Brain, Vol. 123, No. 4, 710-717,
April 2000
© 2000 Oxford University Press
Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relationship to immune therapies
1 `Giorgio Spagnol' Service of Clinical Neuroimmunology, 2 Dino Ferrari Centre, Institute of Clinical Neurology and 3 Haematology Service, G. Marcora Centre for Blood Diseases, IRCCS Ospedale Maggiore Policlinico, Milan University, Milan, Italy
Correspondence to:
E. Nobile-Orazio, MD, Institute of Clinical Neurology, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy E-mail: eduardo.nobile{at}unimi.it
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Abstract |
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Many data point to a pathogenetic role for IgM antibodies to the myelin-associated glycoprotein (MAG) in the neuropathy associated with IgM monoclonal gammopathy, supporting the use of immune therapies in affected patients. Almost 50% of patients have been reported to improve with these therapies, but the effect of treatment on the long-term prognosis of the neuropathy remains unclear. We analysed the outcome of 25 of the 26 patients (mean age at entry 65 years, range 45–85 years) with neuropathy and high anti-MAG IgM, first examined by us between 1984 and 1994. By January 1999, after a mean follow-up of 8.5 years (range 2–13 years) and a mean duration of neuropathy symptoms of 11.8 years (range 3–18, >10 years in 16), 17 patients (68%) (aged 58–84 years, mean 73.4) were alive, while eight (32%) (aged 69–78 years, mean 73.1) had died 3–15 years (mean 10.6) after neuropathy onset; in none of them was death caused by the neuropathy, although in three it was possibly related to the therapy for the neuropathy. By the time of last follow-up or patients' death, 11 patients (44%) were disabled by severe hand tremor, gait ataxia or both. The disability rates at 5, 10 and 15 years from neuropathy onset were 16, 24 and 50%, respectively. Of the 19 patients treated during the follow-up for 0.5–11 years (mean 4 years) with various immune therapies, five reported a consistent and four a slight improvement in the neuropathy (total 47%) after one treatment or more, but in only one patient was improvement persistent throughout, to the end of follow-up. In 10 patients (53%), severe adverse events, possibly related to therapy, occurred during treatment and were considered responsible for the patient's death in three. The neurological impairment did not differ between treated and untreated patients at the end of a similar follow-up. Our findings indicate that (i) the majority of patients with neuropathy and anti-MAG IgM have a favourable prognosis even after several years, and (ii) current immune therapies, though temporarily effective in half of the patients, are associated with considerable side effects which limit their prolonged use and efficacy, suggesting that until more effective or safer therapies become available, they should probably be reserved for patients impaired in their daily life or in a progressive phase of the disease.
neuropathy; myelin-associated glycoprotein; therapy; IgM monoclonal gammopathy; prognosis
MAG = myelin-associated glycoprotein
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Introduction |
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In ~50% of patients with neuropathy and IgM monoclonal gammopathy, the M-protein reacts with the myelin-associated glycoprotein (MAG) and other glycoconjugates in nerves bearing the carbohydrate epitope HNK-1 (Latov et al., 1988
; Nobile-Orazio et al., 1994; Chassande et al., 1998). Many data point to a pathogenetic role of anti-MAG IgM in the neuropathy, thus supporting the use of immune therapies in these patients (reviewed in Latov et al., 1988; Nobile-Orazio, 1998): (i) high titres of anti-MAG IgM antibodies are almost invariably associated with a chronic, slowly progressive, predominantly sensory, demyelinating neuropathy (Nobile-Orazio et al., 1994; Van den Berg et al., 1996; Chassande et al., 1998); (ii) pathological studies on nerve biopsies show segmental demyelination with deposits of IgM M-protein and complement (C3d, TCC) on nerve myelin (Nemni et al., 1983; Vital et al., 1989; Hays et al., 1988; Monaco et al., 1990; Nobile-Orazio et al., 1994; Van den Berg et al., 1996); (iii) complement-mediated demyelination of nerve has been induced experimentally in animals by intraneural or systemic injection of anti-MAG IgM M-proteins (Hays et al., 1987; Tatum, 1993; Monaco et al., 1995); and (iv) with only a few exceptions (Ernerudh et al., 1992), therapeutic reduction of anti-MAG IgM levels correlates with improvement of the neuropathy (Latov et al., 1980; Haas and Tatum, 1988; Kelly et al., 1988; Nobile-Orazio et al., 1988; Blume et al., 1995), although sometimes there is improvement without