A Long Term Follow up Study of Patients with Post Poliomyelitis Neuromuscular Symptoms
A LONG-TERM FOLLOW-UP STUDY OF PATIENTS WITH POST-POLIOMYELITIS NEUROMUSCULAR SYMPTOMS
MARINOS C. DALAKAS, GREGORY ELDER, MARK HALLETT. JOHN RAVITS, MICHAEL BAKER, NICHOLAS PAPADOPOULOS, PAUL ALBRECHT, AND JOHN SEVER Abstract A “post-polio” syndrome characterized by new from 1 to 10 years. None of the patients had amyotrophic neuromuscular symptoms, including muscle weakness, lateral sclerosis. Oligoclonal bands (IgG) were found in may develop years after recovery from acute paralytic po- the cerebrospinal fluid of 7 of 13 patients studied, but liomyelitis. We studied 27 patients (mean age, 50.6 years) no specific elevation of antibodies to poliovirus was in whom new muscle weakness developed a mean of 28.8 observed in the cerebrospinal fluid. The newly affected years after recovery from acute polio. We reevaluated muscles that were evaluated longitudinally with follow-up these patients during a mean follow-up period of 8.2 years muscle biopsies and electromyography showed signs of (range, 4.5 to 20) after they were originally studied at the chronic and new denervation. Groups of atrophic muscle National Institutes of Health. The total mean follow-up pe- fibers (group atrophy) and “neurogenic jitter” were not riod after the onset of new weakness was 12.2 years present. (range, 6 to 29). The patients were assessed with quanti- New post-polio muscle weakness is not a life-threaten tative muscle testing, muscle biopsy, electromyography, ing form of motor-neuron deterioration. It appears that this and virologic and immunologic examination of the cere- weakness is not due to a loss of whoie motor neurons, as brospinal fluid.
in amyotrophic lateral scierosis, but that it is due to a dys Muscle strength had declined in all patients. The rate of function of the surviving motor neurons that causes a slow decline averaged 1 percent per year. The decrease was disintegration of the terminals of individual nerve axons. irregular, with subjective plateau periods that ranged (N Engl J Med 1986; 314:959-63.) iologic, single-fiber electromyographic, and muscle biopsy studies. Virologic and immunologic investiga tions of the serum and cerebrospinal fluid were also conducted.
METHODS
Patient Selection
MUCH anxiety has arisen among the estimated IV 300,000 survivors of polio in the United States because (* recent reports about a new muscular weak ness, often called the “post-polio syndrome,” that de velops in some of these persons. It is known that some people may experience new neuromuscular symptoms many years after their recovery from acute paralytic poliomyelitis.2-8 These symptoms vary from simple nonprogressive deterioration of function, with joint pain, fatigue, and subsequent stabilization, 46 to atypi cal forms of spinal muscular atrophy2,3 or to what appears to be a form- fruste of amyotrophic lateral sclerosis (ALS) 2.0,1. The new, slowly progressive muscle weakness, which we have termed “progressive post-poliomyelitis m»scular atrophy (PPMA),47 may occur in lauscles that were previously affected by polio and recovered or in muscles hat were clinically un affected by ho acute liseas. The cause and rate of progression of PPMA, the future anticipated dis ability, and the ink of ALS (which has been reported in smail series) 9,10 mong patients with the disorder are unknown.
In an attemp to answer some of these questions, we reevaluated 2 Patients who had recovered from polio and who were nically admitted to the National Institutes of Health’ in 1960 to 1981 because of PPMA that was diagnosed by complete neurologic and electro physiologic examinations and studied by means of scie biopsies and analyses of the spinal fiuid. In this article, we report our findings in the same group of patients after 2 mean , w-up period of 8.2 years (range, 1.5 to 20). The patients were evaluated with a follow-up series of neurologic, electrophys
All patients, who were studied after giving informed consent, had a history of acute paralytic poliomyelitis in childhood ) adoles cence. This was established by a careful review of records to document as well as possible the clinical occurrence of an acute febrile illness followed by paralysis. We checked ur neighborhood or school epidemics, and we selected patients wr were affected in the United States, particularly during the late ‘ epidemics, when the diagnosis of poliomyelitis was probably made with more accuracy. All patients were referred to the National In-itute of Neurological and Communicative Disorders and Stroke by their private physi cians because they had begun to experience new muscle weakness. The patients enrolled in the study fulfilled the follow ig criteria: they had partial recovery of motor junction aftu, polio and function al stability or recovery for at least 15 yea, they had residual muscle atrophy, weakness, and arerlexia ia at luust one limb but with nor mai sensation; and they had new muscle wea mess and neuromuscu lar symptoms that were unrelated to any otac neurologic or medi cal disorder. Patients with symptom, duc to injury, compression neuropathy from the use of crutches. Wheelchairs, or radiculop athies during the initial evaluation o ne loilow-up visits were ex cluded. Patients were also excluded they had diabetes, polyneu ropathy, collagen vascular disease, expo…re to toxic agents, other major viral illnesses, or a family history of neuromuscular disease. Only patients who were less than 60 years old at the initial visit (mean age, 42.7; range, 24 to 59) were entered in the study. This was done to excluic patients who were subject to a loss of motor neurons due to rmai aging. Ultimately, 15 men and 12 women were included in the investigation.
