PSN Library Files

Predictive Factors for Post-Poliomyelitis Syndrome

Daria A. Trojan, MD, MSc, Neil R. Cashman, MD, Stanley Shapiro, PhD, Catherine M. Tansey, MSc, John M. Esdaile, MD

Arch Phys Med Rehabil Vol 75, July 1994, 770-777

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

From the Department of Neurology (Drs. Trojan, Cashman), Montreal Neurological Institute and Hospital, the Department of Medicine (Dr. Esdaile), Montreal General Hospital, and the Department of Epidemiology and Biostatistics (Dr. Shapiro, Ms. Tansey), McGill University, Montreal, Quebec, Canada.

Submitted for publication September 24, 1993. Accepted in revised form February 9, 1994.

Drs. Trojan and Cashman are Research Scholars, and Dr. Esdaile is a Senior Research Scholar supported by the Fonds de la Recherche en santé du Qébec. This work was supported in part by the Polio Quebec Association.

No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated.

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

© 1994 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

0003-9993/94/7507-0018$3.00/0

ABSTRACT Trojan DA, Cashman NR, Shapiro S, Tansey CM, Esdaile JM. Predictive factors for post-poliomyelitis syndrome. Arch Phys Med Rehabil 1994;75:770-7.

Post-poliomyelitis syndrome (PPS) is generally defined as a clinical syndrome of new weakness, fatigue, and pain in individuals who have previously recovered from acute paralytic poliomyelitis. The purpose of this study was to identify, through a case-control study design, factors that predict subsequent PPS in patients with prior paralytic poliomyelitis. Among patients attending a university-affiliate hospital post-polio clinic, “cases” were patients with new weakness and fatigue, and “controls” were patients without these complaints. A chart review of 353 patients identified 127 cases and 39 controls. Logistic regression modeling was used to calculate adjusted and unadjusted odds ratios. In univariate analyses, significant risk factors for PPS were a greater age at time of presentation to clinic (p = 0.01), a longer time since acute polio (p = 0.01), and more weakness at acute polio (p = 0.02). Other significant associated, but not necessarily causal factors were a recent weight gain (p = 0.005), muscle pain (p = 0.01) particularly that associated with exercise (p = 0.005), and joint pain (p = 0.04). Multivariate analyses revealed that a model containing age at presentation to clinic, severity of weakness at acute polio, muscle pain with exercise, recent weight gain, and joint

pain best distinguished cases from controls. Age at acute polio, degree of recovery after polio, weakness at best point after polio, physical activity, and sex were not contributing factors. These findings suggest that the degree of initial motor unit involvement as measured by weakness at acute polio, and possibly the aging process and overuse are important in predicting PPS. © 1994 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Although acute poliomyelitis is now relatively uncommon in North America,[1] approximately 640,000 individuals who have recovered from acute paralytic poliomyelitis are alive today.[2] Subsequently, as many as half of these individuals may develop post-poliomyelitis syndrome (PPS).[3-7] PPS is defined as a clinical syndrome of new weakness, fatigue, and pain in those who have recovered from acute paralytic poliomyelitis.[2,8,9] Even though PPS is the most prevalent progressive motor neuron disease in North America today, there are few epidemiologic studies that evaluate possible predictors for this condition.

PPS is believed to be caused by a distal degeneration of massively enlarged motor units from axonal sprouting after acute paralytic poliomyelitis.[10,11] Overuse is thought to be a contributing factor.[12,13] This degenerative process can produce neuromuscular junction transmission defects, a possible cause of fatigue,[14-19] and permanent denervation with resultant clinical weakness.[10,11,14,20] Because it is currently unclear how or if pain is referable to disease of the motor unit, this study is concerned with new weakness and fatigue as part of PPS. Pain is studied as a predictor, but not as part of PPS.

The object of this study was to identify factors that predict and are associated with PPS (new weakness and fatigue) in patients with antecedent paralytic poliomyelitis. Previous studies have shown that potential risk factors for PPS include a more advanced age at acute polio,[21,22] a greater severity of initial acute poliomyelitis,[4,6,21,22] a greater recovery in muscular strength after poliomyelitis,[22] presence of permanent impairment after recovery after poliomyelitis,[7] lower disability at presentation to clinic,[21] female sex,[7] a greater length of time since acute polio,[7] and possibly increased recent physical activity.[22] In addition to studying these risk factors, our study evaluated a number of previously evaluated predictors including age at time of presentation to the clinic, usual physical activity prior to development of PPS, and joint pain, and a number of novel predictors including weakness at the time of maximum strength (”best point”) after polio, recent weight gain, and muscle pain (at rest or with exercise). The identification of potentially preventable factors may result in better management of patients with previous polio

METHODS

Study Design

Because of the long delay between acute polio and PPS, a case-control design was used. Based on the numbers of cases and controls identified, this study should have been able to detect an odds ratio of 2.5 for an exposure rate of p = 0.4.[23] Institutional ethics committee approval was ottained for the study.

Study Population

Cases and controls were identified through a chart review of 353 patients evaluated at a university affiliated-hospital post-polio clinic between 1986 and March, 1992. Patients are referred to the clinic for evaluation and treatment of specific problems, however a proportion of patients come simply to obtain information about PPS and on methods for reducing the risk for PPS. A prerequisite for evaluation in the clinic is a history of paralytic polio, therefore virtually all patients have had paralytic polio. In a few cases, the diagnosis of acute paralytic polio was questionable, and electrodiagnostic testing was done in an

attempt to confirm the history. On the initial visit, a standardized history and physical examination form was completed (NRC or DAT) for each patient, and a thorough medical history, physical examination, and appropriate diagnostic tests were performed. Some patients were seen only once, others were seen more frequently. To prevent any bias from use of data obtained on follow-up visits, data obtained from the initial interview and the immediately following laboratory investigations were used. The study was conceived after clinic visits had occurred, but a standardized evaluation form was used on all patients.

Inclusion criteria for cases in the study were based on those suggested by Mulder and colleagues.[24] They were (1) a history of past paralytic poliomyelitis (an illness characterized by high fever, followed by muscular weakness), (2) initial partial or complete recovery of function, (3) at least 10 years of functional stability following initial recovery, and (4) new symptoms of increased or new muscular weakness, and fatigue (muscular and/or general). Muscular fatigue was defined as increasing muscular weakness on exertion, which improves with rest. General fatigue was defined as an overwhelming, “flu-like” exhaustion.[8] Exclusion criteria were (1) presence of past and concurrent medical conditions that could produce weakness and fatigue at initial visit (eg, significant cardiac disease that requires treatment with medication), chronic obstructive pulmonary disease, cancer, cirrhosis, depression, hypothyroidism, anemia, connective tissue disease, chronic infection, diabetes mellitus, and chronic renal failure), (2) presence of other past or concurrent neurological disorders that could produce weakness and fatigue at initial visit (eg, peripheral neuropathy, head injury, stroke, Parkinson’s disease, radiculopathies, spinal stenosis with myelopathy), and (3) presence of severe pain at initial visit that could make differentiation between pain and muscular weakness difficult. One hundred twenty-seven cases were identified.

