Brain, Vol. 125, No. 8, 1875-1886,
August 2002
© 2002 Guarantors of Brain
Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment
Departments of 1 Neurology and 2 Clinical Neurophysiology, Rudolf Magnus Institute for Neurosciences, University Medical Centre Utrecht, The Netherlands
Correspondence to: L. H. Van den Berg, MD, PhD, Department of Neurology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands E-mail: l.h.vandenberg{at}neuro.azu.nl
Received August 23, 2001. Revised February 12, 2002. Accepted February 12, 2002.
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Summary |
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We performed a long-term follow-up study of 11 patients with multifocal motor neuropathy (MMN) who received maintenance treatment with intravenous immunoglobulins (IVIg). Patients were treated initially with one full course of IVIg (0.4 g/kg for 5 days) followed by one IVIg infusion (0.4 g/kg) every week. During follow-up, the frequency and dosage of IVIg infusions were determined for each patient and ranged from one infusion every 1 to 7 weeks and an average dose of 7 to 48 g per week. During the 4- to 8-year follow-up period, muscle strength was assessed by measuring the MRC (Medical Research Council) sumscore of 20 muscle groups and by performing hand-held dynamometry on a selection of weak muscle groups. Systematic electrophysiological studies were performed before treatment and each year during IVIg maintenance treatment. Disability was assessed with the upper limb and lower limb subscales of the Guy’s Neurological Disability Scale before treatment, after the first full course of IVIg and at the last follow-up examination. Muscle strength improved significantly within 3 weeks of the start of IVIg treatment and was still significantly better at the last follow-up examination than before treatment, even though it decreased slightly and significantly during the follow-up period. Upper limb disability was significantly better after the first full course of IVIg than before treatment. Conduction block disappeared in six nerve segments but new conduction block appeared in eight nerve segments during the follow-up period. Changes consistent with improvement (remyelination or reinnervation) occurred in 13 nerves during follow-up and changes consistent with worsening (demyelination or axon loss) occurred in 14 nerves. Electrophysiological changes consistent with improvement were significantly associated with the presence of conduction block before IVIg treatment. In conclusion, IVIg maintenance treatment has a beneficial long-term effect on muscle strength and upper limb disability but may not prevent a slight decrease in muscle strength. The electrophysiological findings imply that IVIg treatment favourably influences the mechanisms of remyelination or reinnervation but that axon loss cannot be prevented.
Keywords: multifocal motor neuropathy; neuropathy; immunoglobulins; demyelination; axonal degeneration
Abbreviations: MMN = multifocal motor neuropathy; IVIg = intravenous immunoglobulins; CMAP = compound muscle action potential; P/D = proximal/distal
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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Multifocal motor neuropathy (MMN) is characterized by slowly progressive, asymmetrical weakness of the limbs without sensory loss. Substantial evidence for an immune-mediated pathogenesis of MMN (Parry and Sumner, 1992
; Willison et al., 1994; Kornberg and Pestronk, 1995; Léger, 1995; Chaudhry, 1998; Nobile-Orazio, 1996) has led to studies of immunological treatments. Prednisolone and plasma exchange are ineffective in most patients, and of the immunosuppressants only cyclophosphamide seems to be effective but has major side-effects (Baker et al., 1987; Pedersen-Bjergaard et al., 1988; Meistrich et al., 1992; Meucci et al., 1997). Various open and placebo-controlled studies have shown that treatment with high-dose intravenous immunoglobulins (IVIg) leads to improvement of muscle strength in patients with MMN (Chaudhry et al., 1993; Nobile-Orazio et al., 1993; Azulay et al., 1994; Bouche et al., 1995; Van den Berg et al., 1995a; Léger et al., 2001; Federico et al., 2000). However, as the effect of IVIg treatment lasts only several weeks, IVIg maintenance treatment is necessary to maintain the effect on muscle strength in most patients. Maintenance IVIg treatment is expensive, and the frequent infusions may be burdensome to patients, but at present there is no therapeutic alternative to IVIg therapy. Therefore, studies of the long-term effect of IVIg treatment are important. In most studies of the effect of IVIg treatment, patients were followed for several months (Kaji et al., 1992; Chaudhry et al., 1993; Nobile-Orazio et al., 1993; Azulay et al., 1994; Comi et al., 1994; Elliott and Pestronk, 1994; Bouche et al., 1995; Van den Berg et al., 1995a, b; Léger et al., 2001); in two studies patients received IVIg maintenance treatment for up to 4 years, but these studies were relatively small (Azulay et al., 1997; Van den Berg et al., 1998).
