Original Article
Plasma Exchange in Polyneuropathy Associated with Monoclonal Gammopathy of Undetermined Significance
N Engl J Med 1991; 325:1482-1486November 21, 1991
- Abstract
- Abstract
Background.
Polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) has been treated with plasma exchange, intravenous immune globulin, and chemotherapy, but the effectiveness of these treatments remains uncertain.
Methods.
We randomly assigned 39 patients with stable or worsening neuropathy and MGUS of the IgG, IgA, or IgM type to receive either plasma exchange twice weekly for three weeks or sham plasma exchange, in a double-blind trial. The patients who initially underwent sham plasma exchange subsequently underwent plasma exchange in an open trial.
Results.
In the double-blind trial, the average neuropathy disability score improved by 2 points from base line (from 62.5 to 60.5) in the sham-exchange group and by 12 points (from 58.3 to 46.3) in the plasma-exchange group (P = 0.06). A similar difference was observed in the weakness score, a component of the neuropathy disability score (improvement, 1 and 10 points, respectively; P = 0.07). After treatment the summed compound muscle action potentials of motor nerves were 1.2 mV lower (worse) than at base line in the sham-exchange group and 0.4 mV higher (better) in the plasma-exchange group (P = 0.07). The greater degree of improvement with plasma exchange was equal in magnitude to or greater than the difference between not being able to walk on the heels or toes and being able to perform these activities. Changes in the vibratory detection threshold, summed motor-nerve conduction velocity, and sensory-nerve action potentials did not differ significantly between the treatment groups. In the open trial, in which patients who initially underwent sham exchange were treated with plasma exchange, the neuropathy disability score (P = 0.04), weakness score (P = 0.07), and summed compound muscle action potentials (P = 0.07) improved more with plasma exchange than they had with sham exchange. In both the double-blind and the open trial, those with IgG or IgA gammopathy had a better response to plasma exchange than those with IgM gammopathy.
Conclusions.
Plasma exchange appears to be efficacious in neuropathy associated with MGUS, especially of the IgG or IgA type. (N Engl J Med 1991;325:1482–6.)
Media in This Article
Table 1
Neuropathic Indexes at Study Entry, According to Treatment Group.*Table 2
Improvement from Base Line in Neuropathic Indexes during the Three-Week Treatment Period, According to Treatment Group.*Article Activity
- Article
THE detection of monoclonal proteins in the serum of a patient with peripheral neuropathy may lead to the diagnosis of amyloidosis,1 2 3 myeloma (multiple4 , 5 or osteosclerotic6 7 8 9), Waldenström's macroglobulinemia,10 11 12 cryoglobulinemia,11 , 12 lymphoma,4 rare leukemias,13 , 14 or most commonly, monoclonal gammopathy of undetermined significance (MGUS).13 14 15 16 17 Increasingly, neuropathies associated with MGUS of the IgM type13 , 14 , 18 19 20 21 22 are being treated as a nosologic entity.
In an earlier study of neuropathy associated with MGUS, we suggested that monoclonal IgM gammopathy should be separated from that associated with IgG and IgA and from chronic inflammatory demyelinating polyradiculoneuropathy.23 24 25 There is some evidence that the occurrence of monoclonal proteins may be implicated in the development of neuropathy: neuropathy may be more frequent among patients with monoclonal proteins than in the general population,26 , 27 MGUS may occur more frequently among patients with neuropathy of unknown cause28 , 29 than in the general population,24 , 30 , 31 and monoclonal gammopathy is found in the majority of patients with the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin hyperpigmentation8 , 9) syndrome. A causal link between monoclonal proteins and the development of neuropathy, possibly mediated by antibodies such as myelin-associated glycoprotein antibodies, has also been suggested.15 , 18 19 20 21 22 , 26 27 28 , 32 33 34
Because neuropathies associated with MGUS often have a progressive course (as in 70 percent of the patients in the study by Gosselin et al.23), persist for many years, and may be associated with prominent disabling sensory and motor symptoms and perhaps even death,14 15 16 17 , 23 improved therapy is needed.
The rationale for using plasma exchange in these neuropathies is that monoclonal protein antibodies may be involved in fiber injury, and plasma exchange has on occasion been associated with improvement of neuropathy. The effectiveness of plasma exchange in neuropathies associated with MGUS is still unproved because previous trials were open, included small numbers of patients, studied heterogeneous disorders, used overlapping treatments, depended on the use of unvalidated outcome measures, or were not controlled.
The hypothesis tested in this sham-controlled trial of plasma exchange was that the removal of plasma components (such as antibodies in monoclonal proteins) might prevent short-term worsening of neuropathy or lead to improvement. Secondary issues included whether any beneficial effect would be limited to neuropathies associated with certain species of monoclonal proteins.