reduction of anti-MAG IgM (Oksenhendler et al., 1995). Several immune therapies have been used in these patients (Table 1) even if their efficacy was only rarely analysed in randomized trials (Oksenhendler et al., 1995; Dalakas et al., 1996; Mariette et al., 1997). Furthermore, in only a few studies did the follow-up of treated patients exceed 2 years (Kelly et al., 1988; Oksenhendler et al., 1995; Notermans et al., 1996), hence the effect of treatment on the long-term outcome of these patients remains unclear. This information would be particularly helpful in view of the long duration of this usually slowly progressive neuropathy (Notermans et al., 1994; Smith, 1994), the harmful side effects of most of these therapies (Gilman et al., 1990) and the advanced age of most affected patients.
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We report the outcome of 25 patients with neuropathy and anti-MAG IgM first examined by us between 1984 and 1994, and followed thereafter for a mean of 8.5 years. We also review the outcome of therapies received by these patients during the follow-up in order possibly to clarify their influence on the long-term prognosis of patients.
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Patients
From 1984 to 1994, we examined 26 patients (22 men, four women) with neuropathy associated with IgM monoclonal gammopathy and high titres of anti-MAG IgM antibodies (>1/6400). An additional 43-year-old man was not included in the study because of the concomitant presence of alcohol abuse and severe inanition that were deemed to be the main cause of his severe neuropathy. He improved after alcohol suspension and vitamin supplementation, but subsequently was lost to follow-up. At the time of the first visit, all patients underwent a thorough neurological, electrophysiological and haematological evaluation according to previously reported methods (Nobile-Orazio et al., 1987
, 1994). The clinical, haematological, immunological and electrophysiological features of 17 of these patients at the time of first visit had been reported previously as part of a large multicentre study (Nobile-Orazio et al., 1994) and were similar to those of the other nine patients who were examined after completing that study. All patients had been neurologically assessed by E.N.-O. or N.M., while the haematological diagnosis was either performed directly or reviewed by L.B. according to previously reported criteria (Baldini et al., 1994).
Clinical assessment and follow-up
After the first visit, patients were examined periodically by us during follow-up or were contacted by telephone during 1998 and offered a neurological examination at our institution. Patients unwilling to undergo this evaluation were interviewed by telephone by one of us (E.N.-O. or N.M.) (see below), while information on the patients who were deceased was obtained from their relatives. In all patients, the severity of the neuropathy was assessed before treatment and at follow-up using a slightly modified functional impairment scale for upper and lower limbs (Nobile-Orazio et al., 1993) adapted for telephone interviews: 0 = asymptomatic; 1 = symptoms not interfering with manual activities/walking normally; 2 = some minor difficulties in manual activities/walking abnormally without support; 3 = unable to perform some manual activities/walking independently with support; 4 = unable to eat, dress or wash independently/needing help to walk; 5 = no useful tasks performed with the upper limbs/confined to a wheelchair. Patients (or their relatives) interviewed by telephone were asked specifically about their manual activities, including ability to eat, wash, dress and write independently, presence of disabling hand tremor, gait and balance disturbance and ability to stand or walk independently or with support. All patients were questioned about therapies received during follow-up, including their dosage, duration and any adverse effects experienced during the therapies. Only treatments which had been prescribed at the recommended full dosage and for a sufficient period of time (6 months for cytostatic agents and steroids, 2 months for plasma exchange or immunoglobulins) were included, unless they had to be suspended due to adverse effects. In only five of the 19 treated patients were one or more therapies either not prescribed by us or their effect not directly assessed by us, so that response to therapy could only be evaluated anamnestically. Improvement was graded as consistent if the improvement observed by us or reported by the five patients treated elsewhere unequivocally achieved at least one point in the above-mentioned scale, and slight if, though noticed by both the patient and the examiner, it was not sufficient to modify the functional impairment score.
