PSN Library Files

Anticholinesterase-responsive neuromuscular junction transmission defects in post-poliomyelitis fatigue

Daria A. Trojan, Daniel Gendron and Neil R. Cashman

Department of Neurology

McGill University

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

(Received 27 May, 1992)

(Revised, received 18 August, 1992)

(Accepted 28 August, 1992)

Journal of the Neurological Sciences, 114 (1993) 170-177

© 1993 Elsevier Science Publishers B.V. All rights reserved 022-510X/93/$06.00 Lincolnshire Post-Polio Library copy by kind permission of Dr. Trojan

 

Correspondence to: Neil R. Cashman, M.D., Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Tel.: (514) 398-8532: Fax: (514) 398-8540.

Key words: Postpoliomyelitis syndrome; Neuromuscular junction; Single fiber electromyography; Fatigue; Anticholinesterase; Electromyography

Summary

Disabling generalized fatigue and muscle fatiguability are common features of post-poliomyelitis syndrome (PPS). In 17 fatigued PPS patients, we measured jitter on stimulation single-fiber electromyography (S-SFEMG) for at least 3.5 min before and after i.v. injection of 10 mg edrophonium. We observed reduction in jitter (defined as a significant difference in jitter means before and after edrophonium, unpaired t-test P < 0.05) in 7 patients, no change in 8, and a significant increase in 2 patients. Blinded to their edrophonium results, the 17 patients were treated with pyridostigmine 180 mg/day for 1 month, with a subjective improvement of fatigue in 9 patients, and with a significant reduction in mean Hare fatigue scores in the entire group of 17 patients (pre = 2.71, and post = 1.71; Wilcoxan signed rank sum test, P < 0.05). Edrophonium-induced reduction of jitter on S-SFEMG was significantly associated with pyridostigmine-induced subjective improvement of fatigue (Fisher’s exact test, P < 0.04). A significant reduction in fatigue with pyridostigmine was observed only in the 7 patients who experienced a significant reduction in jitter with edrophonium (Wilcoxan signed rank sum test, P = 0.03). In addition, the 9 pyridostigmine responders experienced a significant reduction in jitter means pre-

and post-edrophonium (100% vs. 88%, Bonferroni corrected, P < 0.01). We conclude that neuromuscular transmission as measured by jitter on S-SFEMG can improve with edrophonium in a proportion of PPS patients, and that generalized fatigue and muscle fatiguability in some patients with PPS may be due to anticholinesterase-responsive NMJ transmission defects.

Introduction

Progressive new weakness following decades of motor stability in individuals with antecedent paralytic poliomyelitis has been recognized since the time of Charcot (Cornil and Lepine 1875; Raymond and Charcot 1875). Recent investigators have stressed generalized fatigue and pain as additional features of a “postpoliomyelitis syndrome” (PPS; Halstead et al. 1985; Codd et al. 1985; Dalakas et al. 1986; Jubelt and Cashman 1987; Speier et al. 1987; Windebank et al. 1987; Munsat 1991). PPS is the most prevalent progressive motor neuron disease in developed countries, with an estimated 22-41% (Codd et al. 1985; Speier et al. 1987; Windebank et al. 1987; Munsat 1991), of survivors of paralytic poliomyelitis being at risk for developing the syndrome during their lifetimes. Generalized systemic fatigue is reported by most patients with PPS (Halstead et al. 1985; Codd et al. 1985; Trojan and Cashman 1989), and may be their most disabling symptom.

Fatigue as a symptom of disease is subjective, heterogeneous, and common, which frustrates controlled studies of its cause and treatment. In PPS, patient complaints appear to suggest both “central fatigue” (for example, mental symptoms such as difficulties in concentration and memory), and “peripheral fatigue” (for example, abrupt decline in strength upon sustained exertion). Muscle fatiguability on physical examination and electromyographic evidence of neuromuscular junction (NMJ) transmission defects (such as decrement on repetitive stimulation (Hodes 1948) and increased jitter on single fiber electromyography (SFEMG; Wiechers and Hubell 1981; Cashman et al. 1987; Wiechers 1988), suggest that a proportion of PPS patients may indeed suffer from fatigue referable to the NMJ.

Clinical and electrophysiologic similarities between PPS and other diseases with established NMJ pathology, such as myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS; Mulder et al. 1959; Stalberg et al. 1974; Stalberg et al. 1975; Denys and Norris 1979; Bernstein and Antel 1981; Engel 1986; Bradley 1987), have prompted the use of anticholinesterase agents such as pyridostigmine for treatment of postpoliomyelitis fatigue and muscle fatiguability (Raymond 1986; Trojan and Cashman 1989). However, it has been difficult to implement a blinded controlled trial of pyridostigmine in PPS fatigue due to associated side effects, predominantly increased gut motility early in treatment.

We designed a trial to assess the effect of anticholinesterase agents on NMJ transmission, and on fatigue in PPS. The primary objective was to determine the effect of the intravenous, short-acting agent edrophonium on NMJ transmission, as assessed by stimulation single-fiber electromyography (S-SFEMG) in fatigued PPS patients. A secondary objective was to determine if a relationship was present between the results of the S-SFEMG/edrophonium test, and the patients’ subsequent response to the oral anticholinesterase pyridostigmine. This was performed by administering pyridostigmine to all patients, blinded to the results of the edrophonium test, and rating their fatigue and functional level before and one month after initiation of low dose pyridostigmine.

Materials and methods

Patients and clinical evaluation

Seventeen PPS patients (age range 34-74) and 10 normal control subjects (age range 28-39) provided their informed consent to participate. All PPS patients were evaluated with a standardized history and physical

examination (Cashman et al. 1987), and provided a history consistent with prior paralytic poliomyelitis followed by partial or complete recovery, with at least 25 years of functional stability. For inclusion in the study, all patients complained of at least 2 years of new symptoms, including muscle fatiguability (defined as increased weakness on sustained exertion which improves with rest), general fatigue, and at least 2 of the following 3 symptoms: (a) increased weakness in at least 1 extremity, (b) pain in at least 1 joint or spine, (c) muscle pain in at least 1 extremity. Severity of initial acute poliomyelitis was estimated by use of a 6-point modified index as described by Klingman et al. (1988), with 1 point given for involvement of each of 4 extremities, of speech and/or swallowing, and for respiratory involvement. Other entry criteria included objective muscle fatiguability in at least 1 muscle on physical examination (decline of 1 Medical Research Council (MRC; Medical Research Council 1982) strength grade with 20 or less repetitive isotonic contractions), and lack of sufficient response to treatment with more conservative measures (such as rest periods during the day, activity planning, discontinuation of any medications associated with fatigue). No patient has concurrent medical or neurological disorders which could have interfered with the interpretation of electrophysiological testing or could be associated with fatigue.