Neuromuscuiar Evaluation and Laboratory Studies
From the National Institute of Neurological and Communicative Disorders and Stroke. Varonai Insurutes of Health, Bethesda, Md. Address corint scuests to Dr. Dalakas ar Bldg. 36, Rm. 5D06, VIH, NINCDS, Bethesda, MD
0892.
All patients were given neurologic examinations by several neu rologists from the institutes; specific attention was paid to neuro muscular function and quantitation of the patients’ muscle strength in relation to the scale developed by the Medical Research Coun cil. Evaluations performed during both the initial and follow-up emissions to the National Institutes of Health included a compiere
Reprinted from the New Englund Journal of Medicine
314:959-963 (Avni 10), 1986
blood count, blood chemistry and cerebrospinal fluid analyses, as sessment of serum muscle enzymes, creatine kinase, aspartate aminotransferase, and alanine aminotransferase, electromyogra phy, nerve-conduction studies, and open-muscle biopsy of a speci men from one of the currently affected muscles.
The muscle biopsy specimens were processed for histochemical analyses of muscle enzymes.”? During the follow-up admission, six patients were also tested with single-fiber electromyography that used standard techniques. 13 These data were analyzed for fiber den sity, which is the average number of muscle fibers recorded by the needle during a single placement; jitter, which is the mean consecu tive difference in the intervals between the activation of two muscle fibers in the same motor unit; blocking, the failure of a muscle fiber to activate when its motor unit is activated; and neurogenic jitter, a synchronous variation of at least two muscle fibers with respect to a third that must be due to an abnormality of the nerve rather than the neuromuscular junction. In the follow-up visits, serum and cere brospinal Auid from 13 patients were tested for oligoclonal bands with immunofixation, as previously described, 14,15 and for viral antibodies to measles and to poliomyelitis virus type 1 (Maloney strain), type 2 (mouse-embryo fibroblast strains), and type 3 (San kett strain), with a neutralizing antibody assay and with an enzyme linked immunosorbent assayi6 (and Dalakas MC: unpublished data). The extent of production of poliovirus antibody inside the blood-brain barrier was determined by making a correction for the permeability of the blood-brain barrier by use of the ratio between the cerebrospinal fluid and the serum albumin level.”
Neuromuscular Quantitation of Strength
The patients’ own descriptions of the functional decline in their muscle strength were recorded. We also used an objective quantita tive assessment of the newly developed muscle weakness in order to establish the degree of progression of that weakness. Because the initial quantitative muscle testing of patients with PPMA was based on the Medical Research Council rating, we used the same Medi cal Research Council scale during our follow-up evaluation to esti mate the degree of decline in the strength of the affected muscles. Since almost all the patients had a residual asymmetric weakness from the attack of polio years earlier and PPMA is predominantly a focal condition involving the muscle groups of one or two extrem ities, +7 we needed a formula that would allow quantitative determi nation of the changes in the function of all four extremities, based on the Medical Research Council rating for each muscle group in each limb. For this reason, we considered the total normal strength. of the four limbs as 100 points of neuromuscular function and assigned 25 of those points to each of the four extremities. These 25 points were equally distributed among five major muscle groups (e.g., in the leg, 5 points each were assigned to the foot extensors, foot flexors, knee extensors, knee flexors, and hip flexors and exten sors). Five points of neuromuscular function of each of the ma or muscie groups corresponded to a “5” (normal) rating on the Mecim cal Research Council scale.” Weaker muscle groups that rated 4, 3 2, 1, and 0 on the scale received 4, 3, 2, 1, and 0 points, respectively. These calculations provided an automatic estimate of the cumula tive total strength of every limb. The points for the total strength that remained at the initial and subsequent follow-up visits were plotted against the age of the pauent at those visits, as shown in Figure 1 for the 12 patients with the longest follow-up period (aver age, 11.6 years).
ciculations were noted in all patients, even in muscles that did not appear to have become weaker.