Inclusion criteria for controls in the study were (1) a history of past paralytic poliomyelitis (an illness characterized by high fever, followed by muscular weakness), (2) initial partial or complete recovery of function, and (3) at least 10 years of functional stability following initial recovery. Exclusion criteria were (1) presence of past and concurrent medical conditions that could produce weakness and fatigue at initial visit leg, significant cardiac disease [that requiring treatment with medication]), chronic obstructive pulmonary disease, cancer, cirrhosis, depression, hypothyroidism, anemia, connective tissue disease, chronic infection, diabetes mellitus, and chronic renal failure), (2) presence of other past or concurrent neurological disorders that could produce weakness and fatigue at initial visit leg, peripheral neuropathy, head injury, stroke, Parkinson’s disease, radiculopathies, spinal stenosis with myelopathy), (3) presence of severe pain at initial visit that could make differentiation between pain and muscular weakness difficult, and (4) presence of new symptoms of increased or new muscular weakness, and/or fatigue (muscular and/or general). Thirty-nine controls were identified.

Data Collection

Data were obtained from a chart review of patients included in the study. Data on the following independent variables were obtained: age (at time of presentation to clinic), sex, age at acute polio, latency or time in years between acute polio and presentation to clinic, presence of pain (muscular and/or joint; muscular pain included pain with exercise and/or pain at rest), weakness at acute polio, weakness at “best point” after acute polio, weakness at time of presentation to clinic, recovery after polio, hospitalization at time of acute polio, ambulation disability index at “best point” after acute polio and at presentation to clinic, reported recent weight gain (within last 5 years), physical activity index, and motor strength score at presentation to clinic in each of four extremities. The scales used are described below.

Degree of weakness was estimated on the same 0 to 6 scale at three different time periods: at time of acute polio, at “best point” after acute polio, and at presentation to clinic. The measure was based on subjective patient estimates of percent weakness in each of four limbs, respiratory muscle weakness, and

speech/swallowing dysfunction. During the initial interview, each patient was asked to rate the amount of weakness in each of four limbs from 0 to 100 (0 being normal or not paralyzed, and 100 being completely paralyzed) at each of three time periods. For respiratory muscle function, a 50 was assigned for some weakness, and a 100 for weakness requiring use of a ventilator. A 50 was assigned for some speech and/or swallowing dysfunction, and a 100 for complete loss of speech and/or swallowing. The sum total score of all six figures was divided by 100 to make the final scale easier to interpret in further analyses. In this way, a scale ranging from 0 to 6 was produced.

Recovery after acute polio was measured as the difference between severity of weakness at time of acute polio and severity of weakness at “best point” after acute polio.

A motor strength index at time of presentation to clinic was estimated for each of four extremities. This index was based on motor strength determined on physical examination in each of five muscle groups in the upper extremities (deltoid, biceps, triceps, wrist extensors, hand intrinsics) and in each of five muscle groups in the lower extremities (hip flexors, quadriceps, hamstrings, dorsiflexors, plantarflexors) by a 0 to 5 Medical Research Council (MRC) scale.[25] The results obtained for each muscle group in a particular limb were summed to arrive at a motor strength index for each extremity.

An ambulation disability index, modified from one developed by Klingman and coworkers,[22] was also computed at “best point” after acute polio, and at presentation to clinic. It ranged from 0 to 5; 0 = no functional disability, 1 = mild difficulty with ambulation without need for braces, 2 = moderate difficulty with ambulation with need for braces, 3 = severe difficulty with ambulation with need for braces for short distances, and a wheelchair for longer distances, 4 = severe disability, wheelchair bound, and 5 total disability and bedridden.

Physical activity before onset of PPS for cases, and recent physical activity for controls (within last 5 years) were calculated in the following manner, similar to that used by Klingman and associates[22]: 1 = little or no regular participation in sports, manual labor, or walking, 2 = occasional moderate sports activity (greater than or equal to 20 min one or two times per week), and/or mild to moderate demands at work and at home (eg, frequent ambulation for several hours at a time or occasional light lifting), 3 = frequent participation in sports (greater than or equal to 20 min two or more times per week), and/or moderate to heavy activities at work or home (eg, frequent heavy lifting or manual labor).

Some of the variables had a large number of missing values. Because at least some data were available on most subjects, estimates for the two variables of weakness at acute polio, and consequently the degree of recovery were made during the chart review (for 36 and 28 patients, respectively) if some information were present. If a patient stated that an extremity, speech/swallowing function, or respiratory muscles were involved, but that degree of involvement was not known (eg, partial vs complete), a 75 was imputed for that limb, a 50 for speech/swallowing dysfunction, and a 50 for respiratory muscle weakness. If a limb, respiratory muscles, or speech/swallowing function were partially involved, a 50 was ascribed. If a patient had no knowledge as to involvement of limbs in the past, no estimates were imputed.

Reliability and Validity of Variables

Inter-rater reliability of the dependent variable (case/control status) was estimated by having another rater (NRC) review a random sample of 10% (n = 16) of charts, and assign case/control status to these patients. Percent agreement between the two raters was 94%. Coefficient Kappa,[26] which corrects the percent agreement score for chance agreement, was 87.5%.

The reliability of the variables weakness at time of acute polio and age at acute polio were assessed. This

was determined by a review of all available medical records of patients hospitalized in the Montreal area at the time of acute polio. From the information available in the old records, a weakness score (using a 0 to 6 scale) at time of acute polio was estimated for each patient in a manner similar to that described above. This weakness score was based on information on degree of weakness in each of four limbs, respiratory muscle weakness, and speech/swallowing function. If a limb was unaffected, a 0 was assigned, if mildly weakened (MRC grade 4) a 10, if moderately weakened a 50, if severely weakened (MRC grade 1 to 2) a 90, and if completely paralyzed a 100 was assigned. For respiratory muscle function a 50 was assigned for some weakness, and a 100 for weakness requiring use of a ventilator. For speech/swallowing function, a 50 was assigned for some speech/swallowing dysfunction, and a 100 for complete loss of speech and/or swallowing. The sum total of all six figures was then divided by 100 to arrive at a 0 to 6 score for each subject. Patients tended to overestimate their weakness at acute polio; however, their assessment of age at which they had acute polio was accurate. Patient estimates of weakness at acute polio was 2.98 ± 1.49 (mean ± SD) compared with data from old charts of 2.11 ± 1.16 (p = 0.05, n = 19, mean difference 0.86 ± 1.47). Patient estimates of age at acute polio was 8.72 ± 9.46 years compared with 8.95 ± 9.36 years from old records (p = 0.9, n = 28, mean difference 0.23 ± 0.49). The effect of case/control status on recall of these variables is unknown because old records were available on only two controls.