Electrophysiological evaluation

The 17 patients and 10 controls were studied with S-SFEMG, which allows the evaluation of the NMJ of 1 muscle fiber at a constant stimulation frequency (Trontelj et al. 1986; Jabre et al. 1989), obviating the need for patient voluntary effort required in conventional SFEMG (reviewed by Stalberg and Trontelj 1979). Because of the known variability of jitter with different muscle fiber stimulation rates in other conditions affecting the NMJ (Stalberg et al. 1974, 1975; Schwartz and Stalberg 1975; Schiller and Stalberg 1978), this technique may be the most reproducible electrophysiological method for assessment and comparison of NMJ dysfunction.

Muscles examined in patients had been previously affected by acute paralytic poliomyelitis, and were present in an extremity where the patient reported new decreased muscle endurance and increased fatiguability. NMJ transmission defects in the chosen muscles were confirmed by finding increased jitter by conventional SFEMG in at least 2 muscle fibers out of 20 or fewer fibers sampled, in comparison to the published limits for normal (Stalberg and Trontelj 1979; Trontelj et al. 1986; Jabre et al. 1989). The muscles studied in the 17 patients were the extensor digitorum communis (5 patients), vastus medialis (11 patients), and the rectus femoris (1 patient). The extensor digitorum communis and the vastus medialis were each studied in 5 normal controls.

S-SFEMG was performed according to published techniques (Trontelj et al. 1986; Jabre et al. 1989). The location of the motor point of the muscle being studied was determined with a surface stimulating electrode by finding the area of the muscle over which stimulation produced the greatest muscular contraction with the least voltage. Axonal stimulation was performed with a set of monopolar needles, one inserted near the motor point of the muscle and another subcutaneously, a few centimeters laterally. A rectangular pulse of 0.05 msec duration, with a stimulation frequency of 10 Hz was utilized. The current was adjusted to obtain the greatest twitch at the lowest stimulus intensity. An SFEMG electrode was then introduced in the area of the twitching fascicle (within 2-3 cm of the stimulating electrode), and was advanced slowly to locate a single muscle fiber (or fibers) with a rise time of < 300 µsec and an amplitude of 200 µV. To ensure suprathreshold stimulation (and thus avoid so-called false “stimulus-jitter”), the voltage was increased gradually to ensure steadiness of the amplitude, and shape of the muscle fiber potential from one stimulus to the next. Jitter was computed as the mean consecutive difference of latency from the stimulation artifact to the depolarization of the muscle fiber being studied of at least 50 discharges. To avoid the utilization of fibers activated by direct muscle fiber stimulation (and thus bypassing the nerve and the NMJ), muscle fibers with jitter values of 5 µsec or less were not utilized in

the analysis. We used a DISA electromyograph for the majority of our patients, however, a Tracer Northern and Nicolet Viking electromyographs were also used (1 patient for each). All 3 machines used the same paradigm for calculating jitter.

Stimulation single-fiber electromyography / edrophonium test

An edrophonium test was performed in the 17 PPS patients while recording jitter in 1 muscle fiber by S SFEMG. Edrophonium was administered only once for each patient since ethical and technical considerations prevented reinjections. In 12 patients a muscle fiber in the quadriceps muscle was studied, whereas in the remaining 5 patients a muscle fiber in the EDC muscle was studied. The muscle fibers selected for the edrophonium test all had elevated jitter (i.e., jitter above 21.74 µsec for the EDC, and above 23.17 µsec for the quadriceps). Other inclusion criteria included the presence of little or no blocking, and the absence of multiple muscle fibers on the screen (which could have caused mutual interference from any neighboring potentials in the calculation of jitter). Muscle fibers with extremely high jitter and blocking were not utilized for the study because of their instability, and the difficulty in following them for the length of time necessary for this test. Once a suitable fiber was located in each patient, jitter measurements were obtained every 30 sec for at least 3.5 min. Axonal stimulation at a frequency of 10 Hz was performed continuously during the entire period of the edrophonium test (i.e., before and after edrophonium injection). Edrophonium, 2.0 mg, was then injected i.v., followed by 8.0 mg in 2.0 min. Jitter was then measured at the time of injection of edrophonium 8.0 mg and every 30 sec thereafter for at least 3.5 min. All jitter measurements obtained up to 300 sec before edrophonium injection, and between and including 30-300 sec after edrophonium injection were used in subsequent analyses.

Pyridostigmine trial

After edrophonium studies were performed on the 17 patients, oral pyridostigmine was initiated at 30 mg per day, and increased every other day by 30 mg to a maximum dosage of 180 mg/day in 3 divided doses. One patient was maintained on a lower dosage of 120 mg/day since she experienced a significant improvement with a minimum of side effects on this dosage. Patients and treating physician were blinded to the results of the S-SFEMG edrophonium test. Side effects from the medication occurred in 47% of patients, primarily in the initial stages of treatment. These included diarrhea, intestinal cramps, muscle cramps, anxiety, blurred vision, and increased- urinary frequency. In 2 patients, persistent diarrhea and increased urinary frequency necessitated the addition of propantheline and bethanechol, respectively, to pyridostigmine. One patient developed increased weakness on pyridostigmine, which resolved immediately on cessation of the medication.

Fatigue and function scales

To measure clinical response to pyridostigmine, the Hare fatigue index (Hare et al. 1985), the modified Barthel ADL index (Granger 1982), and a modified Klingman mobility index (Klingman et al. 1988) were administered for each patient before and 1 month following initiation of treatment. The Hare fatigue symptom scale, originally designed to quantitate exercise-induced fatigue in patients with cardiac disabilities, is an analog scale from 0 to 4 where 0 represents no fatigue, 1 is mild fatigue, 2 is moderate fatigue, 3 is severe, and 4 is unbearable fatigue. The modified Klingman mobility index is a 6 point scale where 0 represents no ambulatory difficulties, 1 is mild ambulatory difficulties without need for braces, 2 is moderate ambulatory difficulties with need for braces, 3 is severe ambulatory difficulties with need for braces and a wheelchair for longer distances, 4 is non-ambulatory, wheelchair bound (manual), 5 is non ambulatory wheelchair bound (electric), and 6 refers to a bedridden patient. Pyridostigmine responders were defined as those patients who experienced an improvement of at least 20% over their initial scores.

Patients and treating physician were blinded to edrophonium test results.