Anti-MAG antibody testing
Patients' sera were tested at entry for the presence of serum anti-MAG antibodies by immunoblot after sodium dodecyl sulphate–polyacrylamide gradient (4–20%) gel electrophoresis of myelin prepared from human autoptic brain (Nobile-Orazio et al., 1994). The reactivity of patients' sera was tested at the initial dilution of 1/200 and titrated by serial 2-fold dilutions until negative. All patients had anti-MAG IgM titres above 1/6400, which in our laboratory is considered the upper normal limit for these antibodies. For correlation with patients' outcome, antibody titres were divided into moderately (1/12 800–1/200 000) and markedly high (>1/200 000).
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Results |
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The clinical and laboratory features at entry of the 26 patients with neuropathy associated with IgM monoclonal gammopathy and high titres of anti-MAG IgM antibodies are summarized in Table 2
. All patients except one were symptomatic for the neuropathy at the time of the first visit. One patient had subclinical neuropathy at entry that became symptomatic 4 years after the first visit (Meucci et al., 1999).
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Of the 26 patients initially examined, 25 (96%) were followed until completion of the study in January 1999 or the patient's death. The only patient lost to follow-up after the first visit was an 85-year-old man with 7 years of neuropathy at the time of the first visit, when he was walking with the aid of a cane. Of the 25 patients available at follow-up, 17 were examined periodically during follow-up or were re-evaluated neurologically at the end of it, while the other eight patients (or their relatives) provided detailed information by telephone interview. All of the 25 patients were included in the study, as the exclusion of those unable to attend the last visit (half of whom had died or were unable to leave home) could have biased the results. All patients directly examined at the end of follow-up were also interviewed by telephone before the last visit. In none of them did the functional score derived by telephone interview differ from the one determined at the visit. All patients had been examined periodically by a haematologist who provided information on the haematological evolution.
The clinical and laboratory features of the 25 patients available at follow-up are summarized in Tables 2 and 3
. By the end of follow-up, 17 patients (68%, aged 58–84 years, mean 73.4 years) were alive, while eight (32%, aged 69–78 years, mean 73.1 years) had died 3–15 years after onset of neuropathy (mean 10.6 years). In none of the patients could death be directly related to the neuropathy: in four patients, death was caused by haematological diseases, two of whom developed acute leukaemia during treatment with chlorambucil; two patients died of cardiac diseases, one of whom developed acute pulmonary oedema 3 days after completing a course of chemotherapy that included high-dose steroids; one patient died of pneumonia; and one patient of lung carcinoma.
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The overall duration of the neuropathy in the 25 patients at the time of last follow-up or death ranged from 3 to 18 years (mean 11.8), being longer than 10 years in 16 patients (Table 2
). Fifteen patients (60%) had deteriorated by at least one point on the functional scale at last follow-up (Table 3), whereas one had improved by one grade; 11 patients (44%) compared with two (8%) at entry were disabled (functional score >2) at the end of follow-up by severe hand tremor (four patients), difficulty in walking, mainly due to gait ataxia (five patients), inability to walk due to the severe inanition caused by uncontrolled and ultimately fatal Waldenström's macroglobulinaemia (one patient), or both tremor and gait impairment (one patient). Two patients had progression of the haematological disease from monoclonal gammopathy of undetermined significance to Waldenström's macroglobulinaemia, one developed amylodosis and two acute leukaemia (see above). In all patients, at least 5 years had elapsed from onset of neuropathy symptoms to completion of the study in January 1999. The mortality and disability (functional score >2) rates at 5 years in these patients were 8 and 16%, respectively. The corresponding rates at 10 years for the 17 patients whose neuropathy onset preceded the end of the study by at least 10 years were 6 and 24%, respectively. Among the 12 patients in whom this interval reached 15 years, the mortality and disability rates at 15 years were 33 and 50%, respectively.