Evidence of motor nerve conduction block is considered the electrodiagnostic hallmark of MMN. The results of previous studies of the effect of IVIg treatment on motor nerve conduction are not consistent. An improvement in conduction block after several months of IVIg treatment has been described in some studies but others could not detect significant differences on electrophysiological examination (Chaudhry et al., 1993; Nobile-Orazio et al., 1993; Comi et al., 1994; Bouche et al., 1995; Van den Berg et al., 1995a, b; Léger et al., 2001).
In the present study, we measured the long-term effect of IVIg maintenance treatment on muscle strength and disability in 11 patients with MMN who had been treated with IVIg for 4–8 years. In addition, we performed a systematic long-term analysis of the changes in motor nerve conduction during IVIg treatment and attempted to explain these changes in terms of remyelination, reinnervation, demyelination or axon loss.
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Patients and methods |
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Patients
Eleven patients were included who met the following four criteria: (i) clinically, the presence of asymmetrical limb weakness at onset or motor involvement with a motor nerve distribution in at least two peripheral nerve sites, predominant upper limb involvement, disabling weakness of MRC (Medical Research Council, 1976
) grade 4 or less in at least one muscle (Hughes, 2001); (ii) electrophysiological evidence of one site with definite motor conduction block or one site with probable conduction block according to previously defined criteria (Van den Berg-Vos et al., 2000a); (iii) response to IVIg according to criteria that were described in previous studies (Van den Berg et al., 1995a, 1998; Van den Berg-Vos et al., 2000a, b); and (iv) IVIg maintenance treatment lasting at least 4 years. Patients who had bulbar signs or symptoms, or upper motor neurone signs (spasticity, hyperreflexia, extensor plantar response) were excluded. Mild sensory symptoms were not an exclusion criterion provided there were no sensory deficits on examination, and the results of sensory nerve conduction studies were normal. The clinical and laboratory features of the 11 patients are described in Table 1. The follow-up during IVIg maintenance treatment ranged from 4 to 8 years. Data for the maximally 4-year follow-up of Patients 1–6 have been reported earlier (Van den Berg et al., 1998). Serum IgM anti-GM1 antibody detection (Van den Berg et al., 1992) and MRI of the brachial plexus were performed as described previously (Van Es et al., 1997).
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Study design
Patients were treated initially with one full course of IVIg (0.4 g/kg for 5 days) (Gammagard; Hyland Baxter, Los Angeles, CA, USA) followed by one IVIg infusion every week during the first year of IVIg maintenance treatment (Van den Berg et al., 1998
). The dosage and frequency of IVIg infusions during the remainder of the follow-up were tailored to each patient on the basis of functioning in daily life. If patients reported that functioning in daily life remained stable or improved, the maintenance dose was not changed. If patients deteriorated in their functioning in daily life, we used the results of hand-held dynamometry (see below) to titrate the increase in maintenance dose of IVIg for that individual patient. In Patients 2, 3 and 4, an intravenous access system (Port-a-Cath; Deltec Saint Paul, Minnesota, USA) was implanted, which enabled them to receive IVIg infusions at home supervised by a nurse as part of the home-care programme of our hospital. During follow-up, we measured muscle strength, disability and electrophysiological changes as described below.