Statistical analysis

Jitter comparisons between normal controls and post-polio patients were evaluated with the unpaired t test. Change in NMJ transmission due to edrophonium was assessed by comparing pre and post edrophonium jitter means with the unpaired t-test. All jitter measurements obtained up to 5 min before and after edrophonium injection (but at least 3.5 min before and after) were used for this and appropriate subsequent analyses. Non-parametric tests were used with non-normal data distributions or ordinal measurement scales (Wilcoxan signed rank sum test for paired data, or Mann-Whitney U test for unpaired data). Fisher’s exact test was used to compare proportions. To assess jitter in pyridostigmine responder and non-responder groups, pre- and post-edrophonium jitter means (normalized to 100% of pre-edrophonium values for each patient) were subjected to one-way analysis of variance, followed by post-test analysis using the Bonferroni corrected P-value for multiple comparisons. Statistical significance was accepted at P < 0.05.

Results

Previous studies have demonstrated abnormally increased jitter by conventional SFEMG in PPS muscles (Wiechers and Hubell 1981; Cashman et al. 1987; Wiechers 1988). We confirmed NMJ transmission defects in 17 fatigued PPS patients using S-SFEMG, a more controlled technique which eliminates the variation of stimulation rates in voluntarily activated muscles. In 10 normal subjects, mean jitter in the extensor digitorum communis by S-SFEMG (21.7 µsec ± SD 8.7) was similar to that obtained in a previously published report (21.66 µsec ± SD 3.12) (Jabre et al. 1989). There have been no previously published normal values for quadriceps muscles. Mean jitter values obtained in all PPS muscle fibers were significantly higher than those obtained in normal controls (unpaired t-test, P < 0.0005 for quadriceps, P < 0.01 for extensor digitorum communis; see Fig. 1). Even though our normal controls were younger than the PPS patients, and jitter is known to increase slightly with age after approximately 65 years (Stalberg and Trontelj 1979), this effect would have been relatively small compared to the abnormally increased jitter observed in our PPS patients. Only 4 of our patients were over 65 years of age.

Fig. 1. S-SFEMG jitter is increased in PPS extensor digitarum communis and

quadriceps muscles. Mean jitter of PPS extensor digitorum communis muscle

fibers (36.61 ±30.9 µsec) ±SD was significantly higher (P < 0.01) than that of

normals (21.74 ±8.77 µsec). Mean jitter of PPS quadriceps muscle fibers

(56.48 ±34.34 µsec) was significantly higher (P < 0.0005) than that of

normals (23.17 ±8.63 µsec).

Jitter values in the muscle fiber used for the SSFEMG / edrophonium test were recorded continuously every 30 sec for at least 3.5 min before and 3.5 min after injection of edrophonium 10 mg. After edrophonium, mean jitter declined (for example, Fig. 2) in 7 patients (defined as a significant reduction in mean jitter between pre- and post-edrophonium injection, unpaired t-test, P<0.05), was unchanged in 8 patients, and was significantly increased in 2 patients. (The phenomenon of edrophonium-induced increased jitter in a subset of NMJ is described in myasthenia gravis, and is of uncertain significance (Stalberg et al. 1974.) Reduction of jitter with edrophonium was not associated with the severity of pre edrophonium jitter. In other words, severity of NMJ transmission defect did not predict improvement with edrophonium. In addition, there was no significant difference between edrophonium responders and non responders with respect to age, sex, age at acute poliomyelitis, acute poliomyelitis severity score, duration of new symptoms, presence of weakness and pain, or pre-treatment fatigue and function scores (Fisher’s exact test and Mann-Whitney U test, P> 0.05).

FIGURE 1 Graph

Fig. 2. Pre- and post-edrophonium jitter as determined by S-SFEMG in the

vastus medialis muscle of a pyridostigmine responder. Upper panels show

examples of raw data; the numerical jitter value is determined by the mean

consecutive difference between the stimulation artifact (single arrows) and

the unstable potential (double arrows) in 50 superimposed stimulations. Jitter

means (lower panels) were recorded every 30 sec for 5 min before and 5 min

after injection of edrophonium 10 mg (2 mg test dose followed by 8 mg 2 min

after). Mean jitter for the 5 min before edrophonium (95.3 ±5.09 µsec SEM)

significantly differed from mean jitter for the 5 min after edrophonium (47.6

± 8.41 µsec, T = 4.65, P < 0.0001). Thus, this subject was judged to have a

significant reduction in jitter with edrophonium in the studied unstable

potential.

Nine of the 17 fatigued patients reported improvement on the Hare fatigue symptom scale 1 month after initiation of pyridostigmine. These patients experienced a reduction in systemic fatigue of 20-88% (mean 56%). Patients described dose-related fluctuations in fatigue which were consistent with the pharmacokinetics of pyridostigmine. All 9 patients also reported decreased muscle fatiguability, such as increased distance of ambulation, and the ability to perform activites which they has previously been unable to do. Of these 9 responders, 1 patient also improved in activities of daily living (modified Barthel index), and 1 improved in mobility (modified Klingman mobility index). Even though only 2 of 9 pyridostigmine responders showed improvement on the functional scales utilized, all 9 patients reported improved daily function and requested continuation of the medication (despite the presence of mild side effects in some). Duration of treatment in the responders ranged from 0.3 to 2.3 years, mean 1.22 years. A comparison of mean fatigue scores before and after treatment with pyridostigmine in the entire group of 17 patients revealed a statistically significant difference between these scores (Wilcoxan signed rank sum test, P = 0.0039, mean before treatment 2.71, mean after treatment 1.71). Comparison of pyridostigmine responders with non-responders revealed no significant differences with respect to age, sex, age at acute poliomyelitis, acute poliomyelitis severity score, duration of new symptoms, and presence of weakness and pain. However, patients who responded to pyridostigmine were significantly more fatigued on the pre treatment Hare fatigue scale than patients who did not respond (Mann-Whitney U test, P = 0.01).

A significant association was seen between SSFEMG / edrophonium test results and clinical response to

pyridostigmine. Six of 7 patients with decreased jitter on edrophonium were less fatigued with pyridostigmine, and 7 of 10 patients with no change or increased jitter on edrophonium did not respond to pyridostigmine (Fisher’s exact test, P < 0.04). We then separately analyzed this relationship from the perspectives of edrophonium response and pyridostigmine response. The 7 patients who has significantly decreased jitter on edrophonium injection experienced significant reduction of fatigue with pyridostigmine (fatigue pre = 3.0, post = 1.5; Wilcoxan signed rank sum test, P = 0.03; Fig. 3). The minor reduction of fatigue with pyridostigmine in the 10 patients who did not experience jitter reduction on edrophonium injection did not reach statistical significance (pre = 2.5, post = 1.85; P = 0.25).

Fig. 3. Reduction in jitter with edrophonium predicts response of

fatigue to pyridostigmine. In 7 patients with significant jitter

reduction on edrophonium (+), but not in 10 patients without jitter

reduction (-), a significant reduction in fatigue is reported (Hare

fatigue index) with oral pyridostigmine therapy (mean fatigue score

3.0 pre-pyridostigmine, 1.5 post-pyridostigmine, Wilcoxan signed

rank sum test, P = 0.0313). Error bars = SEM.

