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Post-Polio Syndrome: Pathophysiology and Clinical Management
Anne Carrington Gawne and Lauro S. Halstead

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V. PATHOLOGY IN CHRONIC POLIOMYELITIS.

The pathological changes that cause the symptoms of PPS are not well understood; however, a number of possible theories have emerged in recent years.[30] These are summarized in Table 1. We explore each of these separately.

TABLE 1 Proposed Etiologies of Post-Polio Syndrome.
Motor unit dysfunction due to overuse or premature aging of large motor units.
Musculoskeletal overuse.
Musculoskeletal disuse.
Loss of motor units with normal aging.
Predisposition to motor neuron degeneration because of glial, vascular, and lymphatic changes caused by acute polio.
Chronic polio virus infection or virus reactivation.
An immune mediated syndrome.
The effect of growth hormone.
The combined effects of disuse, overuse, pain, weight gain, or other illnesses.

A. Motor Unit Dysfunction Due to Overwork or Premature Aging of Polio Affected Motor Units.

In 1902, Gowers proposed that progressive weakness in many degenerative neuronal diseases is due to abiotrophy; the neurons are exhausted and they simply wear out.[31] The original viral attack of the anterior horn cells may have left some motor neurons functional but impaired, making them more vulnerable to dysfunction as time passes. Tomlinson observed that many neurons were smaller than normal in the spinal cords of persons who survived long after the acute polio episode.[32,33] Consistent with Bodian’s findings,[34] his observation led him to conclude that the protein synthetic mechanisms of any cell invaded by polio are likely to be permanently damaged.

At this time, we can only speculate that premature exhaustion may be due to abnormalities in DNA and RNA repair or protein synthesis.[30] If this is a major factor, it is most likely that this is a combination of damage to both neurons affected by polio and those that have increased metabolic demands because of increased motor unit territory.[35] According to this theory, neurological dysfunction results from this increased metabolic load after a critical number of years. This has been demonstrated in electrophysiological studies. Weichers and Hubbel[26,27] and Dalakas et al.[36] found neuromuscular transmission abnormalities suggesting that the giant motor neurons may not be able to sustain indefinitely the metabolic demands of all their sprouts. As a result, individual terminals slowly deteriorate and reinnervated muscle fibers drop off, as Figure 7 shows.[21]

Figure 7
FIGURE 7. Pathophysiology in post-polio muscular atrophy (PPMA). (Adapted from ref. 21.)

Possibly then, it is prolonged overwork with increased metabolic demand of the greatly enlarged motor units that compounds injury to the motor unit sustained during acute infection. The overworked anterior horn cells' control over a greater than normal percentage of muscle function may cause them to succumb "prematurely" to the aging process, resulting in pronounced weakness beginning as early as the fourth decade and steadily worsening with advancing age. Thirty to 40 years after recovery, the giant motor units appear to have lost their ability to sustain all of the terminal sprouts supplying so many muscle fibers. Consequently, the number of muscle fibers driven by each motor neuron declines, and the polio survivor experiences new weakness and other symptoms of neurological dysfunction.

While there is no direct experimental data demonstrating that this increased metabolic demand results in premature aging of the neuron soma, pathologically it does appear that collateral reinnervation is greater, not surprisingly, in weak muscles.[30,37] The more muscle fibers lost, the more apparent is the slowly progressive weakness. This hypothesis is intuitively attractive and conceivably explains new weakness in some polio patients but remains unsubstantiated by muscle biopsy changes like group atrophy that would reflect the new loss of whole motor units. Also, no studies have demonstrated permanent biochemical or physiological damage to the surviving motor neurons.[9]

B. Muscle Overuse.

Muscle overuse is less well understood, although studies suggest relationships between the number of motor units, muscle damage, exercise intensity, and duration.[38-42] However, the extent to which a primary muscle defect is weakening some polio survivors remains unknown. Overuse has a cumulative effect over time. Chronic mechanical strains on joints, ligaments, and soft tissues that have not been supported well for 30 or more years produce a self-perpetuating cycle of further complications. Recognizing overuse complications early and implementing effective interventions may avert severe post-polio disablement in middle or old age.

