infections can be divided into minor and major forms (22) (Fig. 1). The minor illnesses occur 1 to 3 days before the onset of paralysis, with gastrointestinal complaints of nausea and vomiting, abdominal cramps and pain, and diarrhea and the systemic manifestations of sore throat, fever, malaise, and headache.

FIG.1. Schematic diagram of the clinical forms of poliomyelitis correlated with the times at which virus is present in various sites and the development of serum antibodies. (From Ref. 22, with permission.)

The major illness includes all forms of central nervous system (CNS) disease caused by poliovirus, including aseptic meningitis or nonparalytic polio, polioencephalitis, bulbar polio, and paralytic poliomyelitis, alone or in combination. It can follow the minor illness immediately or more often within 3 to 4 days or occur without the minor illness. It is common for patients to have aseptic meningitis recognized by stiff neck, back pain, photophobia, and headache before the onset of paralytic polio. Polioencephalitis precedes paralysis and rarely occurs alone. It can manifest as tremulousness, obtundation, agitation, and autonomic dysfunction. The latter is recognized by labile hypertension, hypotension, tachycardia, arrhythmias, and excessive sweating. There may be upper motor neuron (UMN) signs of spasticity and hyperreflexia and Babinski signs (23). Muscle pains, muscle cramps, fasciculations, and radicular pain rarely occur without paralysis, but when they do, they usually precede paralysis by 24 to 48 hours. Paralytic disease is due to poliovirus infection of the motor neuron. Spinal cord anterior horn cells and other motor neurons are selectively vulnerable to poliovirus infection (24-27). Infection by poliovirus results in a variable distribution and variable extent of paralysis.

Clinical Symptoms and Signs.

Paralytic poliomyelitis can be of bulbar, spinal, or bulbospinal types (28). Paralytic disease accounts for 0.1 to 2.0% of all poliovirus infections during an epidemic (22,29). Spinal paralytic poliomyelitis is the most common type. It affects the lower extremities more frequently than the upper, and paralysis is usually asymmetric, flaccid, patchy, and more proximal than distal (30). As paralysis progresses, reflexes are lost. Over several days, the other extremities may become paralyzed, and bulbar involvement may occur. Extension of paralysis is unlikely to occur 5 to 6 days after the onset of paralysis. Atrophy develops over several weeks. Rarely, a transverse myelitis with paraparesis, urinary retention, sensory complaints and signs and autonomic dysfunction including hyperhidrosis or hypohidrosis, and decreased limb temperature may occur (31,32).

Bulbar or brainstem poliomyelitis occurs in 10 to 15% of paralytic cases (30). It can involve any of the cranial nerves and the medullary reticular formation. Affected adults usually have bulbospinal poliomyelitis, whereas children are more likely to have isolated bulbar involvement. The most frequently involved cranial nerves are the VIIth, IXth, and Xth, resulting in facial weakness and difficulty with swallowing and phonation. Reticular formation involvement can result in respiratory problems with ataxic breathing, lethargy and obtundation, and cardiovascular dysfunction including hypotension, hypertension, and cardiac arrhythmias (33).

Chronic or persistent poliovirus infection occurs infrequently in children with immunodeficiency who receive the live oral vaccine (34,35). The immunodeficiency is usually agammaglobulinemia, but infection also rarely occurs in those with cellular immunodeficiency usually several months after vaccination (34-36). The affected individual may present with lower motor neuron (LMN) paralysis and progressive cerebra! and intellectual dysfunction, with death in several months. Similar chronic infections have been caused by other enteroviruses (37).

Epidemiology.

Incidence.

The incidence of paralytic poliomyelitis peaked in the United States in 1952 with more than 20,000 cases (38). Because of the introduction of the killed IPV, or Salk vaccine, in 1954 and the live attenuated OPV, or Sabin vaccine, in 1961, the incidence has decreased to less than 10 cases per year in the United States (Fig. 2) (1,8,9,39). There is still a relatively high occurrence of the disease in Asia and Africa (40,41).

FIG. 2. Incidence of poliomyelitis in the United States, 1935-1964. (From Ref. 1, with permission.)

Transmission.

Poliovirus is primarily spread by fecal-hand-oral transmission from one host to another. The virus is shed in oral secretions for several weeks and in the feces for several months (22,42). It is often introduced into the household by small children who are not toilet trained (43) and spreads in a family very rapidly, infecting most members in 4 to 5 days (42,44). Household spread depends on prior immunity, household size, and sanitary hygiene conditions (45). Transmission is related also to environmental factors such as sanitation, level of hygiene, crowded conditions, geography, the season, and host characteristics.

Endemic Versus Epidemic Activity.

