PSN Library Files

Anticholinesterases in Post-Poliomyelitis Syndrome^a Daria A. Trojan and Neil R. Cashman

Department of Neurology

Montreal Neurological Institute and Hospital

McGill University

3801 University Street

Montreal, Quebec, H3A 2B4, Canada

Reprinted from The Post-Polio Syndrome: Advances in the Pathogenesis and Treatment Volume 753 of the Annals of the New York Academy of Sciences

May 25, 1995

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

^a This work was supported in part by the Fonds de la recherche en santé du Québec, the Québec March of Dimes and the Association Polio Québec.

New weakness, fatigue, and pain after decades of functional stability in those who have recovered from acute paralytic poliomyelitis constitutes post-poliomyelitis syndrome (PPS).[1-7] The cause of PPS is unknown, but it is thought to be due to a distal degeneration of enlarged post-polio motor units produced by terminal axonal sprouting during the recovery process after acute polio.[8,9] The symptoms of weakness and fatigue may be a direct result of this distal motor unit degeneration;[2,7-13] however, it is presently unclear how pain relates to disease of the motor unit. PPS is a slowly progressive motor neuron disease for which there is currently no specific treatment.[4]

FATIGUE IN POST-POLIOMYELITIS SYNDROME

The symptom of fatigue in PPS is common, occurring in 59 to 89% of patients with new symptoms,[1-3, 14] and is attributable to a wide variety of etiologies. It may be the most disabling symptom for patients. In PPS, patient complaints seem to suggest both a central fatigue and a peripheral fatigue.[15] Symptoms

which suggest a central fatigue include complaints of difficulties in concentration and memory, or an increased sleep requirement. Some proposed central causes of fatigue include chronic pain, “type A” behavior, depression, dysfunction of the reticular activating system, sleep disorders, and respiratory dysfunction.[16-19] Complaints of decreased muscular endurance, or muscle fatigability (defined as

increased weakness on exertion improving with rest) are suggestive of a peripheral fatigue. Proposed etiologies of peripheral fatigue include metabolic exhaustion of massively sprouted motor units, neuromuscular junction transmission defects, and overuse myopathy.[2,20-23] A recent study showed that symptoms of generalized fatigue are as common in PPS patients as in normal controls, whereas symptoms

attributable to muscle fatigability are significantly more common in those with PPS.[24] Therefore, a peripheral fatigue may be specific for PPS, and central fatigue symptoms may occur as a result of the peripheral fatigue.

Muscle fatigability observed in PPS is similar to that seen in patients with myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS), and may be due to neuromuscular junction transmission defects. Electrophysiological evidence for neuromuscular junction transmission defects (decrement on repetitive stimulation, and increased jitter on single fiber electromyography; SFEMG) is observed in patients with MG,[25,26] ALS,[27-30] and antecedent poliomyelitis.[8,9,11,31] In MG, the neuromuscular defect is postsynaptic and occurs secondary to autoimmune destruction or blocking of muscle acetylcholine receptors.[25] In ALS and PPS, the defect is believed to be presynaptic, probably secondary to ineffective conduction along immature axonal sprouts, or to limitations in quantal number or content of acetylcholine vesicles at motor nerve terminals.[8,9,12,28-34] The oral anticholinesterase pyridostigmine, which prolongs the survival of acetylcholine at the neuromuscular junction, is useful in the treatment of muscle fatigability in MG and ALS. Because of the similar clinical and electrophysiological findings in PPS and other diseases with established neuromuscular junction pathology, anticholinesterases may be useful in the treatment of post-poliomyelitis fatigue and muscle fatigability.

RESPONSE OF SINGLE FIBER ELECTROMYOGRAPHY

ABNORMALITIES IN PPS TO EDROPHONIUM

We studied the effect of the intravenous, short-acting anticholinesterase edrophonium on neuromuscular junction transmission in 17 patients with PPS.[12] No patient had concurrent medical or neurological disorders which could have interfered with the interpretation of electrophysiological testing or could be a cause of fatigue. The technique of stimulation SFEMG (S-SFEMG) was used to evaluate the neuromuscular junction in all patients. This technique allows the evaluation of the neuromuscular junction of only one muscle fiber and obviates the need for patient voluntary effort required in conventional SFEMG.[35] Like conventional SFEMG,[36] S-SFEMG allows the computation of jitter, a measure of neuromuscular junction transmission adequacy.