Both Windebank et al. at the Mayo Clinic and Maynard found that in persons with similar neurological involvement, new weakness occurred more often in the weight-bearing muscles of the legs than in the non-weight-bearing muscles of the arms.[38,39] And those limbs affected the most by the original disease were the most susceptible to new weakness. Perry et al. observed that patients with new lower-extremity weakness had a less efficient gait, with an increase in both the duration and intensity of the extensor muscle contraction.[40] Halstead and Gawne showed more patients had mild involvement or subclinical polio in their arms, while clinically unstable polio or atrophic polio was more common in the lower extremities.[41] Agre and co-workers found that symptomatic post-polio subjects had evidence of more severe original polio involvement by history, were weaker and capable of performing less work than asymptomatic subjects, and recovered strength less readily than controls.[42] Finally, evidence of anatomical damage to muscle fibers is indirectly shown by elevation of creatinine kinase levels found in patients with unstable polio.[43,44]

C. Muscle Disuse.

It is well known that disuse leads to both deconditioning and muscle weakness in healthy individuals.[45] Similarly, polio individuals have been noted to have similar short-term increased weakness when forced to remain sedentary with illness or injury.[46] What part this plays in the development of long-term weakness, however, is less clear.

D. Loss of Normal Motor Units with Aging.

While anatomical and electrophysiological studies have demonstrated that there is a loss of motor neurons with advancing age, this becomes prominent only after 60 years of age.[33,35] While some studies of post-polio survivors have failed to show a positive relationship between the onset of new weakness and chronological age,[38,47] a recent study by Trojan et al. demonstrates that older individuals are more likely to develop PPS.[48] Nevertheless, the most consistent variable is the length of the interval between onset of polio and the appearance of new symptoms, so most patients develop new weakness 30 to 40 years after their initial infection, and the age of onset of symptoms is variable. Therefore, while chronological age may contribute to the development of new weakness, it is probably not the primary causative factor. Also, it is unlikely that polio patients retain "normal" motor neurons. So, the first hypothesis (overuse of large motor units) is more likely.

E. Predisposition to Motor Neuron Degeneration Due to Glial, Vascular, and Lymphatic Damage.

Some investigators have suggested that damage to the glial cells and vascular supply at the time of infection can lead to secondary dysfunction of anterior horn cells.[49] While vascular damage is sometimes seen, it is believed that this is secondary to the severe inflammatory responses that can occur. Most studies show that polio affects only the neural cells and not the glial or vascular endothelial cells.[50,51] For these reasons, it is unlikely that these changes play a large part in the clinical deterioration seen with post-polio syndrome.

F. Virus Reactivation or Persistent Infection.

Animal studies have shown that poliovirus and other picornaviruses may persist in the CNS and produce late or chronic disease.[52,53] When looking for evidence of persistent infection, investigators either study the immune response, by examining oligoclonal bands in the cerebral spinal fluid (CSF), isolating the virus through histochemical or hybridization studies, or looking for evidence of viral genetic material using the polymerase chain reaction (PCR) technique and probe detection. Recently, much work has been done in this area.

Dalakas and co-workers first found evidence of oligoclonal IgG bands in the CSF in seven of 13 symptomatic post-polio patients.[36] However, total IgG levels, the IgG index, and IgG synthesis in the CSF were normal, and there were no antibodies to poliovirus. No oligoclonal bands were found in the CSF of six asymptomatic patients.

Evidence for possible reactivation of polio virus was demonstrated by Sharief et al. in 1991 in a study that examined the intrathecal immune response in polio survivors.[54] They assessed the antibody response to poliovirus and the production of interleukin-2 and soluble interleukin-2 receptors in 36 patients with PPS and 67 controls, including 13 who had a history of polio but no new weakness and 18 patients with amyotrophic lateral sclerosis. Oligoclonal IgM bands specific to poliovirus were detected in the CSF of 21 of 36 patients with PPS but in none of the controls. In quantitative studies, there was evidence of increased intrathecal synthesis of IgM antibodies to poliovirus only in those with PPS and no increased IgM to other viruses. The patients with PPS had significantly higher mean CSF levels of interleukin-2 and soluble interleukin-2 receptors, corresponding to increased levels of IgM. The presence of an intrathecal immune response to poliovirus in patients with PPS is suggestive that recrudescence of weakness may be caused by persistent or recurrent infection with some part of the poliovirus.