Methods
Study Design
When this study was designed, we had insufficient information on the characteristic features and course of neuropathy associated with MGUS, although it was known that spontaneous improvement could occur. Therefore, it was not possible to estimate the number of patients and the duration of treatment that would provide the study with sufficient power to demonstrate a treatment effect, if one was present. A similarly designed double-blind, sham-controlled trial of plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy had produced convincing evidence of efficacy in 29 patients given twice-weekly plasma exchange for three weeks.35
Postulating that a similar degree of improvement might occur in patients with neuropathy associated with MGUS, we decided to enroll 40 consecutive patients with the disorder in the present trial and to use a treatment period of three weeks. Patients whose condition was improving were not recruited.
Patients had to meet the following criteria for entry into the study: (1) they had to have polyradiculoneuropathy or polyneuropathy and a serum monoclonal gammopathy unassociated with amyloidosis, myeloma, Waldenström's macroglobulinemia, or lymphoma, which were ruled out by appropriate tests (for example, biopsy of bone marrow, nerve, or other tissue) and a radiographic survey of bones; (2) their neuropathy disability score had to be ≥35 points36 , 37; (3) their neuropathy had to be stable or worsening; (4) other causes of neuropathy had to have been ruled out; (5) they had to have had no immunotherapy in the past six weeks; (6) they had to agree to undergo the appropriate follow-up evaluations; and (7) they had to sign an informed-consent form approved by our institutional review board.
The patients were assigned to receive sham exchange or plasma exchange by restricted randomization, so that the groups were approximately equal with respect to age (<50 vs. ≥50 years) and sex. Treatment was given on Monday and Thursday or on Tuesday and Friday for three weeks. The only investigators who were not blinded to the patients' treatment assignments were the patient coordinator, the biostatistician, and the blood-bank consultant and personnel. During treatment, a curtain separated the apheresis equipment from the patient. For sham exchange, blood was drawn, separated into plasma and cells, recombined, and reinfused into the patient. For plasma exchange, blood was drawn and separated into cells and plasma; the cells were combined with reconstituted albumin and reinfused into the patient. The patient and the examining physicians were unaware of the nature of the treatment.
Evaluation of Neuropathy
The prospective neurologic evaluation used to determine the neuropathy disability score has been described elsewhere.36 , 37 In brief, selected items from the neurologic examination were scored and summed. Muscle weakness was scored as follows: 0 = normal, 1 = 25 percent weakness, 2 = 50 percent weakness, 3 = 75 percent weakness, and 4 = 100 percent weakness. Muscle-stretch reflexes were graded as follows: 0 = normal, 1 = decreased, and 2 = absent. Sensation (touch—pressure, joint motion, vibration, and pinprick on index finger and great toe) was graded in the same way as reflexes. Scores could range from 0 to 244. The examiner judged what was normal considering the patient's age and sex, occupation, and level of physical fitness, the anatomical location, and related factors. The assessment of the vibratory detection thresholds has been outlined previously.38 , 39 Thresholds were converted to normal-deviation scores.
Nerve-conduction studies were performed on motor fibers of ulnar, median, peroneal, and tibial nerves with standard placement of surface electrodes and precautions to guard against abnormalities due to faulty stimulation and recording techniques, anatomical crossover of nerve fibers, or temperature. The summed compound muscle action potentials, conduction velocities, and distal latencies of nerves were determined. Nerve-conduction studies were also performed for sensory nerves.
Statistical Analysis
Changes from base line were compared in the plasma-exchange and sham-exchange groups by means of two-sided two-sample t-tests. In the group that underwent sham exchange initially (in the double-blind trial) and then plasma exchange (in the open trial), we compared the changes in various indexes during the sham-exchange and plasma-exchange periods with Student's paired t-test. Since two-sided tests were used to assess for one-sided questions, we used P = 0.01 as the criterion for statistical significance.
Results
Of the 39 patients enrolled in the study, 20 were assigned to sham exchange (10 with IgM gammopathy and 10 with IgG or IgA gammopathy), and 19 to plasma exchange (11 with IgM gammopathy and 8 with IgG or IgA gammopathy). One patient was found to have osteosclerotic myeloma, and therefore the data on this patient were not used in the analysis. The randomization procedure resulted in treatment groups that were reasonably balanced with respect to neuropathic abnormality and other factors (Table 1Table 1
Neuropathic Indexes at Study Entry, According to Treatment Group.*).Plasma exchange was performed with an intermittent-flow cell separator (Haemonetics model 30 or V50) or a continuous-flow device (IBM/Cobe 2997). The average volume exchanged in the plasma-exchange group was 3564 ml, or an average of 49 ml per kilogram of body weight. The replacement consisted of a 5 percent solution of normal serum albumin (two thirds of volume) and 0.9 percent solution of sodium chloride (one third of volume). The average volume of plasma processed in the sham-exchange group was 3466 ml, or an average of 47 ml per kilogram.