We performed an edrophonium test in the 17 PPS patients while recording jitter in one muscle fiber by S SFEMG. Muscles selected (the quadriceps in 12 and the extensor digitorum communis in 5 patients) had been previously affected by acute paralytic poliomyelitis, were present in an extremity where the patient

reported new muscle fatigability, and had evidence for neuromuscular junction transmission defects by conventional SFEMG. The muscle fibers selected for the edrophonium test had elevated jitter. Axonal stimulation was performed continuously at a frequency of 10 Hz during the entire period of the test. Once a suitable fiber was located in each patient, jitter measurements were obtained every 30 s for at least 3.5 min. Edrophonium (2.0 mg i.v., followed by 8.0 mg in 2 min) was then injected, and jitter was measured at the time of injection and every 30 s thereafter for at least 3.5 min. All jitter measurements obtained up to 300 s before edrophonium injection and between 30 and 300 s after edrophonium injection were used in further analyses.

We found that neuromuscular junction transmission as measured by jitter on S-SFEMG improved in a proportion of patients who underwent the edrophonium test. An example of the amelioration in jitter with edrophonium is illustrated in FIGURE 1. Mean jitter pre- and post-edrophonium was compared with the unpaired t test. Mean jitter significantly declined in 7 patients (p < 0.05), was unchanged in 8 patients, and was significantly increased in 2 patients. Edrophonium-induced increased jitter has been described in MG; however, the significance of this phenomenon is unknown.[26] The finding of decreased jitter with edrophonium was not associated with pre-edrophonium jitter values, and thus the severity of the

neuromuscular junction defect (unpaired t test, p > 0.05). The clinical characteristics of edrophonium responders and nonresponders were compared with Fisher’s exact test and Mann-Whitney U test. We found no significant differences between edrophonium responders and nonresponders in terms of age at evaluation, sex, age at acute poliomyelitis, acute poliomyelitis severity score (as measured on a 0 to 6 scale with one point being given for involvement of each of four extremities, one point for speech/swallowing dysfunction, and one point for respiratory involvement), duration of new symptoms, presence of weakness and pain, pretreatment fatigue scores (measured on a subjective 0 to 4 Hare fatigue scale[37]), and modified Klingman mobility scores[38] (measured on a 0 to 6 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 nonambulatory and wheelchair bound [manual], 5 is nonambulatory and wheelchair bound [electric], and 6 is bedridden). Thus, there were no apparent distinguishing clinical and electrophysiological features of the edrophonium responders as compared to the nonresponders in our sample of patients.

FIGURE 1 Graph

FIGURE 1. Pre- and post-edrophonium jitter as assessed by S-SFEMG in the

quadriceps muscle of a pyridostigmine responder. The upper panels illustrate

raw data; jitter is automatically computed as the mean consecutive difference

between the stimulation artifact (single arrows) and the unstable muscle fiber

potential (double arrows) in 50 superimposed stimulations. The lower panels

illustrate jitter recorded every 30 s for 3.5 min before and after injection of

edrophonium 10 mg i.v. This patient had a significant reduction in jitter

(unpaired t test, p < 0.05) with edrophonium in the studied potential.(From

Trojan et al.[12] Reprinted with permission from the Journal of the

Neurological Sciences.)

RESPONSE OF FATIGUE IN PPS TO PYRIDOSTIGMINE

After completion of the edrophonium test, we evaluated response of fatigue to pyridostigmine.[12] Patients and treating physician were blinded to the results of the edrophonium test. All 17 patients were initiated on oral pyridostigmine at 30 mg per day, and increased every other day by 30 mg to attain a maximum dosage of 180 mg per day in three divided doses. One patient was maintained on 120 mg per

day because of side effects at a higher dose. Clinical response to pyridostigmine was assessed by evaluating fatigue and function on the subjective Hare fatigue scale,[37] the modified Barthel ADL index, [39] and a modified Klingman mobility index[38] before and one month after initiation of treatment. A pyridostigmine response was defined as an improvement of at least 20% on the Hare fatigue scale over initial scores.

Side effects from the medication occurred in approximately one-half of patients, usually in the early stages of treatment, and included symptoms typical of increased cholinergic activity (diarrhea, intestinal cramps, blurred vision, increased urinary frequency, muscle cramps, and anxiety). In two patients, additional medications were started (propantheline and bethanechol) because of the development of persistent diarrhea and increased urinary frequency. One patient developed transient increased weakness, which resolved with discontinuation of the medication.

We found that subjective fatigue improved in a proportion of patients with pyridostigmine. Nine of 17 patients (53%) experienced a reduction in systemic fatigue of 20 to 88% while on the medication. All 9 patients also reported decreased muscle fatigability and the ability to perform certain activities which they had previously been unable to do. However, only 2 patients were noted to have an improvement on the functional scales used, probably because of the low responsiveness of these scales to treatment effect in this patient population. All 9 patients requested continuation of the medication (for a period of 0.3 to 2.3 years, mean 1.22 years) because of the perceived benefits derived from treatment. Pyridostigmine responders were not differentiated from nonresponders in terms of age at evaluation, sex, age at acute poliomyelitis, acute poliomyelitis severity score, duration of new symptoms, function scores, and presence of weakness and pain. However, pyridostigmine-responders were significantly more fatigued than nonresponders on the subjective Hare fatigue score before treatment (Mann-Whitney U test, p = 0.01).