Following publication of Sharief’s article in the New England Journal of Medicine, letters to the editor by Drs. Salazar-Grueso, Roos, Dalakas, Jubelt, and Cashman pointed out that there was IgM detected in 21 patients, with poliovirus specific IgG in only seven patients.[55] They felt it was inconsistent to have IgM but no IgG in a chronic viral infection. More studies were then done to duplicate the findings.

In 1994, Muir and Sharief examined CSF in 24 patients with PPS, 36 with stable polio, and 36 controls.[56] Three of 24 patients with PPS had evidence of enterovirus RNA compared with no patients in the other groups. All three of these patients had high intrathecal levels of poliovirus specific oligoclonal IgM bands, which they suggest is evidence that patients with a history of polio are susceptible to persistent enterovirus infection.

In another study, Melchers et al. examined skeletal muscle biopsies in six patients and CSF specimens in an additional 10 patients who met the criteria for PPS, examining the CSF for IgM antibodies to poliovirus and the muscle biopsy for presence of poliovirus RNA by PCR.[57] In none of these specimens was any evidence of poliovirus detected. Control CSF specimens in patients with acute poliovirus were positive, while controls in patients with aseptic meningitis (not polio) were negative.

On the other hand, Jubelt et al. examined sera and CSF from 19 post-polio patients and found increased anti-poliovirus (anti-PV) antibodies to type 1 and 2 in seven.[58] However, in another study, no anti-PV antibodies were found.[59] They have concluded that there was little evidence of intrathecal production of anti-PV antibody.

Leparc and colleagues examined CSF from eight patients with PPS and 10 controls.[60] Although no viruses were cultured, using enzymatic amplification of viral DNA, genome sequences were found in several PPS patients and in no controls. They suggest that these results are in favor of the persistence of poliovirus for several decades in PPS patients.

Finally, in 1994, Monzone and Dalakas examined serum and CSF of patients with PPS, comparing them to patients with acute polio, other neurological diseases, and normal controls.[61] While both IgM and IgG were highest with acute polio, moderate levels of both were seen in PPS patients compared with the controls. Poliovirus was seen in one of 18 PPS patients by PCR, and amplified genetic product was seen in four of 12 PPS patients. They concluded that high titers of IgM antiPV antibodies imply an ongoing antibody response to antigen, and the presence of viral RNA suggested possible viral persistence.

In summary, regarding the hypothesis of persistent or reactivated infection, an active controversy still exists. However, the lack of consistent findings from study to study and the failure to find conclusive findings in all patients with PPS suggests that this is not the single cause of new weakness. Most researchers feel this is an area that needs to be studied further.

G. An Immune-Mediated Syndrome.

Another hypothesis proposes immunologic involvement. A study by Pezeshkpour and Dalakas described what appeared to be evidence of an ongoing inflammatory or immune response -- active inflammatory gliosis, neuronal chromatolysis, and axonal spheroids in the spinal cords of polio patients who died many years later of other causes.[62] Steegman also found inflammatory infiltrates, including lymphocytes, plasma cells, and macrophages in the parenchyma and perivascular spaces in five of seven post-polio patients.[49] Whether these changes represent a primary lesion in the cord or a response to a lesion in the distal axon is unknown.