The geographic location and the accompanying temperature changes are factors that result in endemic or epidemic poliovirus activity. In tropical and semitropical areas, poliovirus circulates year around, the so-called endemic pattern, whereas in temperate zones, epidemics peak in the summer and early fall (45,46). From ancient times until the late 1800s, poliovirus activity was primarily endemic due to crowding, poor personal hygiene, and poor public sanitation (47,48). By early childhood, most individuals had been infected by all three types of poliovirus (49), and infrequently sporadic cases of paralytic poliomyelitis or true "infantile paralysis" were seen (50). This endemic pattern still occurs in semitropical and tropical underdeveloped areas of the world.

In the late 1800s, in developed temperate areas of the world, epidemic activity began to occur probably due to improved personal hygiene and public sanitation (2,51); accordingly, infants and small children were not previously exposed to poliovirus, creating a large pool of susceptible older children, adolescents, and adults. Because the latter are more likely to develop severe disease (3), when poliovirus infection sweeps through this virgin population, a high rate of paralysis can occur (22).

Predisposing Factors.

There are other predisposing factors for paralytic poliomyelitis (3). Age is one factor; older children, adolescents, and adults have more severe and extensive paralysis and a higher incidence of death than infants and young children (52-54). Men and boys have a greater susceptibility to poliomyelitis (52,54). Tonsillectomy before or at the time of infection is associated with a higher incidence of bulbar involvement. Traumatic and injected extremities are more likely to become paralyzed, the so-called provoking effect (55). Physical exertion predisposes to more severe paralysis, whereas pregnancy increases the incidence of paralytic disease by about threefold (56).

Pathology and Pathogenesis.

As previously noted, polioviruses and other enteroviruses are spread by fecal-hand-oral transmission. After replication in the oropharynx and intestinal mucosae, the virus replicates in the submucosal lymphatic tissue (57), leading to a primary viremia, followed by replication in nonneural target tissues, and secondary viremia and CNS invasion. The exact route the poliovirus takes to enter the CNS is unclear, but viremia is required for CNS invasion (58,59). There is evidence to suggest that poliovirus enters the neuraxis at areas where the blood-brain barrier is defective, such as the area postrema (60). Another possibility is that the virus reaches the neuromuscular junction during the viremia, entering the distal axon and transported by retrograde axonal transport to the CNS (61-63). Poliovirus dissemination in the CNS occurs along nerve fiber pathways, probably by fast axonal transport (57,63,64).

Pathologic changes are seen several days after poliovirus infection of anterior horn cells. Initially, the Nissl substance shrinks and dissolves, leading to diffuse chromatolysis and loss of basophilic staining (6). If infection does not resolve at this point (65), nuclear shrinkage, eosinophilic type B inclusions, and cellular membrane disintegration occur. The inflammatory response consists of meningeal, perivascular, and parenchymal infiltrates, initially composed of polymorphonuclear leukocytes over the first 24 to 48 hours, followed by mononuclear and microglial cell responses with neuronophagia (25,66).

Laboratory Studies.

General laboratory tests are uninformative. The complete blood count may reveal a peripheral leukocytosis. Cerebrospinal fluid (CSF) abnormalities are similar to those seen with many other CNS viral infections. The CSF cell count is increased, which initially may be a polymorphonuclear leukocytosis followed by a shift to mononuclear cells in 12 to 48 hours (3). At times it may be important to repeat the lumbar puncture to exclude bacterial infection. The cell count often reaches several hundred cells per mm³ but can be as high as several thousand. It usually declines precipitously within 2 weeks. Initially, the CSF protein is normal or mildly elevated but may rise to 100 to 300 mg/dL over several weeks and may remain high for months. Hypoglycorrhachia is rarely seen (3). Newer generation magnetic resonance imaging studies may show localization of inflammation to the spinal cord anterior horns (67). Virus isolation and serologic studies are needed to confirm the diagnosis.

Poliovirus can be isolated from the oropharynx for several weeks and from the stool for several months (22,68). It is almost never isolated from the CSF (69). Because several enteroviruses may be isolated from the stool, serologic testing is needed to confirm the responsible virus type. A fourfold or greater rise in serum antibody titer between the acute and convalescent specimens is considered diagnostic. It is important to obtain the acute phase specimen as soon as possible to detect the fourfold rise. The convalescent phase sample should be obtained at least 2 weeks, and preferably 4 weeks, after the acute phase specimen is obtained. A CSF/serum antibody ratio of greater than 1:150 may also be diagnostic (70), as well as CSF IgM antipoliovirus antibody (71).

Differential Diagnosis.

The combination of fever, headache, stiff neck, and asymmetric flaccid paralysis without sensory loss, and a CSF profile consistent with viral infection make paralytic poliomyelitis likely. The diagnosis may be difficult if these major manifestations are lacking or if unusual manifestations, such as urinary retention or sensory loss, occur. Nonpolio enteroviruses can also cause polio-like paralysis, although it is usually not as severe as that seen with poliovirus (3,72). Several other viruses can occasionally cause acute LMN paralysis, especially rabies (73) and herpes zoster (74). Other disease processes in the differential include transverse myelitis, acute spinal cord compression from epidermal abscess, Guillain-Barré syndrome, acute intermittent porphyria, toxic neuropathies, and botulism (69,72,75).