Assessment of muscle strength
The strength of five muscles or muscle groups of each arm (those involved in shoulder abduction, elbow flexion, elbow extension, wrist flexion and wrist extension) and of five muscles or muscle groups of each leg (those involved in hip flexion, knee flexion, knee extension, ankle dorsiflexion and ankle plantar flexion) was measured bilaterally using the Medical Research Council (MRC) scale, yielding a maximal MRC sumscore of 100. In addition, we performed hand-held dynamometry in a selection (i.e. those muscle groups with an MRC score <5 on more than one occasion) of the muscle groups involved in shoulder abduction, elbow flexion, elbow extension, wrist extension, hand grip, hip flexion, knee flexion, knee extension and ankle dorsiflexion. Muscle strength was measured before the onset of IVIg treatment, within 2–3 weeks after the initial full IVIg course, and once a year during follow-up.
Assessment of disability
Upper and lower limb disability was scored using two disability subscales of the Guy’s Neurological Disability Scale (Sharrack and Hughes, 1999) before the onset of IVIg treatment, after the first full course of IVIg and at the last follow-up examination. Disability of the upper limbs was scored as: 0 = no upper limb problem; 1 = problems in one or both arms, not affecting functions such as doing zips or buttons, tying a bow in string, washing or brushing hair and eating; 2 = problems in one or both arms affecting some but not preventing any of the functions listed; 3 = problems in one or both arms, affecting all or preventing one or two of the functions listed; 4 = problems in one or both arms preventing three of the functions listed; 5 = unable to use either arm for any purposeful movements. Disability of the lower limbs was scored as follows: 0 = walking is not affected; 1 = walking is affected but patient is able to walk independently; 2 = usually uses unilateral support (stick, arm or ankle foot orthoses) to walk outdoors but walks independently indoors; 3 = usually uses bilateral support to walk outdoors, or unilateral support to walk indoors; 4 = usually uses a wheelchair to travel outdoors or bilateral support to walk indoors; 5 = usually uses a wheelchair indoors.
Electrophysiological studies
All electrophysiological studies were performed by the same examiner (H.F.). Motor nerve conduction was measured with a surface electrode EMG (electromyography) on both sides. Prior to an investigation, the arms and legs were warmed in water at 37°C for at least 30 min (Franssen and Wieneke, 1994). Motor nerve conduction was analysed up to the axilla in the median (recording m. abductor pollicis brevis) and ulnar (recording m. abductor digiti V) nerves and up to the popliteal fossa in the deep peroneal (recording m. extensor digitorum brevis) nerve. Additional nerves or nerve segments were investigated to establish the diagnosis of MMN; the results were not analysed because these nerves were not investigated in all patients.
For each compound muscle action potential (CMAP), the amplitude and area of the negative part were determined. For each nerve segment the amplitude reduction on proximal versus distal stimulation (P/D) and area reduction (P/D), calculated as (distal CMAP – proximal CMAP)100%/distal CMAP, were determined. For each nerve the distal amplitude (mV) and distal area (mV/ms), i.e. the amplitude or area of the CMAP on stimulation of the wrist or ankle, the proximal amplitude (mV) and proximal area (mV/ms), i.e. the amplitude or area of the CMAP on stimulation of the axilla or popliteal fossa, and the total amplitude reduction (mV) and total area reduction (mV/ms), calculated as distal minus proximal amplitude or area, were determined. Definite conduction block was defined as an area reduction P/D of at least 50% (Rhee et al., 1990; Franssen et al., 1999; Van den Berg-Vos et al., 2000a) and probable conduction block as an amplitude reduction P/D of at least 30% in an arm nerve (Albers et al., 1985; Franssen et al., 1997; Van den Berg-Vos et al., 2000a). Conduction block was only scored when the distal amplitude of the segment was at least 1 mV. Low CMAPs in a nerve were scored when the distal and proximal amplitude were below the lower limit of normal of our laboratory, i.e. below 3.5 mV for the median nerve, 2.8 mV for the ulnar nerve and 2.5 mV for the peroneal nerve. If necessary, a collision technique was used to detect effects of co-stimulation (Kimura, 1989; Van den Berg et al., 1997). EMGs were performed before the initial IVIg course (t = 0) and once a year (t = 1–8) during follow-up.
