Original Article
Intrathecal Immune Response in Patients with the Post-Polio Syndrome
N Engl J Med 1991; 325:749-755September 12, 1991
- Abstract
- Abstract
Background.
The syndrome of progressive muscular atrophy decades after acute paralytic poliomyelitis (post-polio syndrome) is not well understood. The theory that physiologic changes and aging cause the new weakness does not explain the immunologic abnormalities reported in some patients. An alternative explanation is persistent or recurrent poliovirus infection.
Methods.
We assessed the intrathecal antibody response to poliovirus and intrathecal production of interleukin-2 and soluble interleukin-2 receptors in 36 patients with the post-polio syndrome and 67 controls (including 13 who had had poliomyelitis but had no new symptoms and 18 with amyotrophic lateral sclerosis). Intrathecal antibody responses to measles, mumps, herpes simplex, and Varicella Zoster viruses were also determined.
Results.
Oligoclonal IgM bands specific to poliovirus were detected in the cerebrospinal fluid of 21 of the 36 patients with the post-polio syndrome (58 percent) but in none of the control group (P<0.0001 ). In quantitative studies there was evidence of increased intrathecal synthesis of IgM antibodies to poliovirus only among the patients with the post-polio syndrome; there was no increased synthesis of IgM to measles, mumps, herpes simplex, or Varicella Zoster viruses. The patients with post-polio syndrome had significantly higher mean (±SD) cerebrospinal fluid levels of interleukin-2 and soluble interleukin-2 receptors than the controls (8.1 ±5.3 vs. 1.4±0.8 U per milliliter and 159.6±102.9 vs. 10.7±6.2 U per milliliter, respectively). The intrathecal synthesis of IgM antibodies to poliovirus correlated with the cerebrospinal fluid concentrations of interleukin-2 (P<0.0005) and soluble interleukin-2 receptors (P<0.001).
Conclusions.
An intrathecal immune response against poliovirus is present in many patients with the post-polio syndrome. In some of these patients the recrudescence of muscle weakness may be caused by persistent or recurrent infection of neural cells with the poliovirus. (N Engl J Med 1991; 325:749–55.)
Media in This Article
Figure 1
Electrophoretic Patterns in Cerebrospinal Fluid from a Patient with the Post-Polio Syndrome (Lanes 1 through 4) and a Control Patient (Lane 0).Figure 2
Cerebrospinal Fluid:Serum Ratios of Antipoliovirus IgM Antibody (•) as Compared with Cerebrospinal Fluid:Serum Ratios of Antimeasles IgM Antibody (○) (as a Control) in Patients with the Post-Polio Syndrome and in the Control Group.Article Activity
- Article
POST-POLIOMYELITIS progressive muscular atrophy (post-polio syndrome)1 2 3 is characterized by new, slowly progressive muscle weakness affecting patients decades after there has been maximal recovery from acute paralytic poliomyelitis. The condition has distinctive clinical features that include muscle weakness and atrophy,3 4 5 muscle pain6 and fasciculations,1 , 2 weakness of bulbar3 or respiratory7 muscles, and sleep apnea.8
Although recurrence of muscle weakness several years after the original attack of acute paralytic poliomyelitis was described as early as 1875,9 , 10 the pathogenesis of post-polio syndrome has not yet been established. Current theory suggests that the illness is caused by attrition of surviving motor neurons, with eventual loss of axonal terminals.3 , 11 , 12 However, immunologic studies have demonstrated various lymphocytic abnormalities and the presence of oligoclonal bands in the cerebrospinal fluid of a substantial number of patients with the post-polio syndrome,1 , 13 , 14 suggesting that immunopathogenic mechanisms may contribute to the pathogenesis of the disease process. Activation of poliovirus may contribute to the development of the syndrome, although searches for poliovirus antibodies in the cerebrospinal fluid have yielded negative results to date.1 , 15 , 16
One way of assessing the role of the immune system in the post-polio syndrome is to detect intrathecally produced specific immunoglobulins and soluble products of immune cells, such as cytokines. An antigenic challenge of the central nervous system, as of any other organ, evokes responses of T and B lymphocytes,17 18 19 20 with production of immunoglobulins and cytokines. Among the various isotypes of immunoglobulins, IgM is of particular importance in the evaluation of viral infections, including those of the central nervous system.21 22 23 IgM is sensitive to minimal antigenic stimulation; has a relatively short half-life, with little if any memory; and has an important role in the clearance of viremia.24 Furthermore, we have demonstrated that intrathecal synthesis of IgM is an indicator of recent antigenic stimulation in the central nervous system25 , 26 and that it is useful in assessing disease activity of inflammatory conditions of the central nervous system.27 , 28 In this study, we examined the intrathecal immune response to poliovirus and local synthesis of interleukin-2 and soluble interleukin-2 receptors by the central nervous system in 36 patients with the post-polio syndrome and 67 control patients.