The concurrent criterion-oriented validity of patient estimates of weakness at time of presentation to clinic was evaluated by correlating percent scores of weakness in each limb with the motor strength score (estimated from the physical examination performed at that time) for each extremity for each patient. The correlation coefficients for the left and right upper extremities, and for the left and right lower extremities were -0.67 (n = 184), -0.75 (n = 183), -0.81 (n = 163), and -0.79 (n = 167), respectively.

The construct validity of the weakness measure was evaluated by comparing mean weakness at acute polio in those patients who were and were not hospitalized. Mean weakness was 2.58 ± 1.43 (n = 128) in hospitalized patients and 1.79 ± 1.15 (n = 42) in unhospitalized patients (p < 0.002).

Statistical Analysis

Preliminary analysis involved univariate and bivariate analyses with standard parametric procedures. Continuous independent variables were examined to determine whether they would be used as continuous or categorical variables in the logistic regression model.[27] Age at presentation to clinic, latency, weakness at acute polio, and weakness at presentation were entered as continuous variables. Age at polio (less than or equal to 7, and greater than 7.0 years), weakness at best after acute polio (less than or equal to 0.6, and greater than 0.6), and recovery (less than or equal to 0.6, 0.61-1.6, 1.61-2.6, and 2.61-5) were entered as categorical variables. The variables that were collinear with each other (as identified by high correlation coefficients, and by eigenvalue and condition index analyses) were not entered together in the same multivariate analyses.[28]

A crude odds ratio, with 95% confidence intervals was calculated for each independent variable by univariate logistic regression modeling. Multivariate logistic regression models were computed by a stepwise approach, and adjusted odds ratios with 95% confidence intervals were calculated for all variables. A significance level of p less than or equal to 0.10 for improvement in the loglikelihood ratio test was required for entry of a term and a value of p less than or equal to 0.15 was required for a term to stay in the model. Specific interaction terms of interest were the relationship of: (1) weakness at acute polio to recovery; (2) physical activity to weakness at best point after acute polio; (3) recent weight gain to weakness at presentation to clinic; (4) weakness at acute polio to latency; and (5) recovery to latency.

The stability of the calculated odds ratios was evaluated by assessing the effect of removal of outliers (influential observations) on some of the univariate and multivariate analyses.[28] These analyses showed

that the four outliers identified produced only small changes (in either direction) in the computed odds ratios and their associated confidence intervals. The extreme values that resulted in the identification of the outliers were for the variables age at acute polio, latency, and recovery. In addition, the effect of the imputed missing values on some of the univariate and multivariate odds ratios was assessed by comparing odds ratios both with and without imputed missing values. The addition of imputed missing values did not produce important changes in the odds ratios obtained. They were well within the margin of error.

The statistical analyses were done without correction for the relatively large number of analyses performed. Because the probability of finding a statistically significant finding increases with the number of analyses performed, the p values presented may be underestimations of the true p values.

The statistical packages used for data analyses were SAS^a and BMDP (1988 version).^b SAS was used for calculation of descriptive statistics, a-tests, XZ tests, correlation coefficients, collinearity analysis, and outlier analysis. BMDP was used for univariate and multivariate logistic regression modeling.

RESULTS

Three hundred fifty-three charts from a university-affiliated post-polio clinic were reviewed. One hundred eighty-seven patients were excluded. Reasons for exclusion included no history of past paralytic polio in 31 patients, history of two episodes of past paralytic polio in 2 patients, no period of at least 10 years of functional stability following initial recovery in one patient, presence of new fatigue (without weakness) in 39 patients, presence of new weakness (without fatigue) in 11 patients, presence of severe pain in 14 patients, presence of other past or concurrent neurological disorders that could produce weakness and fatigue in 40 patients, and presence of past or concurrent medical disorders that could produce weakness and fatigue in 49 patients. In the patients excluded from the study, age at acute polio ranged from 0 to 43 years (mean ± SD, 9.18 ± 10.14 years), age at presentation to clinic ranged from 27 to 87 years (52.37 ± 13.51 years), and 63% were female. One hundred and twenty-seven cases and 39 controls were identified. For the patients included in the study, age at acute polio ranged from 0.05 to 39 years (mean ± SD, 5.98 ± 6.8 years), age at presentation to clinic ranged from 18.9 to 79.5 years (49.4 ± 12.08), 63% were female, 54% complained of muscle pain, and 77% complained of joint pain. The mean length of time that cases had new symptoms was 5.7 ± 5.94 years (mean ± SD).

Descriptive statistics (including means, proportions, standard deviations), along with t-tests, X² tests, 95% confidence intervals of differences in means and proportions between cases and controls are presented in tables 1 and 2. Cases were significantly different (p < 0.05) from controls with respect to an older age at time of presentation to clinic, a longer time since acute polio, a greater weakness at acute polio, and a greater weakness and a greater disability at presentation to clinic. In addition, cases were significantly more likely to have experienced a recent weight gain, muscle pain (at rest and/or with exercise), joint pain, and muscle pain with exercise than controls. There were no significant differences between cases and controls in terms of sex, age at acute polio, weakness at “best point” after acute polio, disability at “best point” after acute polio, recovery, and physical activity.

variables)

The variables weakness at acute polio and recovery had imputed values for 36 and 28 patients, respectively if some information was available. Please refer to text for description of computation of Weakness Measure, Disability Index, and Physical Activity Index.

Univariate (unadjusted) odds ratios with their 95% confidence intervals for each independent variable were calculated by logistic regression modeling. The results are presented in table 3. The variables with significant odds ratios are age at presentation to clinic, latency, weakness at acute polio, weakness at presentation to clinic, disability index at presentation to clinic, recent weight gain, muscle pain, joint pain, and muscle pain with exercise. The risk for PPS increased by 1.8 for each decade of life, and increased by 1.6 for each decade after acute polio. The odds ratio for PPS was 1.5 and 7, respectively, for each increment of 1 on the weakness measure at acute polio and at presentation to clinic. In addition, patients with a greater disability at presentation to clinic were significantly more likely to have PPS (odds ratios ranging from 6.4 to 31.7 for each increment on the disability index). Patients with a recent weight gain (in the last 5 years) were 3.8 times as likely to have PPS, whereas patients reporting muscle pain with exercise were also 3.8 times more likely to have PPS. The odds ratios for muscle pain and joint pain were 2.6 and 2.4, respectively.