Management.

Treatment.

Treatment for paralytic poliomyelitis initially relies on supportive care followed by passive and then active physical therapy and orthopedic measures. Bedrest is recommended during the preparalytic stage because physical exercise can increase the severity of paralysis (3). Treatment of sore muscles with hot packs, fever with analgesics, and anxiety with anxiolytics may be calming. In addition, acute paralysis should be treated with hospitalization, appropriate positioning with splints to prevent contractures, foot boards to prevent foot drop, and frequent turning to prevent decubiti (69). Patients with bulbar involvement generally require fluid and electrolytes and, at times, cardiovascular, autonomic, and respiratory support (76). During the convalescent period, active physical therapy with nonfatiguing muscle-strengthening exercises and hydrotherapy may be beneficial. Braces and other orthoses may be needed for weak muscles or severe extremity paralysis. Arthrodesis, tendon transfers, leg-shortening procedures, and other orthopedic surgical interventions should be deferred for 1.5 to 2 years after maximum recovery has occurred (77,78).

Prevention.

Vaccination is the mainstay of prevention. The injectable killed IPV and the live attenuated OPV have been very effective in decreasing the incidence of poliomyelitis (1,38). The advantages and disadvantages of each vaccine have been extensively debated (3,45). The killed vaccine results in relative short-term immunity of 5 to 10 years, necessitating frequent revaccinations, but it does not cause paralysis. A very high level of vaccination of the population is required with the killed vaccine to prevent the spread of wild-type virulent viruses in the community. In contrast, the live vaccine is effective in producing long-term immunity, possibly lifelong, producing immunity by exposure to vaccine strains circulating in the population (secondary spread) (79) and eliminating the circulation of wild-type virulent strains. However, the live vaccine rarely causes paralysis (55,80). Recently in the United States, the recommendations for vaccination have been changed to a sequential vaccination schedule of two doses each of the IPV followed by the OPV (81). Prevention can also occur by stopping the spread of infection through the use of good personal, family, and public hygiene. Handwashing and the use of clean utensils can decrease person-to-person fecal-handoral transmission (43). Adequate water and sewage treatment can decrease the spread of poliovirus (82).

Prognosis and Complications.

With good supportive care, especially for respiratory insufficiency, death from paralytic poliomyelitis occurs in only 7 to 8% of patients (69). Death is usually the result of bulbar involvement with respiratory and cardiovascular impairment. Patients who survive an acute attack of paralytic poliomyelitis usually have significant recovery of motor function, although permanent and severe residual paralysis of one or two extremities is not uncommon. Motor improvement usually starts within weeks after onset, although in rare cases, extension of localized paralysis can be seen as late as the third or fourth week of illness (83). About a 50% recovery occurs in 3 months, and 75% in 6 months. Minimal further improvement occurs slowly over the next 2 years (84).

Acute and subacute complications include those related to immobility, such as decubiti, contractures, foot and wrist drop, and urinary tract infections. Pneumonia can result from bulbar muscle dysfunction and respiratory insufficiency. More chronic complications include osteoporosis, skeletal deformities such as scoliosis, reduced extremity growth, and PPS, discussed in the following section, which generally occurs 30 to 40 years after acute polio.

POST-POLIO SYNDROME.

History.

New muscle weakness as a late sequela of poliomyelitis was initially recognized by Charcot and others in 1875 (85-87). Between 1875 and 1975, about 200 cases were reported in the world’s literature (23,88). Since 1975, a large "epidemic" of several thousand cases has occurred (23,89,90). They relate to the large epidemics of poliomyelitis that occurred during the first half of this century (reviewed in Ref. 91). Since our last in-depth review of this topic (91), recent advances have centered on the pathophysiology, etiology, and treatment of the muscle weakness. The generalized nonspecific manifestations and sympathetic and UMN involvement in poliomyelitis and PPS, including the epidemiology, muscle biopsy findings, etiologic hypotheses, symptomatic treatment, and management, have been previously reviewed by Jubelt and colleagues (23,91).

Clinical Manifestations.

Definition of the Syndrome.

PPS is a neurologic disorder that produces a cluster of symptoms in individuals who had acute paralytic poliomyelitis usually 30 to 50 years earlier. They commonly include progressive weakness, fatigue, and pain of muscles and/or joints and less commonly muscle atrophy, breathing and swallowing difficulties, sleep disorders, and cold intolerance. Some symptoms such as weakness, muscle fatigue, atrophy, and maybe generalized fatigue appear to be caused by a progressive degeneration or dysfunction of motor units and eventually motor neurons. Other symptoms such as joint pain are more likely the result of excessive wear and tear on different parts of the musculoskeletal system.