Methods
Patients
Paired samples of serum and cerebrospinal fluid were obtained simultaneously from all patients after informed consent had been given. Protease inhibitor (aprotinin; 1000 kallikrein units per milliliter) was immediately added to the samples to prevent protein degradation, and the samples were then frozen in aliquots at — 70°C and thawed just before use.
We have adopted strict criteria for diagnosing the post-polio syndrome2 , 3: there must be a clear history of acute paralytic poliomyelitis in childhood or adolescence during a polio epidemic, with functional stability or recovery for at least 15 years; residual muscle atrophy, weakness, and areflexia in at least one limb, with normal sensation and no sign of upper-motor-neuron weakness; new neuromuscular symptoms in the form of progressive muscular atrophy or musculoskeletal symptoms or both; and no clinical evidence of any known medical, neurologic, orthopedic, or psychiatric illness that could account for the new symptoms. Patients with diabetes, polyneuropathies, connective-tissue diseases, back injuries, or compression neuropathies and those with a family history of neuromuscular disorders were excluded. Only patients below the age of 60 years were studied, to avoid nonspecific changes associated with aging.29 Ultimately, 16 men and 20 women were included in the investigation.
Controls
Paired samples of serum and cerebrospinal fluid were collected from 13 control patients matched for age and race who had a history of paralytic poliomyelitis and whose condition had been stable for 19 to 41 years (mean, 29.6) after the original infection. Lumbar puncture was performed in this group to investigate unrelated symptoms, such as tension headache, blurring of vision, or mild psychoneurotic symptoms. Paired samples were also obtained from 18 patients with classic amyotrophic lateral sclerosis and from 36 age-, sex-, and race-matched patients with various other neuromuscular diseases (6 with chronic progressive multiple sclerosis, 4 with Parkinson's disease, 6 with Alzheimer's disease, 6 with cerebrovascular diseases, 6 with spinal-cord compression, 5 with muscular dystrophy, and 3 with myasthenia gravis). Paired samples from 16 normal subjects (9 of whom were female), who presented with mild, nonspecific tension headache or other nonspecific syndromes, were used to determine reference ranges.
Clinical Examples
The following is a brief clinical history of a representative case of post-polio syndrome: a 49-year-old woman who had had paralytic poliomyelitis at the age of 6 presented with slowly progressive muscle weakness. Hospital records of the original attack documented the occurrence of an acute febrile illness followed by generalized asymmetric muscle weakness. Two of her school friends were also affected. The patient improved after intensive rehabilitation, but her right arm and leg remained weaker, thinner, and shorter than her left arm and leg. She functioned well for 37 years, although she had to wear a leg brace. Six years ago, she noticed slowly progressive weakness and wasting of the left arm and leg (she had not had earlier difficulty with this leg) that was accompanied by deep muscle pains and occasional fasciculations of the newly weakened muscles. Progression remained focal, although she had had to use a manual wheelchair for the past year. In addition to the preexisting weakness and wasting, neurologic examination detected moderate weakness and atrophy of the left biceps, hamstring, and iliopsoas muscles, with normal sensation. No upper-motor-neuron signs were noted, and cranial nerves were not involved. Electromyographic studies revealed active denervation (fibrillation and positive sharp waves) in the newly involved muscles, whereas nerve-conduction studies were normal.