At the reexaminations at the end of the follow-up period (average, 8.2 years; range, 4.5 to 20), the mean age of the patients was 50.5 years (range, 36 to 69); the mean age at which their new symptoms began was 39.6 (range, 25 to 56); and the mean number of years after acute polio when those symptoms began was 28.8 (range, 15 to 54).
All patients were weaker and had a much lower level of function. The pace of worsening during the period between the first and latest neurologic exami nation was very slow and varied from patient to pa tient and within individual patients. Some patients had a stepwise progression of weakness, with subse quent relative stability, whereas others had a slow, continuous decline in strength. Figure 1 depicts the progression of weakness in the 12 patients who had the longest mean follow-up times in the study (11.6 years; range, 6 to 20). In four of these patients (No. 5, 6, 8, and 9), the new muscle weakness had increased but remained almost completely confined to the same muscles that had appeared to be weaker during the initial examination; in three others (No. 1, 2, and 12), new weakness had appeared in additional muscle groups. Three patients (No. 7, 10, and 11) who had a more severe residual disability in one or more groups of muscles from the original disease had increased weakness in all the other muscie groups, and although the new decline in strength w s mild within each mus cle group, the cumulative effect on the patients’ overall neuromuscular function was considerable, and they had become severely disabled. In fact, all three were using electric wheelchairs, whereas 10 years earlier, they had required only crutches. The remain ing two patients (No. 3 and 4), who were followed for 13 and 11 years, respectively, felt a very slight new generalized weakness, which did not substantially alter their life styles or interfere with their everyday activities.
The mean total estimated loss of neuromuscular function for the 12 patients with the longest follow-up was 11.8 points (range, 7.5 to 17.5); for the other 15 patients (mean follow-up, 4.7 years, the mean loss was 4.1 points (range, 2.2 to 6.3). However, the mean cal culated total yearly loss was identical in both groups
– i.e., 1.05 points of muscie strength range, 0.7 to 2.5). Generaily, the new weakness was so mild that it often could not be appreciated on a year-to-year basis; the patients experienced it over a longer period (mean, 3 years; range, 1 to 10).
None of the 27 patients had ALS, which is uefined as new, rapidly progressive, generalized muscle weak ness and wasting and the presence of upper motor neuron signs, bulbar signs, or respiratory difficulties. The age of onset of new symptoms, the sex of the patient, and the degree and type of physical activities of each patient berore the manirestation of the new weakness were not factors in the progression of the veakness. II anden van eminta uave, with rea
RESULTS Clinical Evaluation
All patients had PPMA, as previously defined, *-7 with new muscle weakness and atrophy involving ei ther the muscles that had been previously affected and had fully or partly recovered or muscies that were clinically unaffected by the original disease. In all pa tients, the new weakness was asymmetrical and was often associated with increasing muscular atrophy. Some patients averiancer mungias.
Figure 1. Progression of Muscle Weakness in 12 Patients with Post-Poliomyelitis Muscular Atrophy, Expressed as Total Points of
Estimated Neuromuscular Function at Various Years of Age. Numbers on the left refer to individual patients. Points of muscular function (100 points is the normal strength in all four limbs) are on the ordinate. The continuous line represents the patients’ course after the attack of acute polio and their progressive partial recovery with subsequent long stabilization, as determined from intormation provided by the patient or early records. The interrupted line represents the course of new muscle weakness from onset until the latest follow-up evaluation. Arrows with the year in parentheses represent the time of the acute poiio attack (first arrow), the time of the first examination after the manifestation of new weakness second arrow), and subsequent examinations (third or fourth arrow). The sharp angulations in many of the curves are due to the subjective data on neuromuscular function provided by the patient. A decline in muscular strength that was either continuous or that occurred in a stepwise
fashion took place in all 12 patients between the first and last evaluations (mean follow-up period, 11.6 years).