Cytostatic or immune therapies were prescribed for at least six consecutive months during follow-up in 19 patients (Table 4). In four patients, therapies were prescribed to control the haematological disease, whereas the other patients were treated for the neuropathy. The overall duration of treatment ranged from 6 months to 11 years (mean 4 years). Nine patients (47%) reported a consistent (five) or slight (four) improvement in the neuropathy after one or more therapies, but in only one did improvement persist to the end of follow-up. Plasma exchange and chlorambucil were the most effective therapies in these patients, both singly and in combination. Steroids were only effective when used in association with other therapies, while cyclophosphamide was rarely associated with improvement (Table 4). Ten patients (53%) reported severe adverse events possibly related to ongoing therapies and requiring suspension of therapy, including severe thrombocytopenia in two patients after cyclophosphamide, and in one of them also after chlorambucil; severe hypotension in one during plasma exchange; thoracic Herpes zoster in four patients and hepatitis in one, all receiving chlorambucil; fatal acute leukaemia in two after 1 and 5 years of chlorambucil (both with monoclonal gammopathy of undetermined significance) (Aymard et al., 1985), and fatal acute pulmonary oedema 3 days after completing a second course of chemotherapy for Waldenström's macroglobulinaemia with melphalan, cyclophosphamide and oral prednisone in one. At the end of the follow-up (Table 5), a similar proportion of treated and untreated patients (37 and 33%) had become disabled. Mortality was higher in treated (37%) than untreated patients (17%), a difference probably reflecting the higher frequency of haematological malignancy in treated (37%) than untreated patients (17%).
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No difference in the neurological impairment was observed between patients with moderately (12 patients) and very (13 patients) high anti-MAG titres both at entry (median/mean functional score 1/1.5 versus 1/1.4) and at last follow-up (median/mean functional score 2.5/2.5 versus 2/2.2). A similar proportion of patients in both groups deteriorated by at least one point on the functional scale (65% versus 54%) or had become disabled (50% versus 38%) after a similar follow-up (mean 8.7 versus 8.4 years) and duration of neuropathy symptoms (mean 12.7 versus 10.8 years).
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Discussion |
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Even though the neuropathy associated with anti-MAG antibodies has often been reported to run a slowly progressive course, the long-term prognosis of this neuropathy has been examined specifically only in a few studies. In a series of 17 patients with neuropathy and anti-MAG IgM (12 of whom were treated with immune therapies during the follow-up), Smith reported mortality and disability rates after 7–24 years of neuropathy (mean 14.6) of 28 and 35%, respectively (Smith, 1994
). In the same year Notermans and colleagues reported a disability rate of 22% after 5–10 years of neuropathy in 32 untreated patients with neuropathy associated with monoclonal gammopathy of undetermined significance, seven of whom had anti-MAG IgM (Notermans et al., 1994). In our series of patients, the mortality (32%) and disability rates (42%) after a mean neuropathy duration of 11.8 years were similar to those reported by Smith (1994), probably reflecting the similar duration of the neuropathy in the two studies compared with the shorter follow-up in the study of Notermans et al. (1994). Regarding the probability of these patients of being disabled within a definite time, Smith (1994) reported that two out of 14 (14%) patients were disabled within 10 years from neuropathy onset compared with one out of seven (14%) of those reported by Notermans et al. (1994) after 5 years. In our series, the probability of being disabled 5, 10 and 15 years after the neuropathy onset was 16, 24 and 50%, respectively. The mortality rates after the same periods of time were 8, 6 and 33%, respectively. However, similarly to the report of Smith (1994), in none of our patients could death be directly related to the neuropathy; it was due either to the haematological or other concurrent diseases, or, in three of them, was probably related to immune/cytostatic therapies. These figures seem to confirm that in most patients with anti-MAG IgM, the neuropathy carries an overall good prognosis in the short and middle term and that only after several years (15 in our series) did a consistent proportion of them become neurologically disabled due to severe upper limb tremor (16%), walking impairment (20%) or both (4%).