The following case history is representative of the control group: a 48-year-old woman had paralytic poliomyelitis at the age of 28 months. Her brother had died of pneumonia after a similar illness at the age of five years. The woman had residual muscle weakness and atrophy of both legs but managed well with leg braces and crutches. During the past nine years, she had had joint pain, unsteady gait, and easy fatigability. She had no new muscle weakness or wasting, however, and examination did not detect new neurologic signs. Her condition stabilized after she reduced her work demands and changed her leg braces.
Determination of Poliovirus Antibodies
AU immunologic and virologic assays were performed on coded samples. Sabin poliovirus types 1, 2, and 3 were grown on monolayers of fetal rhesus monkey—kidney cells (FRhK-4T) and then prepared as described previously.30 Viral antigen for the immunoassay was prepared from a mixture containing equal numbers of the three types of poliovirus. Intrathecal production of poliovirus-specific IgM antibodies was determined by a sensitive capture enzymelinked immunosorbent assay.31 IgM antibody levels to measles, mumps, herpes simplex type 1, and varicella–zoster viruses were also measured by the same immunoassay to serve as controls.
The clonal distribution of intrathecally produced antipoliovirus IgM antibody was identified by affinity immunoblotting32 with minor modifications. Unconcentrated cerebrospinal fluid and adequately diluted homologous serum containing 20 ng of IgM were electrophoresed in agarose gel and the separated proteins were then passively transferred to a polyvinyl difluoride membrane coated with 500 μg of poliovirus antigen per milliliter (1 ml per 10 cm2 of membrane area). The proteins were subsequently cross-linked to the polyvinyl difluoride membrane by glutaraldehyde33 before the oligoclonal IgM bands against poliovirus were specifically stained.33
Assays
Levels of interleukin-2 in cerebrospinal fluid and diluted serum were measured by a capture immunoassay,34 and levels of soluble interleukin-2 receptors were measured by an indirect sandwich immunoassay.35 Oligoclonal IgM bands in the test samples were detected as described previously.33 Isoelectric focusing was used to detect oligoclonal IgG bands, whereas IgA bands were detected by agarose electrophoresis.28 The total IgM concentration was measured by an enzyme immunoassay,36 and then the IgM index37 was calculated to determine the amount of intrathecally synthesized IgM as follows: IgM index = (cerebrospinal fluid IgM × serum albumin)/(serum IgM × cerebrospinal fluid albumin).
Statistical Analysis
Nonparametric Wilcoxon rank-sum, chi-square, and Spearman rank-correlation tests were used, as appropriate, for statistical analysis. Analyses were performed with SPSS/PC+ software. All P values were two-tailed.
Results
Clinical Observations
Muscle weakness in patients with the post-polio syndrome involved either muscles originally affected by polio (18 patients) or muscle groups that had been spared by the original disease (14 patients). Nine patients presented with weakness in previously normal muscle groups that were not segmentally contiguous to the already weak ones. New bulbar, respiratory, or sleep difficulties were noticed only in the four patients who already had residual bulbar or respiratory muscle weakness. The mean (±SD) age of the patients at the time of the acute attack of poliomyelitis was 8.7±5.5 years (range, 5 months to 21.5 years), whereas the mean age at the onset of the post-polio syndrome was 40.2±9.1 years (range, 31.5 to 59).
In most patients the onset of new symptoms was insidious. Symptoms in two patients started after minor accidents involving a limb. Four patients had a definite history of exposure to children with acute poliomyelitis or those who had recently received trivalent poliovirus vaccine a few months (mean, 6.8) before the development of the new symptoms.