RELATIONSHIP OF SINGLE FIBER ELECTROMYOGRAPHY STUDIES TO CLINICAL RESPONSE

We assessed the possible relationship between the edrophonium test and clinical response to pyridostigmine by three methods.[12] First, we found that 6 of 7 patients with decreased jitter on edrophonium were less fatigued with pyridostigmine, and that 7 of 10 patients with no change or increased jitter on edrophonium did not respond to pyridostigmine (Fisher’s exact test, p < 0.04). Thus, edrophonium response appeared to predict clinical response to pyridostigmine. Subsequently, this relationship was also separately analyzed from the perspective of pyridostigmine and edrophonium response. We found that the 7 patients who experienced significantly decreased jitter with edrophonium had a significant reduction of fatigue with pyridostigmine (mean pre-Hare fatigue score = 3.0, post- = 1.5, p = 0.03). The 10 patients who did not experiencejitter reduction with edrophonium had a nonsignificant reduction in fatigue scores with pyridostigmine (mean pre-Hare fatigue score = 2.5, post- = 1.85, p = 0.25). We then compared jitter means (normalized to 100% of pre-edrophonium mean for each patient) of the 9 pyridostigmine responders to the pyridostigmine nonresponders (FIG. 2). We found a significant reduction in jitter means pre- and post-edrophonium in the 9 pyridostigmine responders (100 versus 88%, unpaired t test, Bonferroni corrected, p < 0.001). We also found that post-edrophonium jitter means were significantly lower in the pyridostigmine responders than those in nonresponders (101 versus 88%, p < 0.001). No significant difference was found between pyridostigmine nonresponder jitter means pre- and post-edrophonium. Thus, jitter response on edrophonium injection was significantly associated with clinical response to pyridostigmine.

FIGURE 2 Graph

FIGURE 2. Reduction of fatigue with pyridostigmine is associated with

reduction of jitter on edrophonium injection. Pyridostigmine-responders

(open circles) are those who report a reduction of 20% in fatigue on the Hare

fatigue score with pyridostigmine 180 mg per day. Pyridostigmine

nonresponders are illustrated with closed circles. Jitter plots are normalized to

100% of pre-edrophonium mean jitter. A significant reduction in jitter mean

is observed in pyridostigmine-responders with edrophonium (Bonferroni

corrected, p < 0.001). The decline and subsequent increase in jitter after

edrophonium injection is consistent with the known pharmokinetics of the

medication. Post-edrophonium jitter mean in pyridostigmine-responders is

significantly lower (p < 0.001) than in nonresponders. There is no significant

difference in jitter means of pyridostigmine nonresponders before and after

edrophonium injection. Error bars = standard error of the mean. (From Trojan

et al.[12] Reprinted with permission from the Journal of the Neurological

Sciences.)

PYRIDOSTIGMINE EFFECT ON ISOKINETIC NEUROMUSCULAR FUNCTION

The effect of pyridostigmine on isokinetic neuromuscular function in 7 patients with PPS was studied by Kilfoil et al.[40,41] All subjects had a minimum manual muscle strength (measured on the Medical Research Council scale[42]) of 3 in the knee extensors and 2 in the knee flexors. The isokinetic dynamic fatigue protocol used consisted of 25 reciprocal, isokinetic contractions of knee extension and flexion (unilaterally), which was performed by the 7 patients and 15 normal controls. The speed of the movement and the angle of excursion were recorded simultaneously with the torque signal. Angle-specific torques (0.79 and 1.05 rads) of the quadriceps were used for subsequent analyses. This isokinetic fatigue protocol has been found to be reliable in the quadriceps in PPS patients and in normal controls.[41-43] Three baseline assessments were performed on the 7 patients while on pyridostigmine 180 mg per day. After these assessments, the fatigue protocol was again performed two more times while the subject was either on or off pyridostigmine. The sequence of the evaluations on or off pyridostigmine was randomly determined, and the evaluator was blinded to the sequence of drug withdrawal and reinitiation. Measurements off pyridostigmine were performed after discontinuation of the medication for 48 h.

The response of neuromuscular function to pyridostigmine was assessed by comparing measurements on

and off the medication. We found that total work for the 7 subjects did not differ while the patients were on or off pyridostigmine. However, on further evaluation of the data, it was apparent that the pyridostigmine response differed in groups of patients. The torque of isokinetic extension of the male patients off pyridostigmine was lower than the mean ± 2 SD while they were on pyridostigmine. Only one of these subjects demonstrated true fatigability (defined as a greater negative slope of the regression line). The other three male subjects demonstrated less isokinetic torque while off pyridostigmine than on pyridostigmine. The three remaining female subjects did not demonstrate either true fatigability or decreased isokinetic strength while off pyridostigmine.