Ginsberg et al. described activated T cells, including significant alternations in CD4+ subsets in both symptomatic and asymptomatic post-polio subjects when compared with normal controls supporting the possibility that immunologic factors may contribute to late disease progression.[63] Dalakas et al. have reported preliminary evidence of a lymphocytic response in the form of anti GM1 neuronal antibodies and IgG oligoclonal bands in the CSF of some patients with new weakness, whereas patients with no new weakness had no oligoclonal bands in their CSF.[21,36] He later examined muscle biopsies and found perivascular or interstitial inflammatory cells consisting of CD8+ cells, CD4+ cells, and macrophages. These findings suggest that there is a slow hut ongoing inflammatory process not only in the spinal cord but also in the muscle specimens.[64] More recently, immunopathological studies of a patient with PPS showed evidence of focal perivascular interparenchymal inflammatory infiltrates in the CNS. Immunoperoxide staining demonstrated that these were virtually all B lymphocytes, with rare macrophages and no T cells.[65] These antibodies could be directed toward neurons, nerve terminals, or postsynaptic antigens. This suggests that PPS could be an autoimmune disorder mediated by antibodies produced in situ, and not a cell-mediated process. It is possible that autoantigens from neurons, axons, and muscle membranes might be released during the acute phase of polio. Antibodies against neuronal elements or antiidiopathic antibodies could play a role in the pathogenesis of PPS.

H. The Effect of Growth Hormone.

There is an intriguing suggestion by Shetty, Matsson, and Rudman that the aging of the hypothalamus growth hormone (GH) axis may be a precipitating factor in the development of PPS.[66,67] It has been shown that GH secretion drops off dramatically in approximately one third of normal adults over the age of 40. This results in a fall in somatomedin C (SmC) or insulin growth factor (IGF-I), which plays an important role in accelerating the synthesis of DNA and skeletal muscle protein, aids in the proliferation of muscle satellite cells and the regeneration of peripheral nerve sprouting.[68]

In a survey of 10 men with PPS and 94 healthy men ages 35 to 63, 100% of those with PPS had SmC less than or equal to 0.40 µ/ml and 90% had values of 0.35 µ/ml or less, while in the healthy population the numbers were 40 and 27%, respectively. In the PPS group, the values did not correlate significantly with either age, functional level, body weight, or years since acute polio.[66] In a study of 12 stable polio patients and 10 patients with PPS, Rudman and Shetty found that SmC was markedly depressed in those with PPS and was normal in those without PPS.[67]

In a subsequent study with 124 polio survivors and 261 age-matched healthy controls, Rao et al. measured IGF-I in 124 polio survivors and found that the level was significantly lower in those with a history of polio. The IGF-I levels in that group significantly correlated with age, gender, body mass index, dependency, pain, and difficulty with activities of daily living (ADLs). However, it did not correlate with subjective report of recent decline in functional status.[69]

Recently, this hypothesis was tested in six PPS patients with low IGF-I levels.[70] These patients were given low-dose human GH treatment for 3 months. Although two of five patients demonstrated improvements in strength and endurance, this was not consistent, and the overall impression was that there was no significant improvement. It was suggested that a longer trial would be necessary. Further investigation into the role of GH therapy for treatment of PPS presents a challenge for the future.

I. The Combined Effects of Overuse, Disuse, Pain, Weight Gain, or Other Illnesses.

Finally, it is hypothesized that a combination of musculoskeletal disuse, musculoskeletal overuse, or motor unit dysfunction may play a significant role in the development of progressive weakness. Furthermore, they may interact with each other in such a way to multiply the effects of any single factor, as illustrated in Figure 8.[71] With overuse, weakness may develop. This may lead to disuse, weight gain, and further weakness. Musculoskeletal disuse leads to atrophy, weakness, contractures, and diminished endurance, which are complications that have been studied in other groups with sedentary lifestyles or neuromuscular lesions. If there is overuse, musculoskeletal pain may occur, causing the patient to either rest, developing deconditioning, or compensate with improper body mechanics, leading to further overuse, and possibly pain elsewhere. In our experience, most patients present with some combination of these. Treatment can then be centered on minimizing the effects of one or more of these in order to allow the remaining muscles to function at a more optimal level.

Figure 8
FIGURE 8. Schematic model showing possible etiological factors for the late neuromuscular and musculoskeletal complications of poliomyelitis and their interactions.

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