Oligoclonal Poliovirus Antibodies
Oligoclonal IgM was the predominant immunoglobulin in the cerebrospinal fluid of patients with the post-polio syndrome (Table 1Table 1
Distribution of Oligoclonal Immunoglobulin Bands in Samples of Cerebrospinal Fluid from the Study Population.). Either the IgM bands in positive samples of cerebrospinal fluid had no detectable counterpart in homologous serum (17 patients) or the number of bands in cerebrospinal fluid was substantially higher than the number in serum (4 patients), indicating that the synthesis of IgM of restricted heterogeneity in the syndrome was predominantly intrathecal. In each case that was positive, qualitative characterization by immunoblotting identified the oligoclonal bands as IgM antibody against poliovirus (Fig. 1Figure 1Electrophoretic Patterns in Cerebrospinal Fluid from a Patient with the Post-Polio Syndrome (Lanes 1 through 4) and a Control Patient (Lane 0).). Similarly, all oligoclonal IgA bands were found to be virus–specific, and IgG bands were specific for poliovirus in 7 of 12 patients.Intrathecal synthesis of virus–specific oligoclonal IgM bands was seen in all four patients who had been exposed to poliovirus relatively recently before the development of new symptoms and in one patient in whom new weakness developed after a minor accident.
IgM Antibody Levels in Cerebrospinal Fluid
Total and virus–specific IgM levels were determined to obtain quantitative information on intrathecal synthesis of IgM. The mean cutoff value (+3 SD) of the IgM index in the normal reference population was 0.07. Abnormally high values were detected in 17 patients (47 percent) with the post-polio syndrome (all had oligoclonal IgM bands in cerebrospinal fluid) and in 6 control patients (3 with multiple sclerosis, 1 with myasthenia gravis, and 2 with stroke) (P<0.005).
The extent of intrathecal synthesis of poliovirus IgM antibody was determined by measuring antibody optical-density values per unit of weight of IgM in serum and cerebrospinal fluid to correct for permeability of the blood—cerebrospinal fluid barrier and expressing the results as the ratio of cerebrospinal fluid values to serum values.31 Intrathecal synthesis of poliovirus IgM antibody was found in 21 patients (58 percent) with the post-polio syndrome and in none of the 67 control patients (Fig. 2Figure 2
Cerebrospinal Fluid:Serum Ratios of Antipoliovirus IgM Antibody (•) as Compared with Cerebrospinal Fluid:Serum Ratios of Antimeasles IgM Antibody (○) (as a Control) in Patients with the Post-Polio Syndrome and in the Control Group.). High cerebrospinal fluid:serum ratios of poliovirus IgM antibody were detected in four patients with the post-polio syndrome who had normal IgM indexes, providing further evidence that intrathecal production of IgM could occur without concomitant increase in the index value.36 These four patients, however, had virus–specific oligoclonal IgM bands in cerebrospinal fluid. Cerebrospinal fluid serum ratios of IgM antibody to the control viruses were within the normal ranges. In contrast, clearly elevated cerebrospinal fluid:serum ratios of antimeasles IgM antibody were found in six controls (three patients with multiple sclerosis, two patients who had a stroke during a meningoencephalitic illness, and one patient with muscular dystrophy who, on further epidemiologic study, was found to have had measles during the time of cerebrospinal fluid collection) (Fig. 2). As mentioned above, race-matched controls were selected for this study. They included 16 patients from developing countries, which may explain the relatively wide range of cerebrospinal fluid:serum ratios of measles antibody in the control group.None of the patients with the post-polio syndrome had evidence of intrathecal synthesis of antibodies to the other control viruses. The median cerebrospinal fluid:serum IgM antibody ratios (and ranges) were 0.08 (0 to 0.25) for mumps virus, 0.15 (0 to 0.31) for herpes simplex virus, and 0.14 (0 to 0.27) for varicella zoster virus.