Conversely, when jitter means (normalized to 100% of pre-edrophonium mean) of the 9 pyridostigmine responders were compared to the 8 pyridostigmine nonresponders (Fig. 4), ANOVA analysis revealed significant variability between patient groups (F = 14.04, P < 0.0001). A significant reduction in jitter means pre- and post-edrophonium was observed in the 9 pyridostigmine responders (100 vs. 88%, Bonferroni corrected, P<0.001). The decline and subsequent increase in jitter on edrophonium injection is consistent with the known pharmacokinetics of edrophonium (Fig. 4). A significant difference was also observed between the post-edrophonium jitter means of the 9 pyridostigmine responders in comparison with the 8 non-responders (101 vs. 88%, P<0.001). No difference was noted between pyridostigmine non responder jitter means pre- and post-edrophonium. Thus, response to pyridostigmine was associated with reduction of jitter on edrophonium injection.

FIGURE 2 Graph

Fig. 4. Reduction of fatigue with pyridostigmine is associated with reduction

of jitter on edrophonium injection. Patients who report > 20% improvement

in Hare fatigue score with oral pyridostigmine (o) are significantly more

likely than non-responders (·) to have experienced reduction of jitter on

injection of intravenous edrophonium. Jitter plots normalized to 100% of pre

edrophonium mean jitter. Significant differences in jitter means are observed

comparing pyridostigmine-responding patients (n = 9) pre and post

edrophonium (Bonferroni corrected P < 0.001), and between pyridostigmine

responding and non-responding patients (n = 8), post edrophonium (P <

0.001). There is no significant difference of jitter means of pyridostigmine

non-responding patients pre and postedrophonium (P > 0.8). Error bars =

SEM

Discussion

Using S-SFEMG, we have confirmed that NMJ transmission defects are present in patients with antecedent poliomyelitis. Increased jitter on single-fiber electromyography has been noted in other diseases with NMJ pathology (Stalberg et al. 1974, 1975; Schwartz and Stalberg 1975; Engel 1986; Bradley 1987; Schiller and Stalberg 1987). In MG, increased jitter is predominantly due to post-synaptic defects, from autoimmune destruction and blocking of endplate acetylcholine receptors (Engel 1986). In botulism and myasthenic syndrome, the defect is thought to be presynaptic, due to defective release of acetylcholine (Schwartz and Stalberg 1975; Schiller and Stalberg 1978). In ALS, the defect is probably presynaptic, secondary to intermittent conduction failure along immature, poorly myelinated terminal axonal sprouts, or to suboptimal release of acetylcholine (Stalberg et al. 1975; Denys and Norris 1979; Bernstein and Antel 1981; Bradley 1987).

Increased jitter in PPS may reflect several distinct pathological processes. Following widespread denervation consequent to motor neuron cell death in paralytic poliomyelitis, surviving motor neurons undergo extensive distal sprouting to innervate denervated muscle fibers, enlarging the motor unit 7-fold or more (Coers and Woolf 1959; Lange et al. 1989). Recent studies suggest that increased jitter in poliomyelitis, classically thought to occur transiently in reinnervation due to immaturity of axonal sprouts, may never normalize (Wiechers 1988). In addition, constant “remodeling” of motor units apparently occurs in poliomyelitis patients without new symptoms (Cashman et al. 1987; Lange et al. 1989; Ravits et

1. 1990), which is presumably accompanied by increased jitter from turnover of immature reinnervating axonal sprouts. Thus, the finding of increased jitter decades after poliomyelitis can be due to an asymptomatic instability of neuromuscular transmission in enlarged, actively remodeling motor units. However, increased jitter could also be caused by irreversible degeneration of axonal sprouts, which is the most likely pathoetiology of new weakness in PPS (Wiechers and Hubell 1981; Wiechers 1988). It is possible that an early phase of axonal degeneration is manifested by NMJ transmission defects due to defective synthesis, storage, or release of acetylcholine.

Edrophonium has been found to ameliorate NMJ transmission defects in MG and ALS (two disorders with muscle fatiguability and inconstant generalized fatigue) as measured by repetitive stimulation and SFEMG studies (Mulder et al. 1959; Stalberg et al. 1974; Stalberg and Trontelj 1979). An early study by Hodes has also shown that neostigmine (an intravenous anticholinesterase) can improve NMJ transmission in patients with prior paralytic poliomyelitis, as assessed by repair of decrement on repetitive stimulation (Hodes 1948). We have confirmed these findings in fatigued patients with prior paralytic polio utilizing the intravenous anticholinesterase edrophonium and a more sensitive measure of NMJ transmission adequacy. In our study, 7 of 17 fatigued PPS patients demonstrated a statistically significant amelioration of abnormal neuromuscular junction transmission (as measured by jitter on S-SFEMG) with edrophonium in a continuously activated muscle fiber. The fact that only about half of the studied abnormal NMJ’s displayed improved transmission with edrophonium suggests some heterogeneity of transmission defect etiology in PPS, as discussed above.

Generalized fatigue, reported in up to 89% of PPS patients (Jubelt and Cashman 1987), is a complex and common symptom attributed to a wide variety of etiologies, both “central” and “peripheral” (Gow et al. 1987). Among the central problems cited to underly fatigue in PPS patients are chronic pain, depression, “type A” behavior, dysfunction of the reticular activating system, sleep disorders, and respiratory dysfunction (Bruno and Frick 1987; Kohl 1987; Fischer 1987; Halstead 1991). Suggested peripheral defects, involving the motor unit itself, include metabolic exhaustion of massively sprouted motor neurons, NMJ transmission defects, and muscle abnormalities such as overuse myopathy and fiber type disproportion (McComas et al. 1973; Jubelt and Cashman 1987; Grimby and Einarssen 1987; Munsat et al. 1987; Perry et al. 1988). In our study, we found a significant association between the results of the S SFEMG / edrophonium test and subjective fatigue response to low-dose pyridostigmine. These findings suggest that peripheral mechanisms (i.e., NMJ transmission defects) may underlie fatigue in a propertion of PPS patients.

Anticholinesterase agents, which inhibit the hydrolysis of acetylcholine in the neuromuscular junction and prolong its effect, can clearly be associated with acute and chronic toxicity (both pre- and post-synaptic) in normal experimental animals, and probably in human patients (reviewed by Munsat 1984). However, the potentially “excitotoxic” doses used in the past for MG (sometimes exceeding 2 g pyridostigmine per day) are far in excess of those we have used in PPS fatigue (180 mg/day). Despite the common benign side effect of increased gut motility, and reversible increased weakness in 1 patient, we have not observed chronic toxicity in PPS patients maintained for years on this low dose.