Changes during Treatment
By questioning the patients and the examining physicians, we determined that inadvertent disclosure of treatment (plasma exchange or sham exchange) had not occurred. To minimize bias, the neurologic examination was performed before the patient's history was taken and before the patient was asked whether he or she thought that improvement had occurred.
We first evaluated the change in neuropathic end points over the three weeks in the 20 patients who underwent sham exchange to assess whether the condition of the patients in this group had remained stable or had worsened (Table 2Table 2
Improvement from Base Line in Neuropathic Indexes during the Three-Week Treatment Period, According to Treatment Group.*). On average, the neuropathy disability score had decreased (improved) by 2 points, and the weakness score (a component of the neuropathy disability score) by 1 point. Although some indexes showed slight improvement, other measures — such as the summed compound muscle action potential and summed motor-nerve conduction velocity — showed slight worsening, suggesting that little or no change had occurred.The 19 patients who underwent plasma exchange improved, on average, more than the 20 patients who underwent sham exchange. The average neuropathy disability score of the plasma-exchange group decreased by 12 points, whereas that of the sham-exchange group decreased by only 2 points (P = 0.06) (Table 2). The weakness score improved by 10 points in the plasma-exchange group and by 1 point in the sham-exchange group (P = 0.07). With plasma exchange, the summed compound muscle action potential improved by 0.4 mV, whereas with sham exchange it worsened by 1.2 mV (P = 0.07). The differences between the two groups in other measures were not statistically significant.
Patients with IgG or IgA Gammopathy and Those with IgM Gammopathy
We next tested whether the response to plasma exchange was significantly different depending on whether the gammopathy was of the IgM type or either the IgG or IgA type. The differences between these groups were significant only for the weakness score (P = 0.03); improvement was greater for the patients with IgG or IgA gammopathy (data not shown).
We also compared the change in measures of neuropathy between the two treatment groups for only the patients with IgG or IgA gammopathy. The changes in the neuropathy disability score (20 vs. 2 points; P = 0.08) and the weakness score (17 vs. 1 point; P = 0.04) were greater in the plasma-exchange group than in the sham-exchange group (Table 3Table 3
Improvement from Base Line in Neuropathic Indexes during the Three-Week Treatment Period, According to Treatment Group, among 20 Patients with IgG or IgA Gammopathy.*). In the patients with IgM gammopathy, although the direction of the mean change in the indexes of neuropathy favored plasma exchange, the differences did not reach statistical significance for any of the neuropathic end points we studied.Sham Exchange Followed by Plasma Exchange
Among the 17 patients who underwent sham exchange in the double-blind trial and then plasma exchange in the open trial, a greater improvement occurred with plasma exchange than with sham exchange in the neuropathy disability score (P = 0.04), the weakness score (P = 0.07), and the summed compound muscle action potential (P = 0.07) (Table 4Table 4
Improvement from Base Line in Neuropathic Indexes during Sham Exchange and Plasma Exchange in 17 Patients Who Underwent Both Treatments, According to Type of Gammopathy.*).Among the eight patients with IgM gammopathy who underwent sham exchange followed by plasma exchange, there were no statistically significant differences in the changes observed with the two treatments (data not shown). Among the nine patients with IgG or IgA gammopathy who underwent sham exchange followed by plasma exchange, however, the improvement in the neuropathy disability score (P = 0.11), the weakness score (P = 0.07), and the summed compound muscle action potential (P = 0.06) was greater with plasma exchange (Table 4).