Statistical analysis
A paired t-test was used to compare mean MRC sumscores before and after the first full course of IVIg and before IVIg treatment and after the last follow-up examination. The functional impairment scores before and after the first full course of IVIg and the electrophysiological variables before and after follow-up were compared using Wilcoxon’s matched pairs test. Simple linear regression was used to evaluate the change in MRC sumscore and functional impairment score from after the first full course of IVIg until after the last follow-up examination, and the slope was calculated for each patient. A t-test was used to evaluate the null hypothesis that the average of the slopes was not significantly different from zero. Subsequently, a multiple linear regression model was used to evaluate the effect of various baseline variables on the changes in slopes of the MRC sumscores. With a t-test we additionally evaluated whether the slope of the MRC sumscores for the group of patients with disease restricted to the upper limbs at the onset of treatment was significantly different from that for the group of patients with disease in both upper and lower limbs. A P value <0.05 was considered to be significant.
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Results |
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Muscle strength
At onset of treatment, weakness was restricted to the upper limbs in four patients. At the last follow-up examination weakness remained restricted to the upper limbs in two of these four patients. At onset of treatment, only one patient had weakness in muscle groups innervated by one or two nerves; this patient had more widespread muscle weakness at the last follow-up examination. In contrast, two patients showed weakness in muscle groups innervated by more than two nerves at onset of treatment but improved during IVIg maintenance treatment, such that at the last follow-up examination weakness was only found in muscle groups innervated by one or two nerves.
The MRC sumscores for each patient during IVIg maintenance treatment are shown in Fig. 1. The mean MRC sumscore of all patients was 92 (SD 7) before and 95 (SD 6) after the first full course of IVIg (P < 0.001). The mean MRC sumscore at the last follow-up examination was 94 (SD 7), which was also significantly higher than the mean MRC sumscore before the first full course of IVIg (P < 0.001). The average slope of the MRC sumscores from after the first full course of IVIg until the last follow-up examination was –0.2 (SD 0.2). Comparing this average slope with the values at after the first full course of IVIg revealed a significant decline in MRC sumscore during follow-up (P < 0.01). A multiple linear regression model did not show any clinical or laboratory baseline variable to have influenced the average slope of the MRC sumscores. There was no significant difference in the slopes of the group of patients with weakness restricted to the upper limbs at onset of treatment and the group of patients with weakness in upper and lower limbs.
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The results of hand-held dynamometry measured in those muscle groups whose strength improved or worsened by
25% during follow-up are shown in Table 2. These data show that muscle strength either improved or worsened in individual patients, and that only in Patient 10 muscle strength improved in some muscle groups and worsened in others.
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Disability
The upper limb disability scores improved in seven patients and remained unchanged in four patients after the first full course of IVIg, a significant improvement (P < 0.02). The lower limb disability scores of three patients improved and in eight patients the lower limb disability score remained unchanged after the first full course of IVIg; this was not significant (Table 1). The average slope of the upper limb disability scores from after the first full course of IVIg until the last follow-up examination was –0.1 (SD 0.8) and for the lower limb disability scores it was –0.4 (SD 0.7). Comparing these average slopes with the values after the first full course of IVIg revealed that the declines in upper and lower limb disability scores during follow-up were not significantly different from zero.
Electrophysiological studies
Before IVIg treatment, conduction block was found in 18 nerve segments (seven median nerve segments, 10 ulnar nerve segments and one peroneal nerve segment) (Table 3). Conduction block was still present in 12 of these segments (three median nerve segments, eight ulnar nerve segments and one peroneal nerve segment) at the last follow-up examination, and new conduction block was detected in eight nerve segments (four median nerve segments and four ulnar nerve segments). Before IVIg treatment, Low CMAPs were found in 13 nerves (five median, four ulnar and four peroneal nerves). At the last follow-up examination, low CMAPs were still found in these 13 nerves and in addition in one peroneal nerve.