Multivariate models were calculated using a stepwise approach with logistic regression modeling. The best multivariate model for predicting who would develop PPS (using all possible predictive factors with the exception of weakness and disability index at presentation to clinic) was one that included the variables current age, weakness at acute polio, muscle pain with exercise, recent weight gain, and joint pain. The adjusted odds ratios with their 95% confidence intervals for the variables in this model are presented in table 4. If age at presentation to clinic was excluded from the model, the variable time from acute polio to presentation to clinic, entered the model in its place with only a slight loss of statistical

efficiency. Both age and time from acute polio could not be included in the same model because they were correlated with each other. The addition of recovery did not significantly improve the model, even if weakness at acute polio was excluded. None of the interaction terms proved to be statistically significant.

DISCUSSION

The best multivariate model for predicting who will develop PPS indicates that patients who had a greater weakness at acute polio, are currently older, have muscle pain with exercise, a recent weight gain, and joint pain are those most likely to develop PPS. Other factors shown to be important in univariate analyses are a longer time since acute polio, and muscle pain (at rest or with exercise). Age at acute polio, recovery after polio, weakness at “best point” after polio, physical activity, and sex were not contributing factors.

Our sample of patients was similar to that of previous epidemiologic studies, which evaluated possible predictive factors for PPS. The mean age at acute polio in our patients was 6 years as compared to a range of a mean of 7 to 13 years in other studies.[6,7,21,22] Mean age at presentation to clinic was 49.4 years in our study, and ranged from a mean of 41.9 to 49.1 years in previously published reports.[6,7,21,22] Our patient sample was predominantly female (63%), similar to the patient sample in two previous studies (65%[21] and 54% female[6]), but different from one previous study characterized by male predominance (46% female[7]). Thus, any differences in our results are probably not due to a large disparity in basic demographic characteristics of our patient sample compared to those in previously published reports.

Case-control studies are subject to bias in the identification of cases and controls, and in the assessment of exposures (usually assessed by recall). These sources of bias are not all unique to case-control studies.[23]

The controls in our study were identified from a university-aftiliated post-polio clinic. Because these patients may have had a more severe paralytic poliomyelitis, and may have been more likely to be symptomatic than controls with a history of past paralytic poliomyelitis not evaluated at the clinic, the odds ratios calculated in this study may be underestimations. However, unlike a previous population based study that used a self-reported questionnaire for case ascertainment,[7] our study had more stringent criteria for identification of cases and controls, which included a standardized clinical evaluation and laboratory testing, as indicated. We excluded approximately 50% of patients evaluated primarily because of the presence of concurrent medical and other neurological conditions that could produce weakness and fatigue. Most variables considered in our study as possible predictive factors were assessed by recall. This may have produced error because of the length of time since passage of events (with resultant decreased study power), and bias. Cases may overestimate or be more likely to remember certain factors than controls, producing an overestimation of the odds ratios.[23] In addition, recall of time sequence of events may be faulty. For example, cases may be more apt to note increased physical activity prior to onset of PPS than controls, producing an overestimation of the odds ratio for this variable. To evaluate some possible sources of error in our study, we assessed the reliability of case/control selection, and the reliability and validity of some of the potential predictive factors. We determined that inter-rater reliability of case/control status was excellent. Patient recall of age at acute polio and thus length of time since acute polio was accurate. Although patients tended to overestimate the degree of weakness at acute polio as compared to data available from old hospital charts, the weakness measure used correlated well with other weakness estimates. Assuming that cases overestimated their initial involvement to a greater degree than controls, a smaller odds ratio with a higher statistical significance would have been obtained for this variable had more accurate data been available.

Despite the possible sources of error in our study, our findings on the important predictive factors for PPS are consistent with previously proposed hypotheses for PPS. The severity of the original motor neuron destruction during acute polio, as estimated by weakness at acute polio, has been proposed to be important for the development of PPS by other investigators.[4,6,21,22] Because PPS is thought to result from a distal degeneration of enlarged motor units (as a result of the recovery process from acute paralytic polio through axonal sprouting),[10,11] the degree of motor unit enlargement as measured by the degree of muscular recovery after polio may also be a risk factor for PPS.[22] In addition, factors that result in overuse of these enlarged motor units could contribute to the development of PPS.[12,13] Our study confirmed the findings of previous investigators who noted that an increased severity of acute poliomyelitis,[4,6,21,22] and greater length of time since acute polio[7] are risk factors for PPS. Although recovery after paralytic poliomyelitis,[22] age at acute polio,[21,22] recent physical activity,[22] and sex[7] were noted to be significant predictive factors for PPS in previous studies, our data did not confirm these findings. Degree of recovery and age at acute polio were higher in PPS patients than controls (table 1), but the differences were not statistically significant (tables 1 and 3). Physical activity was minimally higher in PPS cases than stable patients after acute poiiomyelitis, and did not result in a significant odds ratio (tables 1 and 3). This lack of association of physical activity with PPS was also noted in a recent study.[7] It is possible that a study with greater power or with the use of more accurate measures may have identitied these variables as significant predictors for PPS. In contrast to the findings of a previous study,[22] we found that the degree of disability at time of presentation to clinic was higher in cases than controls. This may be a reflection of their increased weakness, a diagnostic criterion for PPS. The new findings from our study are that a greater age is important in the development of PPS. In addition, we found that factors that may be signs of overuse (or alternatively consequences of increased weakness) such as recent weight gain, muscle pain particularily that associated with exercise, and joint pain are significantly associated with PPS.

Unlike most previous studies, we evaluated specific interaction terms that may be of clinical relevance in

the prediction of PPS. The possible association between permanent impairment after acute polio and severity of acute polio in predicting PPS has been previously evaluated. The incidence of PPS increased significantly with increasing impairment in both mild and moderate categories of acute polio severity, but not in the severe category.[7] Our study did not evaluate this particular association. We found no significant interaction or association between weakness at polio to recovery, physical activity to weakness at best point after acute polio, recent weight gain to weakness at presentation to clinic, weakness at acute polio to latency, and recovery to latency. This indicates that the presence of PPS did not vary significantly with different levels of the variables considered. For example, degree of recovery was not significantly dependent upon severity of acute polio in predicting PPS. Because our population was relatively small for

such evaluations, it is possible that a larger study with a greater number of observations in different categories would have resulted in the finding of significant interaction terms.