In conclusion, our trial indicates that NMJ transmission defects can ameliorate with anticholinesterases in fatigued post-polio patients, and that these defects may be a cause of fatigue in a proportion of this patient population. We believe that our study provides a physiologic rationale for the use of anticholinesterases in fatigued PPS patients unresponsive to other therapeutic measures, however, it does not assess the long

term risks and benefits of this therapy. Therefore, we recommend further controlled clinical trials prior to the widespread use of pyridostigmine in PPS.

Acknowledgements This work was supported in part by the Fonds de la Recherche en Santé du Québec, The Quebec March of

Dimes, and the Quebec Post-Polio Syndrome Association. We are indebted to the patients who participated in this study, and to EMG technicians Lora Tombari and Susan Murray for their expert assistance, and to L. Cetola and R. Cashman, who assisted in the preparation of the manuscript.

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Electrophysiology and

Electrodiagnosis of the Post-Polio Motor Unit

Daria A. Trojan, MD, Daniel Gendron, MD, Neil R. Cashman, MD Orthopedics December 1991 Vol 14 No 12 1353-1361

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

From the Department of Neurology, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada The authors thank L. Cetola for her help in the preparation of the manuscript.

This work was supported in part by the Fonds de la Recherche en Santé du Québec and by the Association Polio Québec. Reprint requests: Daria A. Trojan, M.D., Montreal Neurological Institute, 3801 University, Montreal, Quebec, H3A 2B4, Canada. Abstract

Post-poliomyelitis syndrome refers to new symptoms that may occur years after recovery from poliomyelitis. The most common of these symptoms are new weakness, fatigue, and pain. This article describes electrodiagnostic studies — conventional electromyography (EMG), single fiber electromyography (SFEMG), and macroelectromyography (macro-EMG) — that have provided information on the post-polio motor unit and on the possible etiology of some post-polio syndrome symptoms. Muscular fatigue, and indirectly, general fatigue, may be due to neuromuscular junction transmission defects in some post-polio individuals, as suggested by reduction of the compound motor action potentials on repetitive stimulation, and increased jitter and blocking on SFEMG. Progressive weakness and atrophy in post-polio syndrome is probably due to a distal degeneration of post-polio motor units with resultant irreversible muscle fiber denervation. Electrodiagnostic evidence of ongoing denervation includes fibrillation and fasciculation potentials on conventional EMG, increased jitter and blocking on SFEMG, and smaller macro-EMG amplitudes in newly weakened postpolio muscles. However, even though electrodiagnostic studies have provided insight into the possible causes of some postpolio syndrome symptoms, no specific electrodiagnostic test for the syndrome is currently available.

The late progression or appearance of neuromuscular symptoms in individuals who have previously recovered from paralytic poliomyelitis is now recognized as a major public health problem in North America. Although a wide variety of symptoms have been reported, weakness, fatigue, and muscle and joint pain are consistently the most frequently noted.[1-9] We favor the term post-poliomyelitis syndrome

for this constellation of new symptoms that often present simultaneously. Although some postpolio syndrome symptoms such as new weakness are almost certainly due to changes in the motor unit, it is unclear how or if pain, which is uncommon in the classical motor neuron diseases such as amyotrophic lateral sclerosis, is referable to disease of the motor unit. Thus, the post-poliomyelitis syndrome may be the most inclusive term, which encompasses symptoms that may or may not be due to motor unit dysfunction, and also refers to the frequent concurrence of these symptoms.

This article reviews the physiology of the post-polio motor unit, emphasizing electrodiagnostic studies, and relates these findings to three post-polio syndrome symptoms that may be explained by motor unit abnormalities: new fatigue, weakness, and atrophy.

Fatigue specific to post-polio patients can be either general or muscular.[10] General fatigue is usually described as a flu-like, diffuse exhaustion. Muscular fatigue (fatigability) can be defined as difficulty with muscular endurance, or increased weakness with exertion that improves with rest. Many causes have been proposed for general fatigue. These include depression, anxiety, malfunction of the brainstem reticular activating system from past involvement during acute polio, emotional stress, and even a subjective interpretation of diffuse muscular fatigability.[9,11,12] Possible causes of muscular or peripheral fatigue are neuromuscular junction transmission defects, overuse myopathy, and fiber type disproportion.[3,13- 15]

New weakness can be reported as permanent, or transient, which is related to activity. We believe that transient weakness is actually muscular fatigue. New atrophy, or loss of muscle bulk, is also reported by post-polio syndrome patients. New weakness and atrophy have been theorized to be due to a number of causes including disuse, progressive denervation, and overuse myopathy.[9] Atrophy is not as frequent a complaint in polio survivors as new weakness and fatigue,[2,5] and may be a relatively late phenomenon in post-polio syndrome.[16]

THE NORMAL MOTOR UNIT

A motor unit, originally defined by Sherrington, consists of a motor neuron and all of the muscle fibers that it innervates or supports. Electrical excitation of a motor neuron in the central nervous system is followed by conduction of an impulse in the axon and its terminal branches, synaptic transmission at the neuromuscular junction mediated by the neurotransmitter acetylcholine, and depolarization and contraction of the muscle fibers it innervates. If enough motor units are stimulated, a clinically apparent muscle contraction will be produced. The ratio of muscle fibers innervated per motor neuron varies within a muscle and between muscles, and can range from six to 10 muscle fibers in extraocular muscles to 2000 muscle fibers in the gastrocnemius muscle.[17] In general, muscles that require greater specificity of action have smaller motor units.

A muscle is generally composed of two types of muscle fibers which differ in their enzymatic composition, speed of contraction, and fatigability. Type I fibers have more oxidative enzymes, are less susceptible to fatigue, and are also referred to as slow twitch fibers. Type II muscle fibers have a higher proportion of glycolytic enzymes, are more easily fatigued, and are also referred to as fast twitch fibers.