Discussion
Previous reports that plasma exchange might be efficacious in neuropathy associated with MGUS needed confirmation because earlier trials were open and uncontrolled, their patient-selection procedures and treatment schedules were heterogeneous, validated neuropathic tests were not used or not administered at predetermined times, the studies were not controlled or blinded, or data were not analyzed statistically.40 41 42
Furthermore, we wished to test whether plasma exchange was equally efficacious in patients with the neuropathy associated with IgM, IgG, and IgA MGUS. The neuropathy associated with IgM MGUS is sometimes considered to be a specific disease.23 , 35 In a recent study of 65 patients with neuropathies associated with MGUS, Gosselin et al.23 found that a number of features were significantly worse in IgM MGUS than in the IgG and IgA types. Specifically, there was a higher frequency of sensory loss and ataxia, a higher frequency of nerve-conduction abnormality (10 attributes of nerve conduction were significantly worse, and none were significantly better), and a higher frequency of dispersion of the compound muscle action potential. They also found a higher frequency of the IgM type in the cohort studied than has been found in patients with MGUS evaluated at the Mayo Clinic or than has been found in epidemiologic studies. Another reason to evaluate the efficacy of plasma exchange in neuropathy associated with MGUS was that humoral antibodies of monoclonal proteins are reported to be injurious to nerve fibers.18 19 20 , 26 27 28 , 33
In this study, plasma exchange (six times in three weeks) prevented worsening of the neuropathic deficit or even ameliorated it, as measured by the neuropathy disability score (P = 0.06), the weakness score (P = 0.07), and the summed compound muscle action potentials of the ulnar, median, peroneal, and tibial nerves (P = 0.07). For the other measures we evaluated (the vibratory detection threshold of the toe, the summed motor-nerve conduction velocity, and the sensory-nerve action potentials), the differences between plasma exchange and sham plasma exchange did not reach statistical significance. Because patients and observers remained blinded to treatment during the trial, the improvement found in the neuropathy disability score and the weakness score cannot be attributed to bias on the part of patients or observers. Similarly, the improvement in the summed compound muscle action potential cannot be attributed to patient or observer bias. Further support for the finding that plasma exchange was efficacious came from the open trial of plasma exchange in patients who had first undergone sham exchange. The average changes in the neuropathy disability score, the weakness score, and the summed compound muscle action potential were greater with plasma exchange than with sham exchange. Although bias on the part of the observers might have influenced judgments concerning neuropathy, such bias should not have affected the improvement in the summed compound muscle action potential.
Was the degree of improvement meaningful? Three lines of evidence suggest that it was. First, the average change in the neuropathy disability score in the plasma-exchange group was approximately 10 points more than in the sham-exchange group — a difference of some magnitude. Second, some patients had so much improvement that it was readily recognized by them and their physicians; for example, some could walk again after not being able to walk. Third, the magnitude of the average change in such measures of nerve conduction as the summed compound muscle action potential was greater than that estimated to be clinically meaningful in patients with diabetic neuropathy.43
To what can the improvement in muscle strength and muscle action potentials be attributed? Three weeks is an insufficient length of time for improvement to be attributed to nerve regeneration. Remyelination of previously demyelinated regions or, more likely, relief of conduction block of motor fibers due to the removal of humoral factors could explain the rapid improvement. Such an explanation is reasonable, since this type of neuropathy is characterized by conduction block and the dispersion of the compound muscle action potential; antibodies may also be implicated in pathogenesis.18 , 19 , 26 27 28 , 33 , 34 The role of deleterious humoral antibodies might also explain why improvement was not long-lasting — generally lasting only 7 to 20 days.
It is not clear why plasma exchange appears to be more efficacious in the neuropathy associated with IgG and IgA gammopathy than in that associated with IgM gammopathy. Among the patients with IgM gammopathy, none of the differences between treatment groups approached statistical significance, whereas plasma exchange clearly led to greater improvement than did sham exchange in patients with IgG or IgA gammopathy. This difference is not due to greater removal of IgG and IgA than of IgM by apheresis. We estimate that, on average, more IgM than IgG or IgA is removed in plasma exchange.44 45 46 At any rate, this study supports the division of neuropathies associated with MGUS into those associated with M and those associated with G and A monoclonal proteins.
Is the neuropathy associated with IgG and IgA gammopathy the same disorder as chronic inflammatory demyelinating polyradiculoneuropathy?20 , 24 , 27 , 29 30 31 , 35 Although the patients' similar responsiveness to plasma exchange suggests that the two are similar, the occurrence of monoclonal proteins and differences in the frequency distribution in various age groups suggest that they are different.23 , 24
Supported in part by the Mayo Foundation and by the Lubin, Geerling, and Kawamura Funds.
Source Information
From the Peripheral Neuropathy Research Laboratories and the Department of Neurology (P.J.D., P.A.L., A.J.W., S.S.J., S.G., P.B., K.M.K., J.L.K., B.A.E.), the Section of Transfusion Medicine (A.A.P.), the Section of Biostatistics (P.C.O.), and the Division of Hematology and Internal Medicine (R.A.K.), Mayo Clinic and Mayo Foundation Rochester, Rochester, Minn., and the Section of Neurology, Mayo Clinic Scottsdale, Scottsdale, Ariz. (B.E.S.). Address reprint requests to Dr. Dyck at the Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
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