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Changes of >2.0 mV in CMAP amplitude or of >25% in amplitude reduction P/D or area reduction P/D (van Dijk et al., 1999
) were scored to analyse changes in electrophysiological variables during IVIg maintenance treatment. These criteria are based upon intraobserver studies on CMAP amplitude and conduction block performed by one of the authors (H.F.) in patients with MMN who were investigated several times at an interval of 1 week (unpublished). Six types of change during IVIg treatment were identified (see below) (Table 3), and these changes were attributed to one or more pathophysiological mechanisms: remyelination, reinnervation, demyelination and axon loss. The six types of change included: Type 1: Increase in the amplitude of all CMAPs. We attributed this to remyelination that restored conduction in previously blocked fibres distal to the wrist or ankle, or to reinnervation either due to collateral sprouting or due to axonal regeneration (ingrowth of previously damaged axons along the basal lamina) in previously denervated motor units. This occurred in six nerves: three median nerves (Patients 1, 4 and 8), two ulnar nerves (both in Patient 11) and one peroneal nerve (Patient 11).
Type 2: Decrease in the amplitude of all CMAPs (Fig. 2A). We attributed this to distal demyelination yielding conduction block distal to the wrist or ankle or to axon loss. This was seen in 11 nerves: five median nerves (Patients 1, 3, 5, 9 and 11), one ulnar nerve (Patient 5) and five peroneal nerves (Patients 3, 5, 6, 7 and 11).
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Type 3: Decrease in CMAP reduction P/D in a nerve segment without change in the distal CMAP. We attributed this to remyelination of the nerve segment that either restored conduction in previously blocked nerve fibres or decreased temporal dispersion. This was seen in seven nerves: five median nerves (Patients 1, 3, 5, 8 and 11) and two ulnar nerves (Patients 8 and 10).
Type 4: Increase in CMAP reduction P/D in a nerve segment without change in the distal CMAP (Fig. 2B). We attributed this to demyelination of the nerve segment that either yielded conduction block or increased temporal dispersion. This was seen in six nerves: three median nerves (Patients 1, 2 and 5) and three ulnar nerves (Patients 1, 4 and 7).
Type 5: Increase in CMAP reduction P/D in a nerve segment due to increase in the distal CMAP; the CMAP reduction P/D now fulfilled criteria for conduction block (Fig. 2C). We attributed this to distal remyelination that restored conduction in previously blocked nerve fibres, which in turn resulted in the appearance of conduction block in a more proximal segment, or to reinnervation due to axonal regeneration but not to collateral sprouting of previously denervated motor units. This occurred in four nerves: in the lower arm segment of one median nerve (Patient 6), in the upper arm segment of one median nerve (Patient 4) and in the lower arm segment of two ulnar nerves (Patients 2 and 4).
Type 6: Decrease in CMAP reduction P/D in a nerve segment due to decrease in the distal CMAP; the CMAP reduction P/D no longer fulfilled the criteria for conduction block. We attributed this to distal demyelination which yielded distal conduction block or to axon loss in previously blocked nerve fibres. This was seen in two nerves: in the lower arm segment of one median nerve (Patient 6) and in the upper arm segment of one ulnar nerve (Patient 2).
Changes consistent with improvement (‘remyelination’ or ‘reinnervation’, i.e. a change of type 1, 3 or 5) occurred in 13 nerves and changes consistent with worsening (‘demyelination’ or ‘axon loss’, i.e. change of type 2, 4 or 6) occurred in 14 nerves during the follow-up period. In one of the nerves (Table 3; median nerve of Patient 5) two sequential changes were observed, both implying worsening. In three nerves, two to four changes per nerve were observed, implying improvement followed by worsening (Table 3; median nerve of Patients 1 and 11) or worsening followed by improvement (Table 3; ulnar nerve of Patient 2); these nerves were not scored as showing improvement or worsening. In 36 of the 66 investigated nerves no changes were observed. Improvement was significantly associated with the presence of conduction block before IVIg treatment: eight of the 13 nerves that improved during follow-up had conduction block before IVIg treatment, whereas only two of the 14 nerves that worsened during follow-up had conduction block before IVIg treatment (P < 0.02).