sonable use of their unaffected muscles. No overexer tion or inactivity was reported. Laboratory, Electromyography, and Muscle Biopsy Findings
The results of blood chemistry evaluations and complete blood counts were normal in all the patients. Four patients had levels of creatine kinase that were up to three times the normal value. Electroneuro graphic studies during the initial and follow-up visits revealed normai motor and sensory conduction veloci ties and accon-potential amplitudes. Repetitive-stim ulation studies of the ulnar nerve and (occasionally) of the axillary nerve in six patients showed no patho logical decrenent at 4. Hz and no pathological incre ment är 50 Hz. Electromyographic studies showed widespread chronic denervation with large-amplitude voluntary motor units (up to 25 mV) in aimost all muscles studied. Chronic denervation was observed even in muscies that were apparently not involved in the original attack of polio. Fibrillation and positive sharp waves were seen in sparse to moderate amounts in many muscles, bur the presence of hese indings did not correlate in an obvious fashion with the recent deterioration. Fasciculations were seen in many on the patients, but the discharge frequency was very low (less than one per minute). The single-iber zlectro myographic studies carried out in six pacients during their follow-up visits showed an increase in liber densi cy and many fiber clusters groups or aree r more fibers with maii cime differences nat nade ormai
jitter analysis impossible). Increased jitter and block ing were seen in most muscles, and the amount of jitter and blocking appeared to correlate with the de gree of recent deterioration. Neurogenic jitter was not observed.
Muscle biopsy studies of previously recovered and newly affected muscles (performed twice in eight pa tients, during the initial and follow-up visits) con firmed the presence of reinner ation, which was indi cated by the formation of large groups that contained both type I and type II fibers, 10 In addition, all the biopsy specimens showed several isolated, atrophic, angulated fibers compressed in the interstices between large fibers (Fig. 2). These small fibers, which stained darkly with an enzymatic reaction, are characteristic of new active denervation 12 The fibers remained iso lated and scattered randomnly throughout the collow up period. No clusters of atrophic fibers (group atro phy) were observed, even in the muscles subjected to two biopsy evaluations. This is in contrast to the findings in the weakening muscles of patients with ALS, in which the atrophic fibers always form groups (group atrophy), and the number of atrophic ibers in the groups increases rapidly until the whole fascicie is atrophies, thereby reflecting the death of wnole neurons. 2.
In 12 of 27 biopsy specimens (including those from muscles thar had two assessments), occasional smail perimvsiai or perivascular iymonocrc nol crates were ooserved, as in earlier studies. *) in two
Figure 2. Transverse Frozen Section of a Muscle Biopsy Speci
men from Patient No. 2. Note the scattered small, angulated fibers with the dark stain (arrowheads). There are no groups of atrophic fibers (indicative of loss of the whole motor unit). The same type of change, but in a milder degree, was noted in the same muscle of the same patient during a biopsy examination 12 years earlier, when the muscle was slightly stronger. Staining was with a nonspecific esterase
histochemical reaction (x125).
patients (No. 5 and 7),” the degree of lymphocytic response was more prominent, prompting a therapeu-. tic trial with 100 mg of prednisone; however, tiie therapy was unsuccessful.
Spinai Fluid Studies
In confirmation of the earlier findings in a smaller series of patients with PPMA,*,5 7 of the 13 patients in our study whose cerebrospinal fluid was examined had two to four oligoclonal bands in that fluid. An immunofixation assay showed that the bands were IgG. The total IgG, the IgG index, and the IgG syn thesis’s in the cerebrospinal fluid were normal. No bands were found in the serum. The calculated ratios of cerebrospinal fluid to serum antibody titers to po liomyelitis and measles virus (for control) were nor mal, 17 indicating that there was no in situ antibody production to poliovirus.
DISCUSSION A reevaluation of 27 patients with PPMA after a mean follow-up period of 3.2 years from the time they were first seen at the Vational Institutes of Health showed that their muscular weakness had progressed. However, the degree or decline of their neuromuscular function was slow, predominantly focal, and minimai (about 1 point of the total 100 points of muscle strength per year), and it was not life-threatening. Progression varied from patient to patient and within individual patients, who often had long periods of sub jective stability. New weakness was not objectively ad preciable on a year-to-year basis. The overall progres sion, although minimal, had a substantial efect on neuromuscular function in patients in whom poiio had caused severe disability and limited muscle reserves
– i.e., pacients who at best were functioning at or below 50 percent of their total strength. Contrary to prerious asorts hat !LS or an ILS-ke ticorrer
occurs more frequently in persons who have had po lio,9,10 none of the 27 patients in our study, who were followed for a mean of 8.2 years (range, 4.5 to 20) from the time they were originally examined and up to 12.2 years (range, 6 to 29) from the onset of their new weakness, were found to have ALS, as indicated by generalized muscle weakness and wasting and respira tory, bulbar, or upper-motor-neuron signs. Similarly, none of a recent group of 11 persons who had recov ered from polio and who had been referred to the Na tional Institutes of Health because of new weakness had ALS (Dalakas MC: unpublished data).