Age at presentation to clinic, as a measure of the normal ageing process has been proposed as a possible contributor to PPS.[9] Our finding that age at presentation to clinic is a significant risk factor for PPS provides support for this hypothesis. However, other explanations are also possible. For example, the likelihood of having PPS may simply increase with the passage of time since acute polio (and thus age). The normal progressive dropout of motor neurons[9,29-31] and the decrease in growth hormone and somatomedin C levels with greater age[32-34] may be precipitating factors for PPS. Anatomic and electrophysiological studies have demonstrated a loss of spinal cord motor neurons with ageing. This loss becomes prominent after age 60.[29-31] It is possible that the superimposition of this process over the already limited number of motor neurons present after polio contributes to the development of PPS.[9] Somatomedin C has been found to be low in 9 of 10 patients with PPS and normal in 12 polio survivors without PPS.[35] The growth hormone/somatomedin C axis stimulates the synthesis of protein and nucleic acids in muscle cells,[36-38] and the regeneration of peripheral nerves after injury including sprouting.[39-41] In a proportion of the population, growth hormone and somatomedin C production ceases with age.[32-34] Thus, aging with progressive loss of motor neurons, and with absence of growth hormone and somatomedin C may be important in the development of PPS.[8,35]

Chronic overuse has also been proposed as a contributing factor to PPS.[12,13] Thus, variables such as length of time since acute polio, joint and muscle pain, physical activity, and weight gain may be possible predictive factors. We found that length of time since acute polio is a risk factor for PPS, and that recent weight gain, muscle pain especially that occurring with exercise, and joint pain are associated factors with PPS, thus providing some evidence for this hypothesis. A greater length of time since acute polio may be a measure of overuse, or it may reflect the greater likelihood of having more patients with PPS with the passage of time since acute polio. Recent weight gain can contribute to overuse, but it may also be a consequence of decreased physical activity resulting from weakness and fatigue. The fact that muscle and joint pain were found to be significantly associated with PPS may reflect the fact that pain is considered to be the third component of PPS,[2,9] or it may be another measure of overuse or even disuse. Joint and muscle pain can be related to exercise, and in this way be indirect measures of overuse.[42-44] Our finding that muscle pain with exercise (as a clinical measure of muscular damage) is significantly associated with PPS is consistent with a previous report of increased creatinine kinase levels in PPS patients and not in asymptomatic post-polio controls.[6] The fact that physical activity was not significantly associated with PPS may indicate that the amount of physical activity is not as important as the intensity at which activities are conducted. Frequent periods of activity, if interspersed with rest and with the avoidance of pain may be safe.[13] The occurrence of pain can also lead to decreased use of certain muscles with the consequent development of disuse atrophy and weakness.[46] Alternatively, increasing weakness may itself cause symptoms of joint and muscle pain. Thus, pain and weight gain can precede or follow the development of new weakness, and may or may not be measures of overuse. Further study should be performed to clarify this issue.

In conclusion, the results from this study provide insight on predictive factors for PPS, and can be applied in the clinical management of patients who have recovered from paralytic poliomyelitis. Our findings support the hypothesis that the severity of initial motor unit involvement as estimated by weakness at acute polio, and possibly the normal ageing process and overuse are important in predicting PPS. Even though patients have no control over the severity of weakness as a result of acute polio, they do have control over some predictive factors for PPS. Patients can be advised that they should avoid gaining weight and exercising to the point of muscle pain because these variables have been found to be strongly associated with PPS. The exact role of physical activity will still need further evaluation; however, the

usual recommendations of low-level aerobic exercise with avoidance of muscle pain and fatigue appear valid. Thus, this study can provide the basis for physiologically reasonable and practical advice to post polio patients to minimize or delay the risk of PPS.

Acknowledgments: We are indebted to Ms. Marielle Olivier for her expert computing assistance, to the reviewers for constructive criticism, and to the patients who participated in the study.

References

1. Wright PF, Kim-Farley RJ, Quadros CA, Robertson SE, Scott RM, Ward NA, et al. Strategies for the global eradication of poliomyelitis by the year 2000. N Engl J Med 1991;325:1774-9. [PubMed Abstract]
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Stimulation frequency-dependent neuromuscular junction transmission defects in patients with prior poliomyelitis *

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

Department of Neurology

McGill University

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

(Received 12 November, 1992)

(Revised, received 2 March, 1993)

(Accepted 30 March, 1993)

Journal of the Neurological Sciences, 118 (1993) 150-157

© 1993 Elsevier Science Publishers B.V. All rights reserved 0022-51OX/93/$06.00

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

* This work was reported in part at the 1991 meetings of the American Academy of Physical Medicine and Rehabilitation (Washington D.C., October 29, 1991).

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: Poliomyelitis; Neuromuscular junction; Electromyography; Neuromuscular disease; Fatigue Summary

Generalized fatigue and muscle fatiguability are major symptoms of post-poliomyelitis syndrome (PPS), and may be due to neuromuscular junction transmission defects, as suggested by increased jitter on single fiber electromyography (SFEMG). To determine the etiology of this defect, we studied jitter at low (1, 5 Hz) and high (10, 15, 20 Hz) frequency stimulation with stimulation SFEMG in 17 post-polio patients with muscle fatiguability, and in 9 normal controls. In 5 of 17 PPS patients and in 1 of 9 controls, jitter was significantly higher (unpaired t-test, P < 0.05) at high frequency stimulation (HFS). In the remaining PPS patients and controls there was no significant difference in jitter at high and low stimulation frequencies. PPS patients with increased jitter at HFS had a significantly longer time interval since acute polio (mean 48.5 years) than PPS patients without increased jitter at HFS (mean 40 years; P < 0.05), but were not distinguished by other historical or clinical criteria. We conclude that the neuromuscular junction defect in post-polio patients is similar to that observed in amyotrophic lateral sclerosis, and is probably due to ineffective conduction along immature nerve sprouts and exhaustion of acetylcholine stores. The

appearance of an increase in jitter with HFS in post-polio patients may be dependent upon time after acute polio.