Most of our patients received immunosuppressive or cytostatic agents during the follow-up and it is therefore not possible to exclude that the relatively benign prognosis in most of our patients was influenced by these therapies. Indeed, similarly to previously reported studies (Tables 1 and 4), almost 50% of our patients responded at least temporarily to some of these therapies. Even though the number of patients never treated during the follow-up was much smaller than that of treated patients, making a comparison very difficult, none of the neurological items examined (Table 5) were better in treated than untreated patients after a similar follow-up. This might possibly be caused by the fact that half of our patients reported severe or even fatal adverse effects which required suspension of possibly effective therapy and caused some reluctance to start new therapies.
Even though no conclusion on the effects of different therapies in neuropathy can be derived from our retrospective study, it is noteworthy that, with only a few exceptions, response to therapies in our patients was similar, at least in the short term, to that observed in previously reported patients (Tables 1 and 4). Plasma exchange has been reported to be effective in approximately half of the patients, used both on its own and in combination with other therapies, even though its combination with chlorambucil was not more effective than chlorambucil alone in a randomized comparative open trial on 44 patients with neuropathy associated with IgM monoclonal gammopathy, 33 of whom had anti-MAG IgM (Oksenhendler et al., 1995). Similarly to our series, chlorambucil was effective in one-third of the patients when used on its own and in a slightly higher proportion when used in combination with other therapies. Approximately half of the patients responded to steroids given in association with other therapies, which were never effective in our patients when given alone. Cyclophosphamide was rarely effective when used alone, whereas it produced effective results in 40–100% of the patients in two open trials with cyclic high-dose oral or intravenous cyclophosphamide associated with steroids (Notermans et al., 1996) or plasma exchange (Blume et al., 1995). High-dose intravenous immunoglobulins were effective in <20% of the patients in two randomized trials (Dalakas et al., 1996; Mariette et al., 1997), whereas 80% of patients improved with interferon-
in a comparative trial with high-dose intravenous immunoglobulins (Mariette et al., 1997), although improvement was restricted to sensory symptoms. More recent reports on the efficacy of fludarabine (Sherman et al., 1994; Wilson et al., 1999), high-dose chemotherapy followed by autologous bone marrow transplantation (Rudnicki et al., 1998) or Rituxan (Latov et al., 1999; Levine and Pestronk, 1999) need to be confirmed in larger series of patients. However, the follow-up of treated patients has exceeded 2 years in only a few studies; therefore, the long-term effect of these therapies on the neuropathy remains unclear. This information would be particularly important to clarify in future studies our results showing frequent slow progression and relatively favourable prognosis of the neuropathy, advanced age of most affected patients (80% of our patients were older than 70 years at last follow-up) and frequent adverse effects of most of these therapies.
In conclusion, our study confirms that the majority of patients with neuropathy associated with anti-MAG IgM have an overall good prognosis for several years. This finding, together with the advanced age of most affected patients, the considerable adverse events frequently observed with the therapies described and their unclear efficacy for the long-term outcome, should prompt some caution in the decision to treat these patients. It is our opinion that, until more effective or safer therapies become available, current immune therapies should probably be reserved for patients impaired in their daily life or in a progressive phase of the disease.
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Acknowledgments |
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We wish to thank Dr Barbara Bossi for her help in assessing the patients and Mrs Sylvia Allaria for measuring anti-MAG antibodies. This study was supported by Associazione Amici Centro Dino Ferrari and by grants from Telethon, Italy (No. 674), Associazione Italiana Sclerosi Multipla and IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
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Received May 25, 1999. Revised August 31, 1999. Accepted September 30, 1999.
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