Because some of the manifestations, especially fatigue, are nonspecific, the syndrome itself can be hard to diagnose unless other musculoskeletal or neurologic components are present. Fatigue is the most common manifestation overall (89,91,92), but new weakness, sometimes accompanied by atrophy, is the signature for the neurologic disorder termed "post-polio progressive muscular atrophy" (23,89). The criteria for PPS now used by most investigators and clinicians in the field were first described by Mulder et al. (93): documentation of paralytic polio, partial recovery of function followed by a period of stabilization, and progressive neurologic deterioration (Table 1). The musculoskeletal manifestations, mainly joint and muscle pain, result from the combination of long-term residual weakness and the stress in joints, ligaments, and tendons.

Neurologic Manifestations.

Fatigue is clearly the most prominent manifestation, occurring in up to 80% of patients (23,89,90,92) (Table 2). It is generally described as a disabling generalized exhaustion, the "polio wall," that follows even minimal physical activity (94). Their fatigue also has been described by patients as "increasing physical weakness," "tiredness," "lack of energy," and "increasing loss of strength during exercise" (95); thus, it can either be perceived as generalized or muscular in origin (94,96). The fatigue can also affect mental as well as physical functioning, as for example when it is severe patients find it difficult to concentrate or collect their thoughts and appear confused (95). It may be improved by decreasing physical activity, pacing daily activities, and taking frequent rest periods and naps (96,97). PPS fatigue appears to respond better to sleep than that of the chronic fatigue syndrome, although frequent rest periods are also helpful.

The pathophysiology of fatigue is not clear. Bruno et al. (98) hypothesized that the age-related attrition of neurons in the substantia nigra and possible degeneration of reticular formation neurons, combined with the already decreased number of these neurons resulting from poliomyelitis, might cause impairment of the brain activating system. Others have related the fatigue to diffuse deterioration of the motor unit at the neuromuscular junction (97,99). Some PPS patients, 10 to 20%, have muscle fatigability reminiscent of myasthenia gravis (100), as similarly reported in amyotrophic lateral sclerosis (101). A number of medications can be used to treat the generalized fatigue as indicated below. One study found that neuromuscular junction transmission, as measured by jitter on single-fiber electromyography (SFEMG), improved with anticholinesterase treatment in up to 50% of PPS patients so studied, and 50% also experienced decreased general fatigue and muscle fatigability (102). A recently completed controlled double-blind trial of pyridostigmine in PPS was, however, negative (personal communication).

New slowly progressive muscle weakness is the most important neurologic problem, occurring in most affected patients (90,91,103) (Table 2). It appears to be related to a disintegration of the LMN unit (104,105) and can occur in muscles previously affected and partially or fully recovered or in unaffected muscles (90,91) (Table 2). Human electromyography (EMG) (106) and animal studies (107,108) indicate that some clinically unaffected muscles were involved subclinically during the acute poliomyelitis, but previously affected muscles were more likely than unaffected muscles to later become weak (90,91) (Table 2). The distribution of the new weakness, which is usually asymmetric, proximal, distal, or patchy, appears to correlate with the severity of paralysis at the time of the acute poliomyelitis and with the amount of recovery and thus with the number of surviving motor neurons (6,104,109). New atrophy does not occur as an isolated manifestation and is seen in fewer than half of patients with new weakness (90,110). In addition to the weakness and atrophy caused by the disintegration of the motor unit, rarely UMN signs can occur (23). They include hyperreflexia, Babinski signs, and occasionally spasticity. Of 180 PPS patients so studied, we found UMN signs in 15 (8.3%), 7 of whom underwent myelography or magnetic resonance imaging of the spinal cord to exclude compression (23). This percentage is very similar to the frequency of UMN signs found during acute poliomyelitis (23). Muscle pain or myalgia, which also occurs in most patients (90,91,103) (Table 2), appears to be due to overuse of weak muscles. Similar symptoms occur in overused weakened muscles in other neuromuscular diseases (23). The pain is a soreness or aching feeling that occurs with minimal exercise. A small number of patients can have muscle tenderness on palpation. Rest, braces, splints, and anti-inflammatory medications may be beneficial.

New muscle weakness may also involve specific muscles groups, causing respiratory insufficiency, bulbar muscle weakness, and sleep apnea. Respiratory insufficiency primarily occurs in patients with severe residual respiratory impairment with minimal reserve (111,112). Similar to limb weakness, respiratory failure is more likely to occur in patients who required respiratory support during the acute disease and hence had more severe disease and in those that contracted polio at an age older than 10 years (111). Patients with PPS and chronic respiratory failure lose an average of 1.9% of their vital capacity per year (113). It usually is due to respiratory muscle weakness but also to central hypoventilation because of the residual damage from earlier bulbar poliomyelitis (33). Other factors such as pulmonary or cardiac disease or scoliosis may contribute to the problem. Initially, respiratory failure begins with nocturnal alveolar hypoventilation, and patients may require only nighttime respiratory support (114). If already on nighttime respiratory support, they may eventually require total ventilator support (115). Bach (116) studied 145 post-poliomyelitis individuals who were managed by noninvasive alternatives to tracheostomy. Mouthpiece intermittent positive pressure ventilation, nasal intermittent positive pressure ventilation, manually and mechanically assisted coughing, and noninvasive blood gas monitoring in the home were the main techniques used for optimizing quality of life and for avoiding complications. With the use of these measures, acute respiratory failure and tracheal intubation were generally avoided.