Introduction

Post-poliomyelitis syndrome (PPS) is a clinical syndrome of new weakness, fatigue, and pain in individuals who have previously recovered from paralytic poliomyelitis (Codd et al. 1985; Halstead et al. 1985; Jubelt and Cashman 1987; Munsat 1991; Speier et al. 1987; Windebank et al. 1987). Fatigue is a major symptom in PPS, occurring in 59 to 89% of patients (Codd et al. 1985; Halstead et al. 1985; Halstead et al. 1987; Trojan and Cashman 1989) and is frequently cited as the most disabling symptom. A recent study showed that symptoms of generalized fatigue may occur equally commonly in PPS and normal controls, whereas symptoms attributable to muscle fatiguability are significantly more common in PPS patients (Berlly et al. 1991). Although the etiology of PPS is unknown, the most likely hypothesis attributes it to a distal degeneration of massively enlarged motor units from axonal sprouting following paralytic polio (Wiechers 1988; Wiechers and Hubbell 1981). Previous studies in postpolio patients have suggested the presence of neuromuscular junction defects by demonstrating decrement of the compound motor action potential on repetitive stimulation (Hodes 1948) and increased jitter on single fiber electromyography (SFEMG) (Cashman et al. 1987; Dalakas et al. 1986; Wiechers 1988; Wiechers and Hubbell 1981; reviewed in Trojan et al. 1991). These neuromuscular junction transmission defects may be due to both a remodeling process characterized by continuous denervation and reinnervation of muscle fibers in enlarged motor units (Cashman et al. 1987; Lange et al. 1989; Wiechers 1988; Wiechers and Hubbell 1981), and/or to ongoing “permanent” terminal axonal degeneration (Wiechers 1988; Wiechers and Hubbell 1981). Thus, evidence for neuromuscular junction transmission defects occurs at all stages following paralytic poliomyelitis, including asymptomatic postpolio patients (Cashman et al. 1987; Wiechers 1988). Because of clinical and electrophysiological similarities of PPS with other disorders characterized by muscle fatiguability and increased jitter, fatigue in PPS may be attributable to neuromuscular junction transmission defects (Bernstein and Antel 1981; Denys and Norris 1979; Engel 1986; Mulder et al. 1959; Stalberg et al. 1974, 1975; Trojan et al. 1993).

The electrophysiological abnormality of increased jitter in disorders of the neuromuscular junction is relatively nonspecific, and may be due to both pre-synaptic and post- synaptic abnormalities (Stalberg and Trontelj 1979). It has been previously shown that the changes in jitter with rate of stimulation frequency provide some information regarding the location and etiology of neuromuscular junction transmission defects (Chaudry et al. 1991; Sanders and Howard 1986; Schiller and Stalberg 1978; Schwartz and Stalberg 1975; Stalberg et al. 1974; Stalberg et al. 1975). For example, in botulism and myasthenic syndrome, jitter decreases with high frequency stimulation (HFS) through a partial correction of the presynaptic defect with higher nerve terminal calcium concentrations at greater discharge rates (Chaudry et al. 1991; McArdle 1984; Sanders and Howard 1986; Schiller and Stalberg 1978; Schwartz and Stalberg 1978; Swift 1981). In amyotrophic lateral sclerosis (ALS), jitter increases with HFS probably secondary to ineffective conduction along immature nerve sprouts or exhaustion of acetylcholine (ACh) stores at higher stimulation rates (Miller 1984; Stalberg 1982; Stalberg et al. 1975; Swift and Greenberg 1984).

To determine the possible etiology of the neuromuscular junction transmission defects in patients with past poliomyelitis, we studied the response of jitter to different stimulation frequencies in 17 fatigued post-polio patients and in 9 normal controls. The technique of stimulation SFEMG (Jabre et al. 1989;

Trontelj et al. 1986) was used for this study because it allows distal motor nerve depolarization and muscle fiber activation by a stimulating needle electrode at a constant stimulation frequency determined by the electromyographer.

Materials and methods

Patients and controls

All post-poliomyelitis patients were evaluated with a standard history and physical examination (Cashman et al. 1987). Data obtained in all patients and used in further analyses included present age, sex, age at time of acute polio, time since acute polio, duration of new symptoms, and presence of other difficulties (new weakness and pain), in addition to fatigue. An index of initial polio severity, a fatigue index, the Barthel ADL index (Granger 1982), and a mobility index were also computed for each patient. A modified Klingman initial polio severity index was used (Klingman et al. 1988). A score from 0 to 6 was obtained on each patient. 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. The subjective Hare fatigue scale (Hare et al. 1985) was used to measure fatigue. This is a 0 to 4 scale where 0 represents no symptoms from fatigue, 1 is mild, 2 is moderate, 3 is severe, and 4 is unbearable symptoms from fatigue. A modified Klingman mobility index (Klingman et al. 1988) with possible scores ranging from 0 to 6 was also used. Zero 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, wheelchair-bound (manual), 5 is non-ambulatory, wheelchair-bound (electric), and 6 is bedridden.

All 17 patients provided a history consistent with prior paralytic poliomyelitis, followed by recovery, and at least 25 years of functional stability. All patients presented with complaints of new muscle fatiguability, defined as increased weakness on exertion, improving with rest. Other complaints included increased weakness in 14 patients, and pain in 12 patients. No patient had concurrent medical or neurological disorders which could have interfered with the results of the electrophysiological evaluation. Age range was 33 to 69 years, with a mean of 52 years. Nine normal controls, without known neurological or medical disorders were also studied. Age range was 30 to 37 years, with a mean of 33 years. All patients and controls provided informed consent for participation in the study.

SFEMG studies

Muscles examined in patients had been previously affected by acute paralytic poliomyelitis, and were present in an extremity where the patient reported new muscle fatiguability. All muscles studied in PPS patients with stimulation SFEMG showed evidence of impairment of neuromuscular transmission. These muscles had increased jitter in at least 2 out of 20 or fewer muscle fibers sampled by conventional SFEMG, in comparison to the published limits for normal (Stalberg and Trontelj 1979). The muscles studied in patients included the vastus medialis (15 patients), biceps (1 patient), and extensor digitorum communis (1 patient), whereas muscles studied in controls were the vastus medialis (4 subjects), and extensor digitorum communis (5 subjects). The data obtained from the one patient studied in the biceps muscle was pooled with data obtained from subjects studied in the extensor digitorum communis muscle in the appropriate analyses.

All 17 patients and 9 normal controls were studied with stimulation SFEMG, an electrophysiological technique similar to conventional SFEMG, which differs in the manner of muscle fiber activation. Both techniques permit the measurement of jitter and blocking. In conventional SFEMG, jitter is the variability in the time of firing of two muscle fibers when both are being repetitively activated by the same motor neuron. An increase in normal jitter occurs with abnormalities in terminal axonal impulse propagation, in the neuromuscular junction, and in the motor end-plate. When the abnormality at any one of these sites is more severe, actual transmission failure or blocking can occur (Stalberg and Trontelj 1979). During

stimulation SFEMG, muscle fiber activation is produced by electrical stimulation of the axon terminal with a monopolar needle electrode, whereas during conventional SFEMG, muscle fiber activation occurs voluntarily by the patient. Because of this, jitter values obtained with stimulation SFEMG reflect the neuromuscular transmission of only 1 muscle fiber, rather than 2, and for this reason they are lower than those obtained by conventional SFEMG (Jabre et al. 1989; Trontelj et al. 1986). On stimulation SFEMG, jitter and blocking can be measured at constant, predetermined stimulation frequencies. In contrast, during conventional SFEMG muscle fiber activation occurs at variable stimulation frequencies since stimulation is under the voluntary control of the patient.