DISCUSSION

Evidence for neuromuscular junction transmission defects as seen by increased jitter and blocking on SFEMG is commonly observed in those who have recovered from paralytic poliomyelitis, and has been reported by many investigators.[7-9,11,12] The presence of increased jitter is not specific for PPS and is found both in patients who are stable after paralytic poliomyelitis and in those with new weakness.[11] Increased jitter is known to occur at all stages following recovery from paralytic poliomyelitis, and may be due to inadequate conduction along terminal axonal sprouts, or to suboptimal release of acetylcholine. [8,9,12,33,34] After acute paralytic poliomyelitis, recovery of muscular strength can occur by terminal axonal sprouting of surviving motor neurons, with partial or complete reinnervation of denervated muscle fibers.[8,9,44] Evidence shows that these enlarged motor units are undergoing a process of continuous remodeling, with constant denervation and reinnervation after paralytic polio.[8,9,11,45,46] Thus, the presence of immature terminal sprouts (which are known to have decreased conduction) at all stages following recovery from acute polio may account, at least partially, for the observed abnormal jitter. Decades after recovery, irreversible degeneration of terminal sprouts without reinnervation may account for the symptoms of fatigue and weakness observed in PPS. An early stage of this degeneration may be neuromuscular junction transmission defects.[12] At this time it is unclear whether neuromuscular junction transmission defects increase with the passage of time.[8,9] However, there is an association between jitter and degree of initial recovery after polio as estimated by fiber density on SFEMG, macroelectromyography motor unit potential amplitudes, and fiber type grouping on muscle biopsy. [11,47] Thus, the extent of recovery may determine the degree of motor unit instability later in life.

Because of the clinical and electrophysiological similarities of PPS with other known disorders of the neuromuscular junction, we assessed the effects of the intravenous, short-acting anticholinesterase, edrophonium, on jitter and of the oral, long-acting anticholinesterase, pyridostigmine, on clinical fatigue. Edrophonium has been found to improve neuromuscular junction transmission defects in MG and ALS as measured by repetitive stimulation and jitter on SFEMG.[26,27,36] An early study showed that neuromuscular junction transmission as measured by repetitive stimulation can improve with the intravenous anticholinesterase neostigmine in patients with prior poliomyelitis.[31] We found that neuromuscular junction transmission as measured by jitter on SFEMG improves with anticholinesterase treatment in a continuously activated muscle fiber in approximately 50% of PPS patients studied. The fact that not all neuromuscularjunctions studied were ameliorated with edrophonium suggests the presence of a variety of neuromuscular junction defects in patients with past paralytic poliomyelitis. Subsequently, we treated all 17 PPS patients with pyridostigmine 180 mg per day, and found that approximately 50% of patients reported decreased general fatigue and muscle fatigability on the medication. We demonstrated a significant association between the results of the S-SFEMG/edrophonium test and clinical response to pyridostigmine. These findings indicate that neuromuscular junction transmission defects may be the cause of fatigue in at least a proportion of patients with PPS. The clinical neuromuscular response to anticholinesterases in PPS is currently unclear: preliminary studies, however, show that a proportion of patients have increased isokinetic strength on pyridostigmine as compared to off pyridostigmine, rather

than improved fatigability.[40,41] Therefore, the beneficial effects of the medication may actually be due to a greater muscular strength.

In fatigued post-poliomyelitis patients, conditions causing fatigue, such as other neurological disorders, depression, and a variety of medical conditions must be considered prior to attributing patient fatigue to PPS. If these other conditions are excluded, and consequently, if fatigue is believed to be due to PPS, then weight loss, energy conservation, better organization of daily activities, and planned short rest periods or naps during the day may be beneficial. If these measures are ineffective or insufficient, pyridostigmine therapy may be warranted. Our finding that pyridostigmine responders were more fatigued initially than nonresponders may provide some guidance in determining which patients are more likely to respond to the medication.