Bulbar muscle weakness is now also a recognized component of PPS (117), of which disphagia is the most common problem. Residual dysphagia occurs in 10 to 20% of polio survivors (118). It is primarily due to pharyngeal and laryngeal muscle weakness; however, local pharyngeal or esophageal problems should also be excluded. Some patients complain of food sticking, making swallowing slow or difficult, often with coughing and choking (118). Videofluoroscopic studies may reveal impaired tongue movements, delayed pharyngeal constriction, pooling in the valleculae or pyriform sinuses, and rarely aspiration, which is usually mild (117). Infrequently, other bulbar muscles, such as the facial muscles and vocal cords, may become weaker in PPS (119); dysarthria has also been reported (23).

Sleep apnea is not an uncommon problem in post-polio patients. It may be central, obstructive, or mixed (120,121). Most patients with central sleep apnea have a history of bulbar polio, and some required ventilatory support (120). It is probable that residual damage to the brainstem reticular formation predisposes to central sleep apnea. In comparison, obstructive sleep apnea appears to be related to pharyngeal muscle weakness, obesity, and musculoskeletal deformities (121). Respiratory muscle weakness may also contribute to sleep apnea (122).

Fasciculation and cramps without weakness, muscle pseudohypertrophy, and tingling paresthesias are other neuromuscular problems that may occur in post-polio patients, with or without new weakness (23).

Musculoskeletal Manifestations.

Pain from joint instability is the major musculoskeletal problem and can occur without new weakness. The long-term overstress of joints because of residual weakness eventually results in joint deterioration. Progressive scoliosis, poor posture, unusual mechanics because of deformed joints, uneven limb size, failing tendon transfers, and failing joint fusions can all contribute to joint pain. It can also arise from overstressed tendons due to joint deformities or because of long-standing muscle weakness. These joint problems frequently lead to loss of mobility and a return to using old assistive devices (123). Compressive radiculopathies and mononeuropathies may occur as secondary musculoskeletal complications (23,124).

Other Manifestations.

Other symptoms much less frequently reported include increased sleep requirements, cold intolerance, and psychologic stresses (23,90). Increased sleep requirements probably relate to severe fatigue. Many PPS patients complain of cold intolerance (90) (Table 2). They report worsening symptoms, including increasing generalized fatigue and weakness when exposed to cold temperatures (125). Patients may also develop coolness and color changes such as cyanosis and blanching of the affected extremity that relate to sympathetic intermediolateral column damage during prior acute poliomyelitis (126). Psychological symptoms, related to the reemergence of a supposedly old resolved problem and to the stresses of the required major changes in lifestyle, can be overwhelming at times (127,128).

Epidemiology.

Prevalence.

Data regarding the incidence and prevalence of PPS is quite variable. Codd et al. (103) found a prevalence of PPS of 22.4% in those with previous poliomyelitis, but a repeat study from the same institution found a prevalence of 64% (129). The 1987 National Health Interview Survey estimated that about half of the 1.63 million people in the United States who survived acute poliomyelitis had new late effects (PPS) (130). Another study from 1987 found a frequency of 42% (131). Ramlow et al. (132) detected a prevalence of 28.5% among all cases of paralytic poliomyelitis. The variation in prevalence appears to relate to the definition of PPS. About 50 to 64% of patients have new problems, but only about 20 to 30% have new progressive weakness. A large number of cases are seen because of the large epidemics of poliomyelitis that occurred in the United States in the 1940s and 1950s (23).

Delay in Onset of Post-Polio Syndrome.

The delay in onset between acute poliomyelitis and PPS ranges from 8 to 71 years in various series (23). The more severe the acute polio, the earlier new symptoms are likely to occur (94). In various series the average interval is about 35 years (23,94,132,133).

Risk Factors.

Several risk factors predispose to the development of PPS. One is the severity of the polio and resulting paralysis (94,129,134,135); another is the age at onset of the poliomyelitis. Acute poliomyelitis in adolescents and adults is more severe than in infants and small children (23), and the former patients are more likely to develop PPS (94,109). Another risk factor is the amount of recovery; the greater the recovery, the more likely PPS will occur (109), suggesting that reinnervation is unable to be maintained 30 to 40 years later. In those who do recover totally or partially, excessive exercise or overuse appears to predispose them to PPS (109,135).