In the 17 nerves with conduction block before IVIg treatment, the mean distal and proximal amplitude and area were higher and the mean total amplitude and area reduction were lower at the last follow-up examination than before treatment (Table 4). This was significant for the proximal amplitude and area. In contrast, in the 42 nerves in which no conduction block was demonstrated before IVIg treatment or after follow-up, the mean distal and proximal amplitudes and areas were lower, and the total amplitude and area reduction were higher after follow-up than before IVIg treatment. This was significant for the distal area and the proximal amplitude and area.
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Adverse effects
In all patients, IVIg maintenance treatment was well tolerated over the years and the side-effects described previously (headache, rash, fatigue) (Van den Berg et al., 1995
b; Van den Berg et al., 1998) only caused minor inconvenience. |
Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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In this study of 11 patients with MMN who received IVIg maintenance treatment for 4–8 years, we found that muscle strength and upper limb disability scores were significantly better at the last follow-up examination than before IVIg treatment. During IVIg maintenance treatment, however, a slight but statistically significant decrease in MRC sumscores was observed. In individual muscle groups strength improved or deteriorated during the follow-up period. This is consistent with the electrophysiological changes, which showed evidence of improvement (remyelination or reinnervation), predominantly in nerves with conduction block before treatment, but also evidence of deterioration (demyelination or axonal loss), predominantly in nerves in which no conduction block was found either before treatment or during the follow-up period.
Only two previous studies have described the long-term effect of IVIg maintenance treatment in patients with MMN, but the follow-up in these studies was <4 years. In a previous study we reported seven patients who were on IVIg maintenance treatment for 2–4 years (Van den Berg et al., 1998). In the present study, we included five new patients, the follow-up was substantially longer and the electrophysiological changes during follow-up were analysed in greater detail. In another study, 12 out of 18 patients with MMN responded to repeated IVIg infusions (Azulay et al., 1997). In contrast to our study, no electrophysiological follow-up was performed. All 12 patients showed an improvement in muscle strength of at least 30% after 9–48 months. In most of these patients long-term IVIg maintenance treatment was necessary to sustain the improvement in muscle strength. However, in two patients treatment could be withdrawn after intermittent IVIg treatment for several months because both patients showed no deterioration after a follow-up of 1 year. Only one of the patients reported in our previous study has been in remission for 5 years after only two IVIg courses. This patient was not included in the present study as he no longer receives IVIg maintenance treatment.
Although remission of MMN, unlike that of chronic inflammatory demyelinating polyneuropathy, is very uncommon, a thorough evaluation of the effect of the first course of IVIg treatment is important before expensive and burdensome IVIg maintenance treatment is started. In none of the patients of the present study was remission induced by long-term IVIg maintenance treatment, because discontinuation of IVIg maintenance treatment led to a deterioration of muscle strength. In another long-term study, six patients were treated with IVIg maintenance treatment in combination with oral cyclophosphamide such that the interval between IVIg infusions could be prolonged and IVIg treatment could be stopped in some patients (Meucci et al., 1997). After a mean follow-up period of 47 months, the MRC sumscore, the Rankin disability scale and the upper and lower limb impairment scores were significantly improved. However, cyclophosphamide was eventually stopped in most patients because of adverse effects (E.Nobile-Orazio, personal communication). Interestingly, in this study one patient developed weakness in muscle groups that were not affected before IVIg treatment was started. Deterioration of muscle strength during IVIg maintenance treatment was also observed in eight muscle groups of our patients. As we tailored the regimen of IVIg maintenance treatment on the basis of functioning in daily life and not primarily on the measurements of muscle strength, we cannot exclude the possibility that deterioration of muscle strength is due to the progression of disease or merely represents an insufficient IVIg maintenance treatment regimen. Due to the high cost of IVIg, it seems rational to increase the dose or frequency of IVIg infusions only when a patient notices deterioration of functioning in daily life.