The muscle fiber type is believed to be determined by the motor neuron by which it is innervated. Thus, a specific motor neuron will innervate either Type I or Type II muscle fibers, but not both.[17] Motor neurons innervating Type II fibers are characterized by a higher threshold for activation, higher axonal conduction velocity, and a higher firing rate than motor neurons innervating Type I fibers.[18] Normally, the two types of muscle fibers are evenly interspersed within a muscle, producing a mosaic pattern.[19] During recruitment of muscle fibers for a muscle contraction, Type I fibers (within smaller motor units)

are usually excited first, followed by Type II fibers (within larger motor units). This method of recruitment allows the use of the less fatigable Type I fibers for continued lower levels of contraction, whereas the more easily fatigable, fast Type II fibers are used for short bursts of activity.[18]

The neuromuscular junction is the interface between a fine terminal nerve fiber of a motor neuron and a muscle fiber. The space between these two structures is known as the synaptic cleft. To produce a muscle fiber contraction, the depolarized motor neuron terminal releases acetylcholine into the synaptic cleft. Acetylcholine then binds to specific receptors on the muscle endplate. If enough acetylcholine is released and bound to receptors, the muscle endplate and muscle fiber sarcolemma will depolarize, calcium will be released intracellularly from the sarcoplasmic reticulum, and a calcium-dependent myofiber contraction will be produced. To allow endplate repolarization, acetylcholine is rapidly hydrolyzed by the enzyme acetylcholinesterase. The muscle fiber is then ready for another depolarization.[17]

THE MOTOR UNIT DURING AND AFTER ACUTE POLIOMYELITIS

During acute poliomyelitis, motor neuron invasion by polio virus can result in either motor neuron death or injury with partial or complete recovery.[20] Motor neuron death will cause denervation of the muscle fibers belonging to its motor unit with resultant loss of voluntary activation of those muscle fibers. If only a few motor neurons innervating a muscle are affected, no weakness may be perceived by the patient because of the normal reserve present in human muscle. More severe loss of motor neurons from acute polio results in partial or complete denervation of the muscles involved, and will be perceived as weakness or complete loss of voluntary muscle contraction by the patient.

Recovery of muscular force after acute poliomyelitis can occur by sprouting from intact motor neurons or by muscle fiber hypertrophy. If a motor neuron survives polio virus attack, within 3 to 4 weeks it will extend sprouts from its terminal axonal branches that will reinnervate locally denervated muscle fibers. [21-24] This process is limited by the number of remaining motor neurons, and by the ability of a motor neuron to form sprouts. It is also possible that the ability of a motor neuron to sprout and reinnervate is correlated with the severity of its own disruption by polio virus infection. As a result of these two limitations, some muscle fibers may not become reinnervated, and will undergo progressive atrophy over the ensuing months to years.[25]

Because terminal nerve sprouts are short (100 to 200 µ, or two to four muscle fiber diameters),[26-27] fiber type grouping of reinnervated muscle will result, and the normal mosaic interspersion of Type I and Type II fibers will be diminished or absent.[28,29] In addition, fiber type transformation from Type II to Type I fibers without selective loss of larger motor neurons (which innervate Type II fibers) can occur in weak, but still functional, post-polio muscles.[30-32] It has been estimated that even with a loss of 50% of the motor neurons supplying a muscle, the surviving motor neurons can achieve complete reinnervation resulting in normal muscle strength.[33] Muscle biopsy studies have shown that motor unit sizes after recovery from poliomyelitis can be up to seven-fold normal size.[34] In other words, a post-polio motor neuron may maintain up to seven times the number of muscle fibers as it would normally supply. In addition to sprouting with reinnervation, muscle fiber hypertrophy of innervated muscle may contribute to the recovery of motor strength after acute polio.[30]

The most likely etiology of new weakness many years after recovery from paralytic polio is a distal degeneration of these abnormally enlarged motor units, as hypothesized by Weichers and Hubbell.[35] Thus, new weakness decades after recovery from acute paralytic polio may be a result of the recovery process itself. Surviving motor neurons which may have permanent abnormalities from earlier polio and are now innervating many more muscle fibers than normal, may be unable to sustain such a great metabolic demand. Over time, terminal axonal sprouts may degenerate, with subsequent denervation of

individual muscle fibers. It is possible that some of these denervated muscle fibers may become reinnervated by sprouts from neighboring motor neurons, producing a continuous “remodeling” of the post-polio motor unit.[29,36-38]

However, some muscle fibers will become irreversibly denervated, causing a reduction in size of the motor unit, and will produce a clinically apparent weakness in the patient.[35,36] The normal aging process involves a dropout of motor units, predominantly after age 60,[39-41] and may have an additional effect on the already borderline or clinically weakened post-polio muscles.

ELECTROPHYSIOLOGY OF THE NORMAL AND POST-POLIO MOTOR UNIT

Conventional Electrolmyography. Electromyography (EMG) is a diagnostic technique used to evaluate the electrophysiology of a motor unit. It is performed by percutaneously inserting a small needle electrode into the muscle being evaluated. The concentric needle electrode can record activity of muscle fibers within a radius of about 1 mm. Activity is amplified and displayed on an oscilloscope. Normally, a muscle is silent at rest after insertional activity (produced by irritation from needle movement) has ceased. With muscle contraction, motor units are activated and motor unit action potentials (MUAPs) appear on the screen, usually as triphasic waves with an initial positive deflection.[17]

Because of the relatively small recording volume of an EMG needle in comparison to the diameter of a normal motor unit (in the biceps muscle motor unit, diameters range in size from 2 to 10 mm),[42,43] only five to 12 muscle fibers from a motor unit will contribute to the MUAP observed on the screen.[44] The amplitude of a MUAP is determined by the number of muscle fibers recorded with the needle. With increasing strength of contraction, there is an orderly recruitment of motor units with the number and size of MUAPs gradually increasing. At full contraction, separate MUAPs will be indistinguishable, resulting in a complete recruitment interference pattern.[45]

During acute polio, motor neuron loss can occur with denervation of muscle fibers. In the first few weeks, an EMG of a paretic muscle is silent at rest. After 2 to 4 weeks, a denervated muscle fiber will periodically depolarize spontaneously, producing fibrillation potentials and positive waves. A portion of or an entire motor unit may also become activated spontaneously, resulting in a fasciculation at rest which can be seen and felt by the patient. Fasciculations can also be seen occasionally in normal individuals, but are considered to be abnormal when accompanied by fibrillation potentials.[46] Motor neuron loss after poliomyelitis will produce a reduction in the number of motor units seen with recruitment.[29,35]

During the recovery process, motor units will enlarge. In addition, local sprouting will increase the number of muscle fibers innervated by the same motor neuron that are within the receptive field of the EMG needle. Motor unit action potentials will thus have abnormally large amplitudes and polyphasia. Decreased recruitment will remain, secondary to a reduction in the number of motor units available for activation during voluntary muscle contraction.[28,29,35]

Classically, it was believed that fibrillation and fasciculation potentials would disappear within 6 to 12 months of deneniration with maturation of the new terminal nerve sprouts.[21,24,35] However, it is now becoming evident that fibrillation potentials may never disappear in a post-polio survivor. The reason for this is unclear, but proposed mechanisms include ineffective or inefficient reinnervation of the very enlarged motor units, continuous remodeling with denervation and reinnervation of the enlarged motor units, and a metabolic abnormality in motor neurons affected by the polio virus that prevent them from providing normal innervation to all reinnervated muscle fibers.[36]