Course of Post-Polio Progressive Muscular Atrophy.

It is difficult to measure the course of many PPS manifestations; however, weakness lends itself to objective analysis. Mulder et al. (93) reported continuous progression of weakness during the 12 years of follow-up. Dalakas et al. (136) used Medical Research Council grading and noted stepwise or steady progression of weakness at an average rate of only 1% per year over a mean follow-up period of 12.2 years. Some studies with shorter follow-up periods of 2 (137), 2.5 (138), and 5 years (139) did not demonstrate progression of the weakness; however, two other studies (140,141), each with 4-year follow-up periods, found a rate of progression of 2% per year. Many patients have a stepwise course with plateaus, and progression may be difficult to demonstrate unless the follow-up period is of adequate duration, generally greater than 5 or even 10 years. Significant objective clinical weakening was noted by others (142), including weakness of bulbar musculature (117).

Laboratory Studies.

Routine blood tests, including erythrocyte sedimentation rate, are normal except for the creatine kinase (CK), which may be mildly elevated (23,129,143,144). In one study, an increased creatine kinase level was more likely to occur in those with progressive weakness (129), and markedly elevated values probably indicate muscle overuse (145). In most studies, CSF parameters have been normal, although a mildly elevated protein content has been seen (23).

Electromyography.

In 1987 (23), we analyzed EMG studies in 26 patients with old poliomyelitis. Concentric needle EMG of patients with old polio showed chronic denervation and reinnervation including abnormally increased motor unit potential amplitude, duration, and polyphasia and decreased interference patterns both in patients and in muscles with or without new weakness, tested years after acute polio, and in muscles that were clinically uninvolved during the acute disease. Active new denervation including fibrillation and positive sharp wave activity was usually of a mild degree (Table 3) and seen in some PPS patients with new weakness (range, 0 to 45%) but also in those without new weakness. Fasciculation was seen more frequently than acute denervation. Nerve conduction velocities were also generally normal. SFEMG revealed increased fiber density and the neuromuscular transmission defects of increased jitter and blocking (Table 3). The number of motor units with abnormal jitter and neuromuscular blocking correlated with the number of years since acute poliomyelitis (146). EMG and SFEMG studies, however, did not discriminate PPS from the asymptomatic cases (104). Wiechers (147) has been the only one to analyze macro-EMG and showed that large reinnervated motor units decreased with time from recovery of the acute disease, suggesting a loss of terminal sprouts.

It now appears that the enlarged motor units that develop by collateral sprouting after acute poliomyelitis never fully stabilize (148). There may be continuous denervation and reinnervation, with denervation becoming more prominent later in life as reinnervation becomes less efficient. Progressive weakness appears to be the "end of the spectrum of all post-poliomyelitis patients" (149). Similar to clinical studies suggesting that good recovery is a major risk factor for PPS (109), SFEMG studies reveal a positive correlation between increased jitter and fiber density. They also suggest that muscles with enlarged motor units due to sprouting or recovery are more likely to become unstable later in life (110,150). Spontaneous activity, like jitter and blocking, appear to be more frequent in symptomatic muscles (151,152). Macro-EMG motor unit potential amplitudes are increased in post-polio muscles (141,153). In some muscles, the macro-EMG amplitudes may decrease in size as motor neurons die (154), whereas in others, it may increase as other motor neurons compensate (141). Despite the fact that EMG studies cannot be used to diagnose PPS because symptomatic and asymptomatic muscles have the same findings, the aforementioned studies have contributed greatly to our understanding of the pathophysiology of neuromuscular junction dysfunction after acute poliomyelitis. EMG studies can also exclude other diagnoses and determine the extent of the old acute poliomyelitis (155).

Muscle Biopsy.

The biopsy findings of patients with old poliomyelitis reveal evidence of chronic denervation, reinnervation, and active denervation (23). The primary sign of chronic denervation and reinnervation is fiber type grouping. A sign of active denervation is the presence of small angulated fibers that arise with terminal sprout denervation; group atrophy, sometimes seen in amyotrophic lateral sclerosis, is an infrequent finding in PPS. The expression of neural-cell adhesion molecules on the surface of muscle fibers is another finding that suggests active denervation (104,105). Unfortunately, chronic denervation and reinnervation and acute denervation have been seen in both symptomatic and asymptomatic post-polio patients, and muscle biopsies cannot clearly distinguish between them. Dalakas (156) found that originally affected muscles that had partially recovered had a variable degree of chronic and acute neurogenic atrophy or fiber-type grouping, with variable group atrophy and angulated fibers in some, combined with secondary myopathic features. Muscles originally affected that had fully recovered also showed signs of both chronic fiber-type grouping and recent denervation or angulated fibers, with few secondary myopathic features. Muscles originally spared clinically but newly symptomatic had signs of chronic denervation and reinnervation and recent denervation, but secondary myopathic features were minimal or absent. Asymptomatic post-polio patients had signs of chronic denervation and reinnervation but no signs of acute denervation or myopathy. These findings need to be confirmed in a larger sampling. The significance of the occasional findings of classic myopathic features (156,157) and lymphocytic infiltrates (156) remains unclear.