Although PPMA appears to be a disorder of the motor neuron, its pathophysiologic aspects differ in a number of ways from those of ALS, the archetypal disorder of motor neurons. Clinically, PPMA is pre dominantly focal and always progresses slowly, with out producing upper-motor-neuron signs or involve ment of bulbar muscles. In biopsy specimens of newly weakened muscles of patients with PPMA, the dener vation is characterized by a few single scattered, angu lated fibers (Fig. 2) and by fiber-type grouping, rather than by the atrophic muscle fibers that form in groups (group atrophy) because of the death of the whole motor neuron that are typically seen in the weakened muscles of patients with ALS.12 This observation on the type of denervation was reinforced by follow-up muscle biopsics in eight of our patients, which indicat ed that even though the patients had a mild but pro gressive weakness for a mean of 11.6 years, the weak muscles did not show group atrophy. ALS is caused by the death of anterior horn cells. In contrast, it would be reasonable to assume that PPMA is caused by the death of individual nerve terminals in the motor units that remain after polio, rather than the death of the whole unit. This would explain most of the clinical, physiologic, and histochemical features of the syn drome. As each terminal dies, the weakness progresses slowly. Regeneration proceeds muscle fiber by muscle fiber, and there is no opportunity to form new groups of fibers. This theory is supported by the presence of single scattered, angulated fibers in the muscle biopsy specimens (without group atrophy) (Fig. 2) and the observation by means of singie-fiber electromyog raphy that there is no “neurogenic jitter.” In single Gber electromyography, increased jitter can be due to instability at the neuromuscular junction or at the brancn points of axons. Newly regenerated axons may show instability at the points of the axon branches during active reinnerration. Neurogenic jitter, which
s characterized by groups of action potentials that jitter together, can be seen in patients with ALS. Its absence in our patients with PPMA supports the ob servation that there is a lack of reinnervation of groups.
Deterioration or individual nerve terminais in PPMA night be an outcome of the process of recovery from an icure attack of polio. After such an attack, the turverint moror neurons sprout to reinner rate more
bers 2007ai. This process prouuces
bands were found in the cerebrospinal fluid of six asymptomatic persons who were examined 3 to 20 years after an initial attack of polio (Dalakas MC, et al.: unpublished data).
REFERENCES
large motor units that may stress the cell body. After a number of years, these hyperfunctioning motor neurons (with their excessive sprouting) may not be able to maintain the metabolic demands of all their sprouts, and a slow deterioration of the individ ual terminals may result, as previously speculated. 18 Some individual fibers may be able to be reinnervated a second time, but eventually enough nerve terminals are destroyed and enough reserves are diminished for weakness to appear. This would be consistent with the focal nature of PPMA and its very slow, stepwise, unpredictable progression. Normal aging alone can not be responsible for this process, since neuronal loss does not occur in persons younger than 60,” and mus cle biopsy specimens from normal persons who are younger than 70 rarely show small scattered, angulat ed fibers20 (and Dalakas MC, Cutler NA: unpublished data). For these reasons, our study included only pa tients who were younger than 60 at the time of their first symptoms of PPMA (mean age, 39.6 years; range, 25 to 56). Furthermore, with the Medical Research Council scale we employed,” the muscle strength was standardized so that the grades of weak ness did not change with normal aging. 11 At this time, the frequency and the possible risk factors of PPMA among polio survivors are unknown.
The roles of virologic or immunologic mechanisms in the development of PPMA are unclear. The lym phocytic response in the biopsy specimens (a response that had previously been observed +-7) and the pres ence of oligoclonal bands in the cerebrospinal fluid may suggest immunopathologic mechanisms. Treat ment with prednisone in two patients (No. 5 and 7) and with interferon in another (No. 9)21 failed to im prove muscle strength or change the progression of muscular weakness. Although poliovirus can cause persistent infection in animals22 and in neural tis sues, 23 searches for poliovirus antibodies in the cere brospinal fluid with a neutralizing plaque assay and enzyme-linked immuncsorben: assays (Dalakas MC, Albrecht P: unpublisher observations) have yielded negative results, indicatin that possible reactivation of the poliovirus in patie 113 with PPMA cannot be substantiated with the methods used. The nature of the IgG oligocionai tands in the cerebrospinal fluid is not clear. The possibility that they represent an anti body response – perhaps directed against viral or neuronal proteins – should be studied further. It is especially interesting, however, that no oligocional
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Copyright, 1986, by the Massachusetts Medical Society
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