It is now known that long after recovery from acute poliomyelitis, many polio survivors will continue to

have abnormalities on conventional EMG regardless of whether or not they are having new symptoms. These include persistence of the spontaneous fibrillation and fasciculation potentials, enlarged MUAPs, and decreased recruitment.[29] Thus, abnormalities observed on conventional EMG do not allow distinction of symptomatic from asymptomatic individuals.[29]

Single fiber electromyography. Single fiber electromyography (SFEMG) is an electrodiagnostic technique that allows evaluation of single muscle fibers within a motor unit. Similar to conventional EMG, it is performed by percutaneous insertion of a small needle electrode into the voluntarily contracted muscle under study. However, the receptive volume of this needle (diameter of 25 µm) is smaller than that of a conventional EMG needle. If the motor unit is normal, this receptive volume includes up to one or two muscle fibers from the same motor unit. Muscle fiber depolarizations are recorded by the electrode, and are displayed on an oscilloscope.[47]

SFEMG allows the quantitation of the parameters of fiber density, jitter, and blocking. Fiber density is an indirect estimate of the number of muscle fibers per unit volume belonging to a single motor unit. In polio survivors, it can be regarded as an index of axonal sprouting, and consequently as a measure of denervation from the original poliomyelitis. Fiber density is measured by randomly inserting a needle into the muscle studied, and determining the number of muscle fibers that are depolarized by a single motor neuron within the receptive field of the electrode. The mean of 20 such measurements determines fiber density. Mean normal fiber density ranges between 1.3 and 1.7, and varies with different muscles. It is slightly higher in children under age 10 and in adults over 60.[47] As noted above, fiber density is increased in conditions which involve denervation and reinnervation by collateral sprouting, and in some myopathies.[47]

Jitter is the variability in the difference in the time of firing of two muscle fibers when both are innervated by the same motor neuron. In polio survivors, it provides an indication of the adequacy of terminal axonal impulse propagation and neuromuscular junction transmission. One jitter reading is obtained by calculating the mean consecutive difference (MCD) of 20 to 50 discharges of two muscle fibers. Usually, 20 jitter measurements are obtained by random insertions of the SFEMG needle electrode. Normal jitter values range from a lower limit of 5 µsec to an upper limit of 35 to 60 µsec for different muscles.[47] Usually, after age 70, jitter values increase slightly.[47]

Jitter is considered to be abnormal if more than one of 20 jitter values in a particular muscle exceed the normal upper limit for that muscle.[47] Blocking occurs when the pathology at any one of these sites is more severe and actual transmission failure is produced. Blocking can be expressed as a percent of muscle fibers within a muscle exhibiting this phenomenon. It is absent in normal muscle. Thus, SFEMG can provide information about neuromuscular transmission with determination of jitter and blocking, and about motor unit reorganization with fiber density.

Stimulation SFEMG is a modification of conventional SFEMG which differs in the method of motor unit activation. During conventional SFEMG, muscle fibers are activated voluntarily; during stimulation SFEMG, muscle fiber activation is produced by a stimulating needle electrode placed near the motor point of the muscle. Stimulation SFEMG also permits assessment of jitter and blocking. However, the jitter readings obtained with this technique will be lower since they reflect the neuromuscular transmission at only one muscle fiber, rather than two muscle fibers as in the more traditional voluntarily stimulated SFEMG.[48,49]

An advantage of stimulation SFEMG is that it allows jitter determination at variable stimulation frequencies chosen by the electromyographer.[48,49] Thus, rather than seeking motor units with different stimulation frequencies as in conventional SFEMG, the electromyographer has direct control over the

study of a single motor unit at a variety of stimulation frequencies. Because of the known dependence of jitter on activation frequencies in several disease processes involving the neuromuscular junction,[50-53] stimulation SFEMG may enable the electromyographer to gather more information on the function of the motor unit.

During the reinnervation process after acute polio, axonal sprouts are initially unmyelinated and conduction is slow and variable. The newly formed neuromuscular junctions may also be a site of transmission slowing or failure. These abnormalities will present as increased jitter and blocking on SFEMG (Fig 1A). In addition, fiber type grouping as a result of motor unit remodeling during reinnervation will result in increased fiber density on SFEMG in the involved muscle (Fig 1B).

Fig 1: Single fiber electromyography of a postpolio muscle. Panel A

illustrates increased jitter in 10 superimposed single muscle fiber action

potentials (mean consecutive difference, 74 µsec; normal for muscle, <35

µsec). Panel B illustrates increased fiber density. Four single muscle fiber

action potentials are observed in the vicinity of the SFEMG needle (mean ±

SD normal value for age, 1.4 ± 0.11).[29]

Contrary to earlier hypotheses that the newly formed axonal sprouts and neuromuscular junctions would mature eventually,[21,35] increased jitter and blocking persist in the polio survivor.[29,36] Thus, abnormalities observed on SFEMG, as on EMG, are not helpful in distinguishing symptomatic from asymptomatic individuals.[29] However, a significant correlation between the percentage of fibers exhibiting jitter and fiber density has been found, suggesting that muscles with the most enlarged motor units as a result of sprouting are more likely to exhibit instability later in life (Fig 2).[29] Whether these abnormalities increase with the passage of time is not clear.[35,36] Certainly, a relationship of these

SFEMG abnormalities and the clinical evolution of post-polio syndrome has not consistently been found.

Fig 2: Graph of percentages of muscle fiber pairs exhibiting increased jitter

versus fiber density index. A significant correlation is observed between

percentage of fiber pairs exhibiting increased jitter and fiber density

(Spearman correlation coefficient r = .77, P<.05). A significant association is

also noted between fiber-type grouping on muscle biopsy (closed circles) and

percentage and fiber pairs with increased jitter (Wilcoxon signed rank sum

test, P<.01).[29]

We have performed stimulation SFEMG studies in symptomatic post-polio patients, and have confirmed the presence of increased jitter with this technique in polio survivors as compared to normal controls (Fig 3). We have also studied the neuromuscular junction in post-polio syndrome patients by evaluating jitter with different stimulation frequencies on stimulation SFEMG. Our preliminary studies suggest that jitter depends on stimulation frequency in a proportion of post-polio syndrome patients in a manner consistent

with a presynaptic defect. A similar relationship between jitter and stimulation frequency is observed in amyotrophic lateral sclerosis, where exhaustion of acetylcholine stores at nerve terminals probably contributes to the neuromuscular defect.[54]

Fig 3: Distribution of jitter (mean consecutive difference) values in individual

muscle fibers in post-polio syndrome and normal quadriceps muscles as

determined by stimulation single fiber electromyography. Mean jitter for

normal quadriceps was 23.17 ± SD 8.63 µsec (n = 48) as compared to mean

jitter for post-polio syndrome quadriceps 56.48 ± SD 34.34 µsec (n = 86).