Etiology.

Jubelt and Cashman (23) outlined nine possible mechanisms for the development of PPS (Table 4). Over the last 10 years, enough information has accumulated that the possibilities can now probably be narrowed even more. Normal aging alone cannot explain the development of PPS. The loss of anterior horn cells and motor units with normal aging does not become prominent until after the age of 60 years (see Ref. 23). In other mammals, terminal sprouting also becomes impaired with aging, and sprouting is no longer able to keep up with the normal loss of terminal fibers that occurs throughout life as part of the constant remodeling at the neuromuscular junction (23). The age at which this occurs in humans is unknown. Muscle biopsy studies do not reveal a significant increase in small angulated fibers until after age 70 years (105). More important than chronologic age is the interval from the acute polio to the onset of symptoms, an interval that averages 30 to 40 years (23). A discussion of more likely possibilities follows.

Premature Exhaustion of New Sprouts Developing after Acute Poliomyelitis and of Their Motor Neurons due to Excessive Metabolic Demand.

EMG and muscle biopsy studies have helped clarify this possible mechanism. Enlarged motor units that develop via sprouting after the acute polio may never fully stabilize (148). Findings from SFEMG studies reveal that the largest motor units are more likely to become unstable later in life (104,152), and with increasing time from the acute polio, neuromuscular transmission becomes more unstable, as increased jitter and blocking occur (146). Several studies have shown that spontaneous activity, jitter, and blocking occurred more frequently in symptomatic muscles (150,151). These findings are supported by muscle biopsy studies that describe an increasing number of angulated fibers accumulating over time with the eventual emergence of group atrophy (105). In fact, 30 to 40 years after the acute poliomyelitis, there is disintegration of the new terminal sprouts that form after the acute infection as demonstrated by the appearance of angulated fibers (156). A contributing factor in some is the reinnervation of fibers that may not result in effective synapses (150). This is followed by degeneration of axonal branches as shown by small group atrophy (104,157). It has been frequently hypothesized that the increased metabolic demand of an increased motor unit territory results in premature exhaustion and death of the motor neuron (23). Even though there are no definitive studies examining the cell soma to prove this, electrophysiologic and muscle biopsy data appear to be supportive. The overuse of muscles resulting in excessive muscular fatigue (158-160) may also contribute to the excessive metabolic demand on motor neurons, and premature exhaustion might also be enhanced by the prior poliovirus infection of motor neurons with residual damage (23).

Chronic Persistent Poliovirus Infection.

Poliovirus and other picornaviruses can persist in the CNS of animals and cause delayed or chronic disease (23,161). Poliovirus and other enteroviruses can also persist in the CNS and systemically in immunodeficient children (23). Studies in tissue culture have found that poliovirus mutants can persist without killing the host cell (162,163) and can also persist in neurons (164). Support for the persistent poliovirus hypothesis was enhanced by the findings of Sharief et al. (165), who demonstrated poliovirus antibodies and poliovirus-sensitized cells in the CSF of post-polio patients. My collaborators and I have been unable to find poliovirus antibodies in the CSF of post-polio patients using isoelectric focusing and ELISA techniques (166,167), similar to others (136,168,169). Conclusive viral isolation and histochemical or hybridization studies have not as yet been reported using spinal cord tissues. However, CSF specimens have been examined for the presence of poliovirus RNA by polymerase chain reaction, and most studies have been negative or inconclusive (169-172).

An Immune-Mediated Disease.

The strongest support for an inflammatory or immune-mediated mechanism for PPS stems from the study of Pezeshkpour and Dalakas (173) in which inflammation in the spinal cords of seven post-polio patients was found. It consisted of both perivascular and parenchymal lymphocytic infiltrates and neuronal degeneration and active gliosis. All changes were more prominent in the three patients with new weakness. Other findings that support this hypothesis are the finding oligoclonal bands in the CSF (136) and activated T cells in the peripheral blood (174). My collaborators and I have not found oligoclonal bands in these patients (104,166); however, other histologic studies suggest an immune-mediated or viral-induced pathogenesis or at least an inflammatory mechanism. Miller (175) examined the spinal cord from a post-polio patient and found perivascular intraparenchymal chronic inflammatory infiltrates primarily composed of B lymphocytes with rare macrophages and no T cells. Kaminski et al. (176) found inflammation in the spinal cords of eight of nine PPS patients so studied.

Management.

The manifestations of PPS, such as fatigue, pain, and weakness, can be caused by other diseases; accordingly, the differential diagnosis and the exclusion of other diseases are important aspects in the evaluation of PPS patients, reviewed previously by Jubelt and Cashman (23).