Anticholinesterases inhibit the hydrolysis of acetylcholine in the neuromuscular junction and prolong its effect. There are some relative contraindications to the use of pyridostigmine which include cardiac arrhythmias, bronchospasm, increased bronchial secretions, and some urological conditions. The chronic effects of anticholinesterases in PPS are currently unknown, but these medications have been used effectively in MG for decades. Anticholinesterases are associated with acute and chronic toxicities, both pre- and postsynaptic in normal experimental animals and probably in humans.[48] However, the doses that were used in animal studies and are used commonly in patients with MG are manyfold higher than the dose we have used in PPS (180 mg/day vs up to 2 g/day in MG). Pyridostigmine was recently used in soldiers involved in the Gulf War as a pretreatment to possible organophosphate intoxication. A two-week double-blinded, placebo-controlled, cross-over trial in 7 male soldiers indicated that chronic pyridostigmine administration did not negatively impact on the ability of soldiers to perform moderate physical work in a desert environment, and did not result in an increase in subjective symptoms.[49] A retrospective study of 41,650 soldiers who self-administered pyridostigmine 30 mg orally every 8 h for 1 to 7 days during Operation Desert Storm found that approximately 50% of the soldiers noted mild physiological changes (e.g., increased flatus, abdominal cramps, soft stools, and urinary urgency), 1% had side effects severe enough to warrant medical attention, and less than 0.1% discontinued the medication because of side effects. Thus, pyridostigmine could be administered to virtually all soldiers.[50] In our study, we found that acute side effects (usually increased gut motility) occurred commonly, but tended to decrease with chronic use. Even though we have not observed evidence for chronic toxicity in PPS patients in our clinic maintained for years on this low dose, it is possible that chronic use could produce permanent morphological alterations at the neuromuscular junction. We also recommend “drug holidays” in patients chronically treated with pyridostigmine, approximately every six months. Occasionally, after months or years of treatment, patients find that the medication is no longer helpful, and it is discontinued. Therefore, pyridostigmine may be helpful only in certain stages of the disease process.

CONCLUSIONS

Our studies indicate that a proportion of fatigued post-poliomyelitis patients can experience an amelioration of defects in neuromuscular junction transmission and of clinical fatigue with anticholinesterases. Because S-SFEMG response was significantly associated with clinical response to anticholinesterases, fatigue in PPS may be caused by defects in neuromuscular junction transmission in a proportion of patients. Preliminary studies in a small group of patients indicate that anticholinesterases may produce their clinical neuromuscular response by producing an increase in isokinetic strength in a proportion of patients. Our studies provide a physiological rationale for the use of anticholinesterases in PPS for the symptom of fatigue. However, further randomized, placebo-controlled, double-blinded trials are needed to establish definitively the benefits and risks of these agents.

ACKNOWLEDGMENTS

We are indebted to the patients from the Montreal Neurological Institute and Hospital post-polio clinic who donated their time to participate in our studies, and to EMG technicians Lora Tombari and Susan Murray for their expert technical assistance.

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37. KILFOIL, M., D. M. M. ST. PIERRE, D. A. TROJAN & N. R. CASHMAN. 1994. Reliability of isokinetic evaluation of neuromuscular fatigue and the effects of pyridostigmine on subjects with post-poliomyelitis syndrome: A pilot study. Submitted.
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41. MASELLI, R. A., N. R. CASHMAN, R. L. WOLLMAN, E. F. SALAZAR-GRUESO & R. ROOS. 1992. Neuromuscular transmission as a function of motor unit size in patients with prior

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An Open Trial of Pyridostigmine in Post-poliomyelitis Syndrome

Daria A. Trojan and Neil R. Cashman

The Canadian Journal of Neurological Sciences Volume 22, No. 3 August 1995 223-227

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

From the Department of Neurology, Montreal Neurological Institute and Hospital, McGill University, Montreal.

RECEIVED DECEMBER 6, 1994. ACCEPTED IN FINAL FORM MARCH 29, 1995.

Reprint requests to: Daria A. Trojan, M.D., Montreal Neurological Institute, 3801 University, Montreal, Quebec, H3A 2B4.

Abstract

Background: One of the major symptoms of postpoliomyelitis syndrome (PPS) is disabling generalized fatigue. Subjects with PPS also report muscle fatiguability and display electrophysiologic evidence of anticholinesterase-responsive neuromuscular junction transmission defects, suggesting that anticholinesterase therapy may be useful in the management of disabling fatigue. Methods: We initiated an open trial of the oral anticholinesterase pyridostigmine, up to 180 mg per day, in 27 PPS patients with generalized fatigue and muscle fatiguability. Response to Pyridostigmine was assessed with the Hare fatigue scale, the modified Barthel index for activities of daily living, and a modified Klingman mobility index. Results: Two patients could not tolerate the medication. After one month of therapy, 16 patients (64%) reported a reduction in fatigue on the Hare fatigue scale; three of 16 showed improvement on the modified Barthel index for activities of daily living, and two of 16 experienced improvement on a modified Klingman mobility index. Pyridostigmine responders were significantly more fatigued than non-responders on the pre-treatment Hare score, but were not significantly different with regard to age, sex, age at acute poliomyelitis, or severity of acute poliomyelitis. Conclusions: Pyridostigmine may be useful in the management of fatigue in selected patients with PPS. Response to pyridostigmine may be predicted by severity of pre-treatment fatigue.

