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Although the Post-Polio Task Force disbanded in 1999 because the research was concluded, the information that was developed for this section of the PHI website remains relevant to this date.

Highlights of 1997 Roundtable Meetings

Pathophysiology Holds Clues to Post-Polio Syndrome Therapy

Recent insights into the pathophysiology of post-polio syndrome (PPS) may hold clues to effective treatment modalities, two leading investigators reported at a roundtable meeting of the Post-Polio Task Force held last April in Boston.

Of approximately 640,000 survivors of paralytic poliomyelitis who are currently living in the United States, 20% to 40% are at risk for PPS, said Neil R. Cashman, MD, Associate Professor at the Montreal Neurological Institute of McGill University and Hospital, Montreal, Quebec, Canada. The key symptoms of PPS are new weakness, fatigue and pain.

Dr. Cashman reminded listeners that the predominant disability of polio results from invasion and destruction of motor neurons by the poliovirus, with subsequent loss of innervation in muscle fibers. The recovery phase is characterized by axonal sprouting, which serves to reinnervate some or all of these muscle fibers. It is currently thought that PPS results because these axonal sprouts cannot remain stable indefinitely, but rather degenerate over time, resulting once again in denervation of the associated muscle fibers.

Using electrodiagnostic tests, including single-fiber electromyography (SFEMG), and muscle biopsy analyses, including immunohistochemical evaluations of neural-cell adhesion molecule (N-CAM, a molecule expressed by denervated muscle fibers), researchers have identified ongoing muscle fiber denervation in post-polio patients (Figures 1 and 2). Fibers that were denervated decades ago can be clearly differentiated from small, angulated fibers that have lost their innervation in recent weeks or months, Dr. Cashman noted. "To me, this is the best proof that there is terminal axonal degeneration going on in people who have had polio in the past," he said.

Figure 1

Figure 1. Single-fiber electromyography (SFEMG) data from an asymptomatic, 64-year-old patient with prior paralytic polio. Shown are 10 superimposed action potentials demonstrating "jitter" associated with motor nerve terminal degeneration.

Figure 2

Figure 2. Angular atrophic muscle fiber in rectus femoris of a PPS patient reporting one year of new leg weakness (hematoxylin eosin stain). Isolated angular atrophic fibers indicate recent motor nerve terminal degeneration.

Terminal Axonal Dysfunction Observed

More recent work by Dr. Cashman's group has suggested that terminal axonal dysfunction may be even more common than terminal axonal degeneration. This research has identified normal-sized myofibers expressing N-CAM (Figure 3, below); these may be fibers that have lost innervation and will ultimately become small, angulated fibers, or they may be only temporarily denervated and may be destined to become reinnervated, he said.

image for Figure 3

Figure 3. Neural-cell adhesion molecule (N-CAM) immunoreactivity in small- and large-diameter muscle fibers. N-CAM expression is associated with muscle denervation; normal-sized myofibers expressing N-CAM may be fibers that have lost innervation and will ultimately become small, angulated fibers, or they may be only temporarily denervated and may be destined to become reinnervated.

"The interesting point is that small, angulated fibers constitute something on the order of 1% of the fibers that one can see on a muscle biopsy [of a patient with a history of polio], whereas the total N-CAM-positive fiber population can represent 10% or more of muscle fibers, strongly suggesting that there is an ongoing process that is much more common than the terminal degeneration of axons," Dr. Cashman said.

In addition to the N-CAM data, there is substantial electrophysiologic evidence that suggests instability of nerve transmission at the neuromuscular junction (NMJ). A marked increase in SFEMG jitter (a measure of terminal axonal function and NMJ transmission) has been observed both in polio survivors who have no new symptoms and in those with PPS. (See Figure 1.) The increase in jitter has been shown to be correlated with the severity of the denervation.

Terminal axonal dysfunction may simply represent an intermediate stage in the process of neuronal degeneration, Dr. Cashman noted. Alternatively, it may reflect the fact that motor units in polio-affected muscles are in a constant state of remodeling. As innervation is lost from one muscle fiber, he said, an axonal sprout is sent from another motor unit to innervate that fiber; this process continues back and forth. There may also be age-related changes in the trophic support of terminal axons, Dr. Cashman noted. Growth hormone secretion diminishes with aging, resulting in decreased levels of circulating insulin-like growth factor I (IGF-1), which plays an important role in the maintenance of terminal axons.

Treatment Implications Noted

Unlike degeneration, which is irreversible, nerve terminal dysfunction may be treatable. Dr. Cashman pointed out that one of the key functions of the terminal motor axon is to release acetylcholine in order to depolarize postsynaptic muscle fibers and induce contraction. Nearly 50 years ago, studies found a defect in acetylcholine release in patients who had recovered from polio.

"Defective release of acetylcholine waxes and wanes; it can be reversible and fluctuant, " he noted. " Fatigability is the sort of symptom that we should be on the lookout for, because it may be responsive to pharmaceutical therapy."

Dr. Cashman explained that the defect in acetylcholine release is reversible with injection of the anticholinesterases neostigmine or edrophonium, which increase the amount of acetylcholine in the NMJ by inhibiting its breakdown. Interestingly, Dr. Cashman noted, response to the anticholinesterase pyridostigmine can be predicted on the basis of a positive SFEMG edrophonium response (i.e., the same patients who respond to edrophonium will also experience improvement in fatigue with oral pyridostigmine therapy).

Overuse Hypothesis Described

Burk Jubelt, MD, Professor and Chairperson of the Department of Neurology at the State University of New York Health Sciences Center in Syracuse, pointed out that neither increasing fiber density nor presence of angulated muscle fibers can serve to differentiate symptomatic from asymptomatic polio survivors. However, he said, several clinical studies have demonstrated that excessive strengthening exercise of partially denervated muscles can lead to progressive weakness. Animal experiments have also shown that overwork of weak and partially denervated muscles results in more weakness.

In light of these observations, Dr. Jubelt suggested that overuse of already weakened muscles accelerates the breakdown of the remaining motor units, resulting in additional weakness. From this perspective, post-poliomyelitis progressive muscular atrophy can be classified as a secondary phenomenon resulting from overstress of motor units for many years in compensation for residual weakness. Non- fatiguing exercise can help reverse the process and may even improve strength by avoiding overstress of the already weakened muscles, he said.

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