Stimulation SFEMG was performed in a manner similar to previously published reports (Jabre et al. 1989; Trontelj et al. 1986). The motor point of the muscle studied was located with a surface stimulating electrode by finding the area of the muscle over which stimulation produced the greatest muscular contraction with the least voltage. Muscle fiber activation was produced by a rectangular pulse of 0.05 msec duration with a pair of monopolar electrodes, one placed near the motor point and the other subcutaneously, a few centimeters away. The current was adjusted to obtain the greatest twitch at the lowest stimulus intensity. A 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 less than 300 µsec and an amplitude of greater than 200 µV. To assure suprathreshold stimulation (and thus avoid false “stimulus-jitter”), the voltage was raised gradually to confirm steadiness of the amplitude and shape of the muscle fiber potential from one stimulus to the next. Jitter was automatically 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 prevent the use of fibers activated by direct muscle fiber stimulation (and thus bypassing the nerve and the neuromuscular junction), muscle fibers with jitter values of 5 µsec or less were not utilized in the analyses. A stimulation frequency of 10 Hz was used while searching for appropriate fibers to study. Once an appropriate fiber was located, jitter values were obtained at stimulation frequencies of 1, 5, 10, 15, and 20 Hz in each single muscle fiber. Inclusion criteria for selection of muscle fibers 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 difficulties in following them for the length of time necessary for the study. Because the fibers selected had little if any blocking, we were unable to assess the effect of stimulation frequency on blocking. Despite these precautions, we were unable to obtain jitter values at all 5 stimulation frequencies for all fibers identified. Therefore, only those fibers for which jitter values were available at 4 or 5 stimulation frequencies were utilized for further analyses. Data on 2 to 10 muscle fibers each studied at 4 to 5 stimulation frequencies was obtained on all patients and controls.

Statistical analysis

Neuromuscular transmission as measured by jitter was compared between PPS patients and controls at each of 5 stimulation frequencies in 2 separate muscle groups (quadriceps, biceps and extensor digitorum communis) with the unpaired t-test. The unpaired t-test was also used to compare mean jitter at low (1 and 5 Hz) and high (10, 15, 20 Hz) stimulation frequencies for each subject, to compare mean jitter at 1 Hz in those patients with and without increased jitter with HFS, and to compare mean jitter (calculated from average jitter at each stimulation frequency for each patient) at low and high frequency stimulation for all PPS patients and all controls. The non-parametric Mann-Whitney U-test was utilized to compare data from ordinal measurement scales between groups of patients. Fisher’s exact test was utilized to compare proportions of patients. Statistical significance was accepted at P < 0.05.

Results

We studied neuromuscular junction transmission by SFEMG in PPS patients and in normal controls. Jitter was measured by stimulation SFEMG at 5 stimulation frequencies in 2-10 muscle fibers in 17 post-polio patients with muscle fatiguability, and in 9 normal controls. Jitter was significantly higher in PPS muscle fibers than in normal controls at all 5 stimulation frequencies in the 2 muscle groups studied, quadriceps and extensor digitorum communis (not shown; Trojan et al. 1993).

The effect of stimulation frequency on neuromuscular transmission in PPS and normal controls was then evaluated. This was done by comparing mean jitter measurements of all fibers (each studied at greater than or equal to 4 stimulation frequencies) at low frequency (1, 5 Hz) and high frequency (10, 15, 20 Hz) stimulation in each patient and control. The data are presented in Table 1. We found that in 5 of 17 PPS patients and in 1 of 9 controls, jitter was significantly higher at high stimulation frequencies (10, 15, 20 Hz) than at low stimulation frequencies (1, 5 Hz) (unpaired t-test, P < 0.05). Fig. 1 illustrates the marked increase in jitter observed with increasing stimulation frequency in the 10 muscle fibers studied in 1 patient. In the remaining 12 PPS patients and in 8 controls, there was no significant difference in jitter at high and low stimulation frequencies. A representative jitter response at different stimulation frequencies in a normal control is illustrated in Fig. 2. The actual data for the patients presented in Figs. 1 and 2 are displayed in Table 2. The effect of baseline jitter (at 1 Hz) on jitter response to HFS was also assessed. There was no significant difference in mean jitter at 1 Hz between groups of patients with and without increased jitter with HFS (28.79 ± 17.79 µsec (n = 24) and 35.73 ± 28.26 µsec (n = 43), respectively).

Fig. 1. Increase in jitter with increased stimulation frequency in 10 quadriceps

muscle fibers of a PPS patient. Jitter (mean ± SEM) for each of 5 stimulation

frequencies is illustrated. Mean jitter at high frequency stimulation (81.9 ±

27.0 µsec, mean ± SD) was significantly higher (P < 0.001) than mean jitter

at low frequency stimulation (39.9 ± 22.5 µsec).

We also analyzed the effect of stimulation frequency on neuromuscular transmission on pooled data from all patients and all controls. Mean jitter (obtained from average jitter for each stimulation frequency for each subject) at low and high frequency stimulation was compared for all PPS patients and all controls. Despite the fact than only approximately 1/3 of PPS patients displayed significantly increased jitter on HFS, a significant difference was found between low and high frequency stimulation for all PPS patients (37.07 ± 16.53 µsec at low frequency stimulation, 48.58 ± 19.61 µsec at high frequency stimulation; P < 0.006), but not in all normal controls (18.39 ± 5.72 µsec at low frequency stimulation, 21.65 ± 7.25 µsec at high frequency stimulation; P = 0.1170).

To evaluate the clinical significance of this neuromuscular junction response to HFS in a proportion of PPS patients, clinical data from patients with significantly higher jitter at HFS was compared with that from patients who had no difference in jitter at low and high stimulation frequencies. There were no

significant differences between these two groups of patients with respect to age at study, sex, age at acute polio, severity of acute polio, duration of new symptoms, fatigue index, Barthel ADL index, or mobility index. However, a significant difference was noted with the variable of time since acute polio. Patients who had increased jitter at HFS had a significantly longer time since acute polio than patients without this electromyographic finding (P < 0.05). A summary of the clinical data is presented in Table 3.