Postpoliomyelitis syndrome (PPS) is a clinical syndrome consisting of new weakness, fatigue, and pain following decades of functional stability after recovery from paralytic poliomyelitis.[1-4] Generalized systemic fatigue is a common complaint in patients with postpoliomyelitis syndrome (PPS;[1-57). Muscle fatiguability, defined as increased weakness on exertion improving with rest, can also be observed in PPS,[6] and is similar to that seen in myasthenia gravis (MG;[7]) and amyotrophic lateral sclerosis (ALS;/87). Neuromuscular junction transmission abnormalities as revealed by decrement on repetitive stimulation and increased jitter on single fiber electromyography (SFEMG) are observed in MG,[7] ALS,/8-12) and in patients with antecedent paralytic poliomyelitis.[3,13-18] In MG, the neuromuscular transmission defect is postsynaptic.[7] In ALS and PPS, the defect is thought to be presynaptic, secondary to defective terminal axonal conduction and/or impaired release of acetylcholine.[6,10,16,17,19] The oral anticholinesterase agent pyridostigmine is useful in the treatment of muscle fatiguability in MG and ALS.[7,8] Neuromuscular junction transmission as measured by repetitive stimulation and jitter on stimulation SFEMG can improve with administration of anticholinesterases in PPS./13,17] In addition, clinical response to pyridostigmine has been associated with improvement of neuromuscular junction transmission with the short-acting, intravenous, anticholinesterase edrophonium indicating that fatigue in PPS is due to anticholinesterase-responsive neuromuscular junction transmission defects in a proportion of fatigued post-polio patients.[17] For these reasons, we initiated an open trial to assess the response of disabling fatigue in patients with PPS to pyridostigmine.

MATERIALS AND METHODS

Patients

A series of 27 patients attending a post-poliomyelitis clinic at the Montreal Neurological Institute and Hospital were selected for the study. All patients provided a history consistent with prior paralytic poliomyelitis followed by prolonged convalescence and partial or complete recovery, and at least 10 years of functional stability. Patients were evaluated with a standardized history and physical examination.[3] All 27 patients provided a complaint of generalized systemic fatigue and muscle fatiguability, and were unresponsive to treatment with more conservative measures. They provided their informed consent to participate in the study.

Methods

Data obtained on all patients included age at time of study, sex, age at acute paralytic poliomyelitis, years since acute poliomyelitis, and duration of new symptoms. An estimate of severity of initial acute poliomyelitis was made by use of a modified index as described by Klingman et al.[20] On this 6-point measure, one point was given for involvement of each of four extremities (partial or complete paralysis), one point for involvement of speech and/or swallowing, and one point for respiratory involvement (with or without mechanical ventilation). The Hare fatigue symptom scale (Table 1)./21] the modified Barthel ADL index,/22] and a modified Klingman mobility index (Table 2)/20) were determined for each month following initiation of treatment. Responders were defined as those who experienced an improvement of at least 20% on initial fatigue scores. The maintenance dosage of pyridostigmine was 60 mg three times a day. To minimize the incidence of side effects, initial dosage was 30 mg every day, increased by 30 mg every other day until the maximum dosage was attained. One patient experienced significant improvement with a minimum of side effects at 120 mg every day, and for this reason was maintained on a lower dosage. Statistical comparisons between the two groups of patients, “responders” and “non-responders,” were performed using the unpaired t-test for continuous data and Fisher’s exact test for proportions. The paired t-test was utilized to compare pre-treatment and post-treatment fatigue scores in individual patients. Statistical significance was accepted at p<0.05.

Table 1: Hare Fatigue Symptom Scale

From Hare et al.: Simplified scale for rating perceived exertion in patients with coronary artery disease. Reproduced with permission. Further reproduction of the table requires authorization from the American Academy of Sports Physicians. Ann Sports Med 1985; 2:64-68. See reference 21. Modified from Klingman et al.: Functional recovery: A major risk factor for the development of postpoliomyelitis muscular atrophy. Reproduced with permission. Copyright 1988, American Medical Association. Modified from Klingman et al. Arch Neurol 1988; 45:645-647. See reference

RESULTS

Twenty-seven patients were entered into an open trial to assess the response of PPS fatigue to pyridostigmine. Two patients were unable to tolerate the medication (see below), and were excluded from further analyses. A significant difference in fatigue scores (Hare fatigue symptom scale, p< 0.0001, with a mean difference + SD of 1.12 + 1.05) was observed when pre-treatment and post-treatment fatigue scores were compared in the entire group of 25 patients that was able to tolerate pyridostigmine (Figure 1). Sixteen patients (64%) reported an improvement on the Hare fatigue score of 20 to 88% (mean improvement 56%) (Figure 1). Of these 16 patients, three patients improved in activities of daily living (modified Barthel ADL index), two improved on mobility indices (modified Klingman mobility index), and one patient who had been unable to work due to fatigue returned to work after initiation of treatment. Mean fatigue score before treatment in the responders was 3.1 + 0.83 (mean