In addition, we have used stimulation SFEMG to probe the relationship between neuromuscular junction transmission defects and the postpolio syndrome symptoms of generalized fatigue and muscle fatigability. Evidence for neuromuscular junction transmission defects on SFEMG studies are seen in post-polio sydrome,[28,29,35-37,55] and also in such disorders as amyotrophic lateral sclerosis and myasthenia gravis.[56-59]

Clinically, all three disorders can present with muscle fatigability, defined as increased muscle weakness on exenion, improving with rest.[55,58,59] Since anticholinesterase agents can ameliorate clinical muscle fatigability and neuromuscular transmission defects in myasthenia gravis and amyotrophic lateral sclerosis,[56,58-60] we have studied their effect in post-polio syndrome.

Preliminary studies have shown that jitter, as measured by stimulation SFEMG, can decrease with edrophonium injection, indicating amelioration of the neuromuscular junction defect in a proportion of fatigued post-polio syndrome patients (Fig 4). We have also found that jitter response to edrophonium is related to the patients’ subsequent subjective fatigue response to the oral anticholinesterase pyridostigmine. Therefore, fatigue in some patients may be due to an anticholinesterase-responsive neuromuscular junction transmission defect.[61] The fact that not all post-polio syndrome neuromuscular junctions responded similarly to an anticholinesterase agent and to high frequency stimulation helps support the notion for different neuromuscular transmission defects in post-polio syndrome.

Fig 4: Jitter (mean consecutive difference) values obtained by stimulation

single fiber electromyography before and after edrophonium injection in three

patients. Jitter is expressed as percent of mean jitter before edrophonium

injection.

Macroelectromyography. Macroelectromyography (macro-EMG) is a newer electrodiagnostic technique that can assess the size of the entire motor unit. Like EMG and SFEMG, it is performed by placing a needle electrode into the muscle being studied. Because the recording surface of the macro-EMG electrode is much larger than that of the EMG electrode, macroEMG can measure the summated action potential of most muscle fibers within a voluntarily activated motor unit. Either the area or amplitude of the macro-EMG motor unit potential (macro-MUP) can be used as an estimate of the motor unit size. [62,63] Simulation studies have shown that macro-MUP amplitude is positively correlated to the total number of muscle fibers and to the mean muscle fiber diameter in the motor unit under study.[64]

During the reinnervation process after acute polio, macro-EMG amplitudes will increase in size, reflecting the larger motor units found in these patients. The median macro-EMG amplitude can be up to seven times the normal limits for age, or 20 to 40 times the upper normal limit for individual motor units.[63,65] It is believed that with time macro-MUP amplitudes may decrease, reflecting the peripheral disintegration of the motor unit. However, a serial study of 11 post-polio patients showed no consistent trend in macro MUP amplitudes measured at yearly intervals over 1 to 2 years.[66] This may reflect the slow progression of the disease process in the relatively short follow-up period.

Macro-MUP amplitudes have been shown to be smaller in post-polio muscles with new weakness and atrophy than in post-polio muscles of normal strength or in weak but stable post-polio muscles.[65]

However, there is no method as of now to distinguish between a small motor unit due to loss of axonal branches, and a small motor unit that was never enlarged by axonal sprouting. Thus, further study is needed of macro-MUP as a diagnostic technique for post-polio syndrome.

UTILITY OF ELECTRODIAGNOSTIC STUDIES IN POST-POLIO PATIENTS

Pathophysiology of the post-polio motor unit. Even though no specific electrodiagnostic abnormality has been observed in symptomatic post-polio patients,[29] electrodiagnostic studies have provided information on the possible etiologies of the post-polio syndrome symptoms of fatigue, weakness, and atrophy. It is possible that a combination of factors, including the degree of motor unit deterioration, reserve present in the muscle affected, the functional importance of the muscle involved, and the general activity level of the patient will determine whether or not new symptoms are perceived by the patient.

Evidence for neuromuscular junction deficits are frequently observed in polio survivors, and may be a cause of muscular fatigue. Earlier studies demonstrated a reduction of compound motor action potentials on supramaximal repetitive stimulation,[55] and numerous recent studies demonstrate increased jitter and blocking on SFEMG.[28,29,35-37] There appears to be a relationship between the degree of neuromuscular junction deficits and the degree of motor unit enlargement after polio. Jitter has been shown to be increased in patients with a higher fiber density (indicating greater motor unit reorganization),[29] increased macro-MUP amplitudes (suggesting larger motor units), and fiber-type grouping on muscle biopsy.[66] Therefore, the extent of initial recovery may predict the degree of electrophysiological deficits later in life.

New, permanent progressive weakness and atrophy in polio survivors is probably due to permanent denervation as a result of a distal degeneration of enlarged motor units.[35] Evidence for this theory includes smaller macro-MUP amplitude in newly weakened patients[65] and angular atrophic muscle fibers indicative of ongoing denervation on muscle biopsy.[29] Some evidence of denervation, including fibrillations on conventional EMG and widespread myofiber immunoreactivity for neural cell adhesion molecule, can be seen in motor units undergoing “remodeling” (ie, denervation/reinnervation without net loss in size of motor units), and thus cannot be regarded as unequivocal evidence for a progressive denervating syndrome in postpolio syndrome.

In addition to providing information on possible etiologies of post-polio syndrome symptoms, electrodiagnostic studies can be used to document changes in the motor unit that occur as a result of treatment. Our studies have revealed the amelioration of jitter with a shortacting intravenous anticholinesterase medication in a proportion of post-polio syndrome patients.[61] An uncontrolled, open trial of pyridostigmine in fatigued polio subjects has also revealed a subjective improvement in fatigue in approximately 60% of subjects.[67] Further controlled studies are warranted to better evaluate the benefits and risks of these medications in post-polio syndrome.

Clinical utility. At present, electrodiagnostic studies in post-polio patients can be used in clinical practice to confirm past poliomyelitis involving motor neurons, and as an aid to exclude other conditions that could be causing symptoms of increased weakness, fatigue, and atrophy. For example, nerve conduction studies that should be normal in polio survivors may be abnormal in those with a peripheral neuropathy. In addition, F-waves, H-reflexes, and somatosensory evoked potentials studies in combination with nerve conduction velocity studies can be helpful to exclude radiculopathies and myelopathies that may mimic post-polio syndrome.

Even though clinical electrophysiologic tests cannot be used currently for the diagnosis of post-polio syndrome,[29] it is possible that macro-EMG studies may prove useful in the future. Further carefully

controlled and clinically correlated electrodiagnostic studies may provide more information about the pathophysiology, diagnosis, and treatment of post-polio syndrome.

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