A decrease in conduction block during IVIg therapy has been reported in several studies (Chaudhry et al., 1993; Nobile-Orazio et al., 1993; Comi et al., 1994; Van den Berg et al., 1995a, b; Federico et al., 2000; Léger et al., 2001), but long-term electrophysiological follow-up studies of patients with MMN are rare (Meucci et al., 1997; Van den Berg et al., 1998). Meucci et al. (1997) reported a significant improvement of conduction block during treatment in 15 of 60 nerves, and new conduction block was found in one nerve. Our electrophysiological studies revealed significant changes during the follow-up period. It is unlikely that these changes were due to intraobserver variation or fluctuations in temperature as the criteria for CMAP amplitude changes were based on our own intra-observer studies and the limbs were warmed in water at 37°C for at least 30 min before each EMG. Histopathological studies of MMN revealed demyelination, small onion bulbs indicative of poor remyelination, axonal damage, and regenerative clusters indicative of axonal regeneration (Kaji et al., 1993; Corbo et al., 1997) Conduction block in MMN is most likely due to demyelination, but blocking of sodium ion channels at the axolemma of the node of Ranvier (Takigawa et al., 1995) cannot be fully excluded despite the failure to induce sodium ion channel blocking by short-term application of anti-GM1 antibodies (Hirota et al., 1997). The presence of muscle atrophy and signs of denervation and collateral sprouting on concentric needle examination that have been found in patients with MMN are also indicative of axon involvement (Parry, 1996; Taylor et al., 2000). Although it is based upon investigations in a few patients, the evidence described above suggests that remyelination, demyelination, axonal regeneration, collateral sprouting and axon loss all occur in patients with MMN. At present, the effects of these mechanisms can be estimated only by repeated electrophysiological investigation. For these reasons, we tried to explain the electrophysiological changes in terms of these mechanisms. However, the relative contributions of these mechanisms are not known. In the present study, 18 nerve segments had conduction block before IVIg treatment; in six segments the conduction block disappeared during the follow-up period. Although this suggests that IVIg treatment induces remyelination, new conduction block developed in four nerve segments during the follow-up period. In four other nerves conduction block appeared during treatment, together with an increase in distal amplitude (a change of type 5). It is possible that the latter does not represent new conduction block but merely the unmasking of previously undetected conduction block in a more proximal segment due to remyelination distal to the wrist (Cappellari et al., 1996). Although these findings suggest a rather limited effect of IVIg treatment, the significant increase in the proximal CMAP amplitude and area in nerves with conduction block before IVIg treatment implies that IVIg treatment favourably influenced the mechanisms of remyelination in these nerves. In contrast, in those nerves in which conduction block was found neither before treatment nor during follow-up, there was a significant decrease in distal CMAP area and proximal CMAP amplitude and area. This can be explained by demyelination yielding conduction block distal to the wrist or ankle, but also by axon loss. An increase in CMAP reduction yielding conduction block in the much longer lower arm or upper arm segments was found in only four nerves without conduction block during the follow-up period. As demyelination probably occurs randomly over the whole length of a nerve (H.Franssen, unpublished observation), axon loss is more likely to occur than is the development of distal conduction block. Our findings therefore suggest that, in MMN, axon loss occurs despite IVIg treatment.
Although IVIg maintenance treatment does not prevent a mild global decrease in muscle strength and does not induce remission of MMN, we found that IVIg maintenance treatment had a beneficial long-term effect on muscle strength, upper limb disability and electrophysiological variables in nerves with conduction block, and that treatment was well tolerated. As there is currently no acceptable alternative treatment, IVIg maintenance treatment is indicated in patients with MMN, although the high cost of IVIg maintenance treatment is a strain on hospital budgets and is the subject of many discussions with insurance companies. The number of IVIg infusions that are necessary to maintain an acceptable level of functioning varies among patients and thus treatment needs to be individually tailored. The (side) effects of IVIg treatment in combination with immunosuppressive drugs that are less toxic than cyclophosphamide need to be investigated in future studies of the long-term treatment of patients with MMN.
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Acknowledgements |
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We wish to thank Hyland Baxter for giving statistical support. This work was supported by a grant from the Prinses Beatrix Fonds. The research of L.H.V.d.B. was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.
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