SD), and after treatment decreased to a mean score of 1.4 + 0.64 (p<0.0001). Mean fatigue score before treatment in the non-responder group was 2.2 +0.94. This score did not change with treatment. Duration of treatment in the 16 responders has ranged from 0.1 to 2.8 years, with a mean of 1.2 years. Of the 11 patients who did not experience a reduction in fatigue with pyridostigmine or who were unable to tolerate the medication, two developed increased weakness which resolved on discontinuation of the medication,

Figure 1: Response of Fatigue to Pyridostigmine. Twenty-seven patients with PPS fatigue were entered in an open trial to assess response of fatigue to pyridostigmine.

Two patients were unable to tolerate the medication and are excluded from this figure. Twenty-five patients were treated with pyridostigmine 180 mg qd for at least one month. Sixteen patients experienced an improvement of 20 to 88% (mean 56%), and 9 patients experienced no improvement in fatigue on Hare fatigue index measured before and at least on month after treatment initiated. Mean fatigue score before treatment in the responders was 3.1, and after treatment decreased to a mean score of 1.4. Mean fatigue score before treatment in the non-responder group was 2.2. This score did not change with treatment.

Sport

Some side effects from the medication were noted in 50% of patients, particularily in the initial stages of treatment. These included diarrhea, gastrointestinal cramps, muscle cramps, blurred vision, and increased urinary frequency. In two patients, persistent symptoms were managed by the addition to pyridostigmine of the muscarinic anticholinergic agents oxybutynin chloride or propantheline bromide, for management of increased urinary frequency and diarrhea.

Historical data in the responders and non-responders was compared in an effort to identify characteristics which could predict response to pyridostigmine. There was no significant difference between the two groups with regard to age, sex, age at time of acute poliomyelitis, severity of acute poliomyelitis, duration of new symptoms, and in initial ADL and mobility scores (Table 3). However, responders were significantly more fatigued than non-responders as determined by pre-treatment Hare fatigue scores (p<0.03). Two illustrative case reports follow.

A 44-year-old female with a history of paralytic poliomyelitis at age eight presented to the post-polio clinic with inability to swallow solid food, increased use of a day-time respirator for eight months, four limbs, and general fatigue. During acute poliomyelitis, she developed paralysis of all four limbs, respiratory involvement requiring use of an iron lung, and involvement of speech and swallowing. She experienced moderate recovery of her weakness, and complete recovery of speech, swallowing, and respiratory function. However, at age 17, new respiratory symptoms necessitated the use of a night-time negative pressure respirator, and at age 40 she started using a day-time positive pressure respirator for five to seven hours per day. Examination revealed kyphoscoliosis, atrophy and weakness in all four limbs, muscle fatiguability, and absent deep tendon reflexes. After failure of nonspecific measures such as discontinuation of lorazepam and activity planning, pyridostigmine 180 mg per day was started. Two weeks following initiation of this medication, the patient was able to reduce use of her day-time respirator from five to seven hours per day, to one to three hours per day. She also experienced reduction of general fatigue (Hare fatigue scale, 4 and 2), and was able to walk at least twice as far as previously, and take much fewer rest periods during the day. Four weeks later she was again able to swallow solid food. Seven months following initiation of pyridostigmine, she was planning to return to part-time work as a school-teacher. A 44-year-old woman with a history of poliomyelitis at age 14 presented to the post-polio clinic with complaints of new weakness in her left upper and left lower extremities, general and local muscle fatigue, and pain. At the time of acute poliomyelitis, her left upper extremity was partially paralyzed, and lower extremities were completely paralyzed. She experienced complete recovery of motor strength in her right lower extremity, and significant recovery in left upper and left lower extremities. Over a period of two to three years prior to presentation, she experienced increased left sided weakness, an increased sleep requirement from seven to ten hours per night with an afternoon nap, decreased ability to ambulate, and muscle pain with minimal exertion. She stopped working as a secretary because of her symptoms. Examination revealed no atrophy, mild weakness in the left upper and left lower extremities, and muscle fatiguability. Deep tendon reflexes were brisk, but symmetric in the arms, and normal in the legs. One month later she was started on pyridostigmine 180 mg per day. Her sleeping time decreased to eight hours per day, and the distance she could walk without stopping secondary to muscle pain increased from one block to one mile. Five months following initiation of treatment with pyridostigmine she returned to full time employment.