Fig. 2. Jitter response to increased stimulation frequency in 5 quadriceps

muscle fibers of a normal control. Jitter (mean ± SEM) for each of 5

stimulation frequencies is illustrated. There was no significant difference

between mean jitter at high frequency stimulation (15.1 ± 4.43 µsec, mean ±

14. SD) than at low frequency stimulation (14.4 ± 5.38 µsec).

Low frequency = 1, 5 Hertz (Hz) stimulation; High frequency = 10, 15, 20 Hz stimulation; SD =

standard deviation; Mean values are average jitter measurements obtained in individual muscle fibers (each studied at greater than or equal to 4 stimulation frequencies) at low and high frequency stimulation. Jitter is measured as the mean consecutive difference (MCD) of latency of the stimulation artifact to the depolarization of the muscle fiber being studied in µsec; P-value = two-tailed P-value for unpaired t-statistic for difference between jitter means at high and low frequency stimulation.

Discussion

We have confirmed the presence of neuromuscular junction transmission defects in patients with a history of antecedent paralytic poliomyelitis by stimulation SFEMG. Significantly increased jitter was present in PPS patients as compared to normal controls at all 5 stimulation frequencies studied. We have also found that in a proportion of fatigued post-polio patients (approximately 1/3) jitter can increase with HFS. This

finding was observed in only 1 normal control, and may thus provide further evidence for a defect in neuromuscular transmission in post-polio patients. The fact that patients with this finding were characterized by a significantly greater time since acute polio may indicate that this defect evolves over time after acute paralytic polio.

Increased jitter on SFEMG or stimulation SFEMG can be indicative of a neuromuscular junction transmission defect (Stalberg and Trontelj 1979). The finding of increased jitter in disorders such as myasthenic syndrome, botulism, ALS, myasthenia gravis (MG), and PPS can be due to a variety of either pre-synaptic or post-synaptic abnormalities of the neuromuscular junction. However, jitter can respond differently to HFS in disorders of the neuromuscular junction. In myasthenic syndrome, a reduced number of functional voltage-gated calcium channels is present, secondary to antibodies directed against calcium channels at motor nerve terminals (Vincent et al. 1989). In botulism, the primary defect is an abnormality in the ACh release process, due to reduced sensitivity of vesicles to calcium-triggered exocytosis (Cull Candy et al. 1976; Howard and Gundersen 1980; Kao et al. 1976; Schiavo et al. 1992; Simpson 1986; Swift and Greenberg 1984). In both myasthenic syndrome and botulism, jitter can decrease with HFS (Chaudry et al. 1991; Schiller and Stalberg 1978; Schwartz and Stalberg 1978) presumably because of summation of calcium transients in the nerve terminal (Sanders and Howard 1986; McArdle 1984; Swift 1981). HFS may thus partially correct the pre-synaptic defect present in these two disorders. In ALS, the neuromuscular defect may be due to the presence of immature axonal sprouts or to limitations in quantal number or content of ACh vesicles at motor neuron terminals (Stalberg et al. 1975; Swift and Greenberg 1984). Jitter has been observed to increase with HFS in ALS probably as a result of ineffective conduction along immature terminal nerve sprouts or depletion of available ACh stores at rapid rates of stimulation (Miller 1984; Stalberg 1982; Stalberg et al. 1975; Swift and Greenberg 1984).

Several mechanisms might be applicable to neuromuscular junction transmission defects in patients with past poliomyelitis. The recovery process after acute paralytic poliomyelitis is characterized by reinnervation by axonal sprouting (Coers and Woolf 1959; Wiechers 1988; Wiechers and Hubbell 1981), a process which can enlarge motor units to 7 times normal size by pathological criteria (Coers and Woolf 1959). Electrophysiological studies in patients with antecedent paralytic poliomyelitis suggest that the

grossly enlarged post-polio motor unit is undergoing continuous remodeling, or ongoing denervation and reinnervation. In addition, electron microscopic, light microscopic, and in vitro microelectrode studies of motor nerve terminals in post-polio patients have shown abnormalities involving the pre-synaptic region

of the neuromuscular junction, which are consistent with reinnervation and denervation (Maselli et al. 1992). Thus, immature sprouts may be present at all stages after paralytic polio (Cashman et al. 1987, 1991; Lange et al. 1989; Wiechers 1988; Wiechers and Hubbell 1981). Immature nerve terminals have

been found to release smaller amounts of ACh in experimental studies (Swift and Greenberg 1984), and also exhibit abnormal transmission properties, which would certainly contribute to neuromuscular junction transmission defects. Microelectrode studies performed in two symptomatic post-polio patients were suggestive of a reduction in quanta available for immediate release at the motor nerve terminal, and a reduction in the average endplate potential quantal content (Maselli et al. 1992). Thus, massively sprouted post-polio motor neurons may be unable to provide normal quantities of ACh at nerve terminals through a variety of mechanisms. Our findings of increased jitter with HFS in approximately 1/3 of PPS patients, and significantly increased jitter with HFS in the entire population of PPS patients and not in normal controls, indicates that of presynaptic disorders, the neuromuscular defect in patients with past poliomyelitis is most similar to ALS. In addition, because jitter response to HFS in patients with antecedent paralytic polio differs from that in myasthenic syndrome and botulism, defective calcium influx is unlikely to account for impaired release of ACh in post-polio motor units. We have also found that increased jitter with HFS within a particular patient is a later phenomenon, suggesting that this finding may be due to acquired, late factors other than remodeling of enlarged motor units, which occurs at all stages after polio. Thus, a new, unknown, superimposed abnormality in the post-polio motor unit may be present which could account for our observations.

The reason why only certain post-polio patients with muscle fatiguability were found to have increased jitter with HFS and why one normal control also displayed this phenomenon is speculative. To our knowledge, the response of jitter to stimulation frequency in normal controls has never been published. Because an increase in jitter with HFS was found in only one control, further studies are indicated in normals prior to drawing any conclusions. There may be several reasons for the finding of increased jitter with HFS in only 1/3 of PPS patients. First, because the occurrence of this phenomenon was found to be related to time after polio, its absence in a proportion of PPS patients may simply be due to an inadequate length of time after the acute illness. In addition, we studied only limited numbers of fibers and only one muscle in each patient. A more thorough examination may have resulted in the identification of this phenomenon in a greater number of patients. Because this study did not include stable post-polio patients, it is not known whether stimulation frequency-dependent neuromuscular junction transmission defects are specific for PPS, or whether they occur after poliomyelitis which is not complicated by new symptoms. Clearly, further study as to the nature, location, and clinical significance of the neuromuscular defects in post- polio patients is indicated.

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 EMG technicians Lora Tombari and Susan Murray for their expert technical assistance, to the reviewers for constructive criticism, and to the patients who participated in the study.

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