It is now recognized that normal aging alone cannot explain the development of post-polio syndrome because the normal loss of anterior horn cells and motor units does not become prominent until after age 60 (Jubelt and Cashman 1987). More important than a patient’s chronological age is the interval from their acute polio to the onset of post-polio syndrome, an interval that averages between 30 and 40 years (Jubelt and Cashman 1987). The presently accepted most likely etiologic possibilities are degeneration of enlarged motor units, a chronic persistent poliovirus infection or an immune-mediated disease.
Degeneration of enlarged motor units. The enlarged motor units that develop via sprouting after the acute polio may never fully stabilize (Wiechers 1985). Findings from single fiber electromyographic (SFEMG) studies reveal that the largest motor units are more likely to become unstable later in life (Cashman et al 1987a; Emeryk et al 1990), and with increasing time from the acute polio, neuromuscular transmission becomes more unstable, as increased jitter and blocking occur (Wiechers and Hubbell 1981). Spontaneous denervation activity, jitter, and blocking occur more frequently in symptomatic muscles (Ryniewicz et al 1990; Maselli et al 1992). These findings are supported by muscle biopsy studies that describe an increasing number of angulated fibers accumulating over time (Dalakas and Illa 1991). This is followed by degeneration of axonal branches as demonstrated by the appearance of small group atrophy (Drachman et al 1967; Cashman et al 1987a). This can be followed by large group atrophy suggesting neuronal degeneration (Dalakas and Illa 1991). 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 (Jubelt and Cashman 1987). Although no definitive studies have examined the cell soma to prove this theory, electrophysiologic and muscle biopsy data appear to be supportive. The overuse of weakened muscles results in excessive muscular fatigue (Sharma et al 1994; Grimby et al 1996; Agre et al 1998; Sunnerhagen et al 2000; Thomas and Zijdewind 2006), which appears to contribute to the excessive metabolic demand on motor neurons and the premature exhaustion.
The pathophysiology of fatigue in post-polio syndrome and West Nile virus is still unclear. Fatigue in these patients appears to result from processes involving multiple domains of function. In post-polio syndrome, it is hypothesized that fatigue results from “exhausted neurons that have been chronically overtaxed as a result of axonal sprouting after loss of neighboring motor neurons” (Cashman and Trojan 1995), starting several decades after recovery and after a long latent period.
Chronic persistent poliovirus infection. Poliovirus and other picornaviruses can persist in the CNS of animals and cause delayed or chronic disease (Jubelt and Cashman 1987; Destombes et al 1997). Poliovirus and other enteroviruses can also persist in the CNS and systemically in immunodeficient children (Jubelt and Cashman 1987). Studies in tissue culture have found that poliovirus mutants can persist without killing the host cell (Colbere-Garapin et al 1989; Borzakian et al 1992) and can also persist in neurons (Pavio et al 1996). Support for the persistent poliovirus hypothesis was enhanced by the findings of Sharief and colleagues (Sharief et al 1991), who demonstrated poliovirus antibodies and poliovirus-sensitized cells in the CSF of post-polio patients. Leon-Monzon and Dalakas (Leon-Monzon and Dalakas 1995) found elevated IgG poliovirus antibodies in the sera of post-polio syndrome patients as compared to controls; however, patients with amyotrophic lateral sclerosis had similar elevated levels. Other investigators have been unable to find poliovirus antibodies in the CSF of post-polio patients (Kurent et al 1979; Dalakas et al 1986; Salazar-Grueso et al 1989; Melchers et al 1992; Jubelt et al 1995). CSF specimens have also been examined for the presence of poliovirus RNA by polymerase chain reaction, and the majority of studies have been negative or inconclusive (Melchers et al 1992; Leon-Monzon and Dalakas 1995; Leparc-Goffart et al 1996; Muir et al 1996). The most positive study was that of Julien and colleagues (Julien et al 1999) who detected poliovirus genome sequences in the CSF of 11 of 20 post-polio syndrome patients but in none of the 20 control patients. These same authors had reported similar findings, post-polio syndrome 5 of 10 positive, controls 0 of 23 positive, in an earlier study (Leparc-Goffart et al 1996). Conclusive viral isolation and histochemical or hybridization studies have not as yet been reported using spinal cord tissues and will be required to resolve this possibility.
An immune-mediated disease. The strongest support for an inflammatory or immune-mediated mechanism for post-polio syndrome stems from the study of Pezeshkpour and Dalakas (Pezeshkpour and Dalakas 1988) in which inflammation in the spinal cords of seven post-polio patients was found. It consisted of both perivascular and parenchymal lymphocytic infiltrates, neuronal degeneration, and active gliosis. All changes were more prominent in three patients with new weakness. Other findings that support this hypothesis are the finding oligoclonal bands in the CSF (Dalakas et al 1986) and activated T-cells in the peripheral blood (Ginsberg et al 1989). Others have not found oligoclonal bands in post-polio syndrome patients (Cashman et al 1987a; Salazar-Grueso et al 1989); however, other histologic studies suggest an immune-mediated or viral-induced pathogenesis or at least an inflammatory mechanism. Miller (Miller 1995) examined the spinal cord from one post-polio patient and found perivascular intraparenchymal chronic inflammatory infiltrates primarily composed of B lymphocytes with rare macrophages and no T-cells. Kaminski and colleagues (Kaminski et al 1995) found inflammation in the spinal cords of 8 of 9 post-polio syndrome patients. Studies support an immune-mediated process with the finding of inflammatory cytokines (TNF-alpha, IFN-gamma, IL-4, IL-10) in the CSF of post-polio syndrome patients (Gonzalez et al 2002; 2004).