Symptomatic Treatment and Supportive Care.

The management of PPS has been primarily symptomatic and supportive (23) and based primarily on empirical observations and subjective reports, not objective analyses (Table 5) (177,178). However, objective treatment studies are beginning to emerge. Respiratory insufficiency is increasingly being managed with noninvasive respiratory support with intermittent positive pressure ventilation using nasal masks and mouthpieces (113,116). Excessive generalized fatigue has been treated with energy conservation measures. Agre and Rodriquez (96) demonstrated that pacing of physical activities with work -- rest programs decreased local muscle fatigue, increased work capacity, and resulted in recovery of strength in symptomatic post-polio patients. Generalized fatigue has also been treated pharmacologically with amantadine, amitriptyline, pyridostigmine, and pemoline. Amantadine lacked benefit in a small controlled study but may be helpful in selected cases (179). Amitriptyline has not been studied in a controlled trial but may help fatigue in a small percentage of cases, possibly by controlling pain. Pyridostigmine was beneficial in an open trial (180) but not in a recently completed controlled trial (personal communication). Pemoline has not been evaluated in a controlled study.

Essential to the treatment of sleep disorders in PPS patients is to first determine whether the cause is central, obstructive, or mixed and if there is respiratory insufficiency (121,122). Dysphagia can be improved by learning swallowing techniques (178). Musculoskeletal pain, muscle pain, and joint instabilities can be treated by pacing activities, decreasing mechanical stress by bracing and wheelchairs, and by the judicious use of antiinflammatory medications (23,181). In a controlled study, Jones et al. (182) demonstrated that aerobic exercise could be tailored to post-polio patients to obtain positive cardiorespiratory training without the untoward effects on limb function.

Muscle-strengthening Exercises.

Many recent experimental treatment studies have addressed the role of exercise in altering the progression of the new weakness, and a number suggest that exhaustive strengthening exercises of partially denervated muscles can result in overwork and progressive weakness (23,91). Excessive exercise along with too few motor neurons may result in progressive weakness (183). These findings are supported by similar results in animal studies (23).

Others have demonstrated that a nonfatiguing exercise program improves strength in post-polio patients. Feldman and Soskoine (184) analyzed the effect of nonfatiguing exercises in six post-polio patients over a 3-month period: 14 muscles improved in strength, 17 were unchanged, and in 1 strength decreased. Einarsson and Grimby (185) and Einarsson (186) analyzed the effects of a 6-week, isometric-isokinetic, nonfatiguing strengthening program at 6 and 12 months after training in 12 post-polio patients. These patients had Medical Research Council grade 4 strength in quadriceps muscle that subsequently increased 29% isokinetically with exercise. Fillyaw et al. (187) studied the effect of nonfatiguing resistance exercises in 17 PPS patients for up to 2 years. Their strength increased significantly in exercised compared with contralateral unexercised muscles. Agre et al. (188) evaluated the effect of a low-intensity, alternate-day, 12-week quadriceps muscle-strengthening resistance exercise program. Strength significantly improved without changes in motor units by EMG or in serum creatine kinase levels. Spector et al. (189) evaluated changes in the dynamic and isometric strength in newly weakened quadriceps muscles and in asymptomatic triceps muscles of six PPS patients after 10 weeks of progressive resistance muscle training. They found that the training led to significant gains in dynamic strength in both symptomatic and asymptomatic muscles, without histologic or serologic evidence of muscular damage. These studies suggest that significant short-term improvement in muscle strength occurs with nonfatiguing submaximal strength, short duration, repetitious exercises. The effects of long-term continuous exercise remains to be determined.

SUMMARY.

Poliomyelitis is now a rare occurrence in the United States although still a significant problem in underdeveloped areas of the world. The large epidemics of poliomyelitis in the 1940s and 1950s are now reflected by the large number of polio survivors who are developing new late manifestations, referred to as the post-polio syndrome, or PPS. It is now a well-recognized entity that occurs on average about 35 years after the acute poliomyelitis. Common manifestations include generalized fatigue, joint deteriorations with pain, cold intolerance, and prominent neurologic problems. Neurologic problems include new weakness, muscle fatigue, muscle pain, muscle atrophy, respiratory insufficiency, dysphagia, sleep apnea, and possibly generalized fatigue. It is estimated that there are 1.63 million polio survivors in the United States and that half will develop PPS. It is a very slowly progressive syndrome. Older age at the onset of the acute poliomyelitis, the severity of the poliomyelitis, the amount of recovery, and overexercise or overuse of muscles are risk factors for early development. The etiology is unclear, although premature exhaustion of the new sprouts that develop after acute poliomyelitis and of their motor neurons appear to be important factors. Other possible causative factors include persistent poliovirus infection and an underlying immune-mediated process. Treatment is primarily supportive; however, nonfatiguing strengthening exercises can clearly improve strength over the short term.

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