Intrathecal Synthesis of Interleukin-2 and Soluble Interleukin-2 Receptors
Detectable levels of interleukin-2 were found in the cerebrospinal fluid of 20 patients with the post-polio syndrome and 5 control patients (3 with stroke, 1 with myasthenia gravis, and 1 with multiple sclerosis). High cerebrospinal fluid levels of interleukin-2 in 18 patients with the post-polio syndrome were not associated with a concomitant increase in serum levels, suggesting local central nervous system synthesis of interleukin-2.38 , 39 Similarly, local central nervous system synthesis of soluble interleukin-2 receptors was detected in 17 patients with the syndrome. The increase in intrathecal synthesis of both interleukin-2 and soluble interleukin-2 receptors in the post-polio syndrome was statistically significant (Fig. 3).
To determine whether intrathecal synthesis of interleukin-2 and soluble interleukin-2 receptors in the post-polio syndrome was related to the immune response to poliovirus, cerebrospinal fluid levels of both factors were correlated with the results of IgM immunoblot analysis. The association between cerebrospinal fluid levels of interleukin-2 and soluble interleukin-2 receptors and the presence of poliovirus-specific oligoclonal IgM bands was significant (Fig. 4Figure 4
Mean Levels of Interleukin-2 and Soluble Interleukin-2 Receptors in Cerebrospinal Fluid and Serum from Patients with the Post-Polio Syndrome, According to the Presence of Oligoclonal IgM Bands in Cerebrospinal Fluid.). Furthermore, cerebrospinal fluid levels of interleukin-2 closely correlated with the amount of locally synthesized poliovirus IgM antibody (Fig. 5). The correlation between cerebrospinal fluid levels of soluble interleukin-2 receptors and locally synthesized poliovirus IgM antibody was also significant (Fig. 5).Discussion
The mechanism of new progressive muscle weakness in patients with the post-polio syndrome is important not only for prognosis, but also for preventive and therapeutic purposes.40 Our finding that poliovirus-specific oligoclonal IgM bands were found only in some patients with the post-polio syndrome suggests that there is an immune response to antigenic stimulation in the central nervous system, probably by poliovirus. The presence of a poliovirus-specific immune response may be regarded as indirect evidence of a viral infection, since poliovirus cannot be isolated from the cerebrospinal fluid41 even during the acute stage of paralytic poliomyelitis.42
In central nervous system infections, immunoglobulin-secreting plasma cells differentiate from a limited number of B cells, so the immunoglobulins produced are of restricted heterogeneity — that is, they are oligoclonal.43 , 44 Oligoclonal bands specific to the causal agent are frequently found in patients with active viral infections of the central nervous system, such as subacute sclerosing panencephalitis45 (caused by measles virus), herpes simplex encephalitis,43 human immunodeficiency virus infection,46 and enterovirus-induced meningitis and encephalitis.47 We failed to detect poliovirus-specific oligoclonal bands in the control patients who had had polio but not the post-polio syndrome, suggesting that the intrathecal immune response to poliovirus in the post-polio syndrome was due to relatively recent or persistent antigenic stimulation. Salazar-Grueso et al.,48 using a silver staining method, failed to detect oligoclonal bands in the cerebrospinal fluid of patients with the post-polio syndrome. Their negative results may be due to the relatively small sample (only nine patients) or to methodologic differences (the disadvantages of silver staining have been discussed elsewhere49). The presence of oligoclonal bands in the cerebrospinal fluid, however, is in agreement with other observations.1 , 13
The possibility that the intrathecal immune response in the post-polio syndrome is due to active Stimulation is further confirmed by our finding of increased intrathecal synthesis of interleukin-2 and soluble interleukin-2 receptors in patients with the syndrome. Local central nervous system production of interleukin-2, the soluble interleukin-2 receptors, or both have been demonstrated during the course of several viral infections of the central nervous system.50 51 52 53 A successful immune response to viral infections involves a complex cascade of events that includes the production of cytokines. The system comprising interleukin-2 and interleukin-2 receptors in particular plays a major part in the immune responses against invading antigens.54 55 56 Interleukin-2, a pluripotent cytokine secreted by antigen-activated T cells,57 has an essential role in promoting replication of T cells and their differentiation into effector cells, induction of B-cell growth, and augmentation of immunoglobulin production. It exerts a pleotropic effect through its specific high-affinity receptor,58 which is present on activated T and B cells, natural killer cells, monocytes, and thymocytes as well as oligodendrocytes59 and endothelial cells.60 This interleukin-2 receptor is formed by the association of a 55-kd a chain (Tac antigen) and a 70-to-75-kd β chain. Cell proliferation after the binding of interleukin-2 leads to the release of a smaller (45 kd) form of α chain, the soluble interleukin-2 receptor.