Fatigue Scores

Figure 2: Pre-treatment Fatigue Scores (Responders vs. Non-responders). Twenty-seven PPS patients were entered into an open trial to assess response of PPS fatigue to pyridostigmine. Two patients were unable to tolerate the medication. Twenty-five patients with PPS fatigue were treated with pyridostigmine 180 mg q d for at least one month. Responders (n= 16) were significantly more fatigued than non-responders (n=9) on pre-treatment Hare fatigue scores

Legend: Responders were significantly more fatigued than non-responders (unpaired t-test, p<0.05) on pre-treatment Hare fatigue scores. There were no significant differences in age, sex, age at acute polio, severity of acute polio, and duration of new symptoms. M=male; F = female; yrs = years; S.D. = standard deviation. Severity of acute polio was estimated on a six point scale. Please refer to text for computation of this measure. Pre-treatment fatigue was assessed on a 0 to 4 Hare fatigue symptom scale (see Table 1).

DISCUSSION

We have observed in an open trial in 27 patients that disabling general fatigue and muscle fatiguability in a proportion of patients with PPS can be effectively managed with the anticholinesterase agent, pyridostigmine, and that response may be predicted by the severity of pre-treatment fatigue. Sixteen in fatigue and functional status. There were no significant differences between responders and non-responders in terms of age, sex, age at acute poliomyelitis, however the two groups of patients were significantly different with regard to reported pre-treatment fatigue scores. In patients with PPS, conditions causing fatigue, such as other neurological disorders, depression, and a variety of medical diseases must be considered and treated before attributing patient fatigue to PPS. If fatigue is believed to be due to PPS, then conservative measures such as weight loss, energy conservation techniques, better organization of daily activities, and planned short rest periods or naps during the day may be beneficial. If these measures are ineffective or insufficient, treatment with pyridostigmine may be warranted in some patients. Some relative contraindications to pyridostigmine include cardiac arrhythmias, increased bronchial secretions and reactivity, and some urological disorders. Our finding that pyridostigmine was more effective in more severely fatigued patients provides information in determining which patients are more likely to respond to this treatment.

The chronic effects of pyridostigmine in PPS are currently unknown; however anticholinesterase agents have been used effectively in the treatment of MG for decades. Anticholinesterase agents are associated with acute and chronic toxicities, both pre- and post-synaptically in experimental animals and humans. 23-25) The doses used in these animal studies and in patients with MG are manyfold higher than the dose which has been used in this trial in PPS (2 g per day in MG versus 180 mg per day in PPS). Pyridostigmine 90 mg per day was recently used in 41,650 soldiers involved in the Gulf War as a pretreatment to possible organophosphate intoxication. A retrospective study found that 50% of soldiers complained of mild side effects (similar to those noted by us, such as soft stools, urinary frequency, abdominal cramps), 1% had side effects severe enough to necessitate medical attention, and <0.1% discontinued the medication because of side effects.[26] In addition, pyridostigmine did not affect soldiers’ ability to perform./26,27] We also found that side effects occurred commonly, but tended to decrease with chronic administration.

The effect of pyridostigmine on muscular function in PPS has been assessed in seven patients with PPS.[28] An isokinetic fatigue protocol was performed by these patients while on and off pyridostigmine. Even though total work for the entire group of patients did not differ while on and off the medication, three patients were weaker and one patient demonstrated increased muscle fatiguability while off the medication. Therefore, pyridostigmine may decrease the subjective symptom of fatigue by not only decreasing muscle fatiguability, but also increasing strength. The basis for the latter effect may be due to enhancing neuromuscular transmission at suboptimally functioning synapses.

Fatigue in PPS has been attributed to a number of sources, both central and peripheral.[29] Possible central causes of fatigue are dysfunction of the reticular activating system, chronic pain including fibromyalgia, depression, sleep disorders, and respiratory dysfunction.[30-34] Proposed peripheral causes of fatigue include metabolic exhaustion of enlarged post-polio motor units, neuromuscular junction transmission defects, and muscular abnormalities. [6,17,35-37] Our data suggest that fatigue in PPS may be multifactorial in nature, but that anticholinesterase-responsive neuromuscular junction transmission defects account for a proportion of this fatigue.

Since our study was an open trial that measured responses of subjective complaints quantitatively, it should be considered preliminary. By employing a specific therapeutic agent, we obtained a response rate of 64% in a selected group of patients, which is higher than that generally attributed to placebo./38]

Based on these encouraging results, a randomized, placebo-controlled, double-blinded trial of pyridostigmine in PPS should be carried out. Pyridostigmine may prove to be a safe and effective treatment of a major disabling symptom of 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 Association Polio Québec. We are indebted to the reviewers for their constructive criticism, and to the patients who participated in the study.

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