Our findings therefore support the possible role of a new or persistent poliovirus central nervous system infection in the pathogenesis of the post-polio syndrome. The possibility that the syndrome is due to persistent infection by an enterovirus is not unlikely. Poliomyelitis virus, an RNA virus, is usually cytolytic but can produce slowly progressive or persistent infections in both animals and immunosuppressed patients.61 62 63 Lipton64 reported a biphasic neurologic disease in mice infected with Theiler's encephalomyelitis virus, a murine enterovirus; the mice developed an acute encephalitic illness immediately after inoculation, followed by a progressive demyelinating syndrome several months later. Moreover, the murine-adapted Lansing strain of type 2 poliovirus causes acute and persistent infections of the central nervous system in mice.65 In fact, even the human poliovirus has been shown to produce prolonged asymptomatic infection of the central nervous system.63
It is unclear from our data whether patients with the post-polio syndrome carry any risk of infectivity. Furthermore, the pattern of possible reinfection needs to be determined, although recent exposure to poliovirus could be a plausible mechanism. Four of our patients experienced new muscular weakness after relatively recent exposure to the virus. Similarly, Dalakas and collaborators1 reported a patient with the syndrome in whom new muscular weakness developed accompanied by an elevation in the cerebrospinal fluid levels of poliovirus antibodies after exposure to children with acute poliomyelitis. In fact, neurologic abnormalities and elevated poliovirus antibody titers may also develop in normal subjects on exposure to the virus.66
Our data provide evidence of intrathecal immune activation against poliovirus during the course of the post-polio syndrome. It is tempting to speculate that reactivation of latent or persistent poliovirus infection in the central nervous system may have a role in the pathogenesis of new muscle weakness in some patients with the syndrome. The unique lack of vascular permeability and absence of a lymphatic system or immunocompetent cells in the central nervous system as well as the static nature of neurons may encourage and promote viral persistence.24 Residual poliovirus could therefore cause persistent infection after the acute episode, possibly by escaping surveillance of the immune system through antibody-induced antigen modulation, generation of suppressor T cells, or production of blocking factors.67 , 68 Persistent poliovirus infection might then have a gradual but progressive cytopathic effect, which would eventually lead to either neuronal-cell lysis or alteration of specialized cellular functions69 and thus potentially impair physiologic function. Longitudinal follow-up of patients with the post-polio syndrome and therapeutic trials with antiviral agents40 , 70 will allow our hypothesis to be tested further.
We are indebted to the patients who participated in this study for their cooperation; to Prof. K. Alam for his critical review of the manuscript; to J. Smalley and N. Saunders for their excellent technical assistance; to M. Smith and K. Hamid for their active role in the epidemiologic survey; and to the employees of the Miriam Marks Department of Neurochemistry and the John Cumming Laboratory of Chemical Pathology, Institute of Neurology, London, for their support.
Source Information
From the Departments of Clinical Neurochemistry (M.K.S.) and Medical Microbiology (M.C.), Institute of Neurology, the National Hospital for Neurology and Neurosurgery, London, and the Department of Neuropsychiatry, Free University of Brussels, Brussels, Belgium (R.H.). Address reprint requests to Dr. Sharief at the Department of Clinical Neurochemistry, the National Hospital, Queen Sq., London WC1N 3BG, United Kingdom.
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