Intravenous immunoglobulin for multifocal motor neuropathy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective is to review systematically the evidence from randomised controlled trials concerning the efficacy and safety of intravenous immunoglobulin in multifocal motor neuropathy.
Background
Multifocal motor neuropathy (MMN) is characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation (Lewis 1982; Parry 1988; Nobile‐Orazio 2001; Nobile‐Orazio 2002). This weakness may be accompanied by muscular atrophy in later stages of the disease, and cramps and fasciculations are reported to occur in approximately 50% of people with MMN (Nobile‐Orazio 2001). The arms are usually more affected than the legs, and at an earlier stage (Van den Berg‐V 2000a; Nobile‐Orazio 2001; Nobile‐Orazio 2002). Tendon reflexes are often decreased or absent in the affected limb. Cranial nerve involvement and respiratory failure due to phrenic nerve palsy have occasionally been reported (Kaji 1992; Pringle 1997; Cavaletti 1998; Beydoun 2000). The hallmark of the disease is the presence of multifocal conduction block on electrophysiological testing outside the usual sites of nerve compression (Cornblath 1991; Kaji 1991; Parry 1992; Parry 1993; Van Asseldonk 2003). Conduction block is a reduction in the amplitude or area (or both) of the compound muscle action potential (CMAP) obtained by proximal versus distal stimulation of motor nerves in the absence of or with only focal abnormal temporal dispersion (Cornblath 1991; Nobile‐Orazio 2001; Kaji 2003). The extent of reduction of the CMAP amplitude and/or area necessary for conduction block is still a matter of debate. Definite conduction block is usually defined as an area reduction of 50% or more between proximal versus distal stimulation in a long nerve segment or an amplitude reduction of 30% or more over 2.5 cm (Rhee 1990; Franssen 1997). Probable conduction block is usually defined as an amplitude reduction of 30% or more between proximal versus distal stimulation in an arm nerve (Albers 1985; Oh 1994).
Almost 80% of people with MMN are between 20 and 50 years of age at onset of the disease (Nobile‐Orazio 2001). Men are more frequently affected than women with a ratio of 2.6:1 (Nobile‐Orazio 2001). The prevalence is estimated to be 1 to 2 per 100,000 (Nobile‐Orazio 2001). The diagnosis of MMN is based on clinical, laboratory and electrophysiological characteristics (Parry 1992; Van den Berg‐V 2000a; Hughes 2001; Nobile‐Orazio 2001). A set of diagnostic criteria has been proposed that combines clinical, laboratory, and electrophysiological features of people with MMN, which may help to predict whether individuals will respond to treatment (Van den Berg‐V 2000a). Recently, the American Association of Electrodiagnostic Medicine has developed five criteria through a formal consensus process for diagnosing MMN with a high level of confidence (Olney 2003). These criteria for definite MMN are: weakness without objective sensory loss in the distribution of two or more named nerves; definite conduction block in two or more nerves outside of common entrapment sites; normal sensory nerve conduction velocity across the same segments with demonstrated motor conduction block; normal results for sensory nerve conduction studies on all tested nerves, with a minimum of three nerves tested; and absence of upper motor neuron signs. The criteria for probable MMN are somewhat less strict for conduction block.
Multifocal motor neuropathy seems to be an immune mediated disorder. Firstly, 30% to 80% of people with MMN have serum IgM GM1 antibodies (Van Schaik 1995). Secondly, increased signal intensities on T2‐weighted MR images of the brachial plexus have been observed in people with MMN suggesting an inflammatory process (Van Es 1997). Finally, a beneficial effect of cyclophosphamide (Pestronk 1988; Krarup 1990; Feldman 1991; Chaudhry 1993; Meucci 1997; Van Es 1997) and INF‐beta1a (Martina 1999; Van den Berg‐V 2000b) in MMN has been suggested in several uncontrolled studies and reviewed in a Cochrane systematic review (Umapathi 2003). The treatment options for people with MMN are sparse. In contrast to the response in people with CIDP, those with MMN do not usually respond to steroids or plasma exchange, and may worsen when they receive these treatments, as reviewed by Nobile‐Orazio (Nobile‐Orazio 2001). Cyclophosphamide has serious long‐term side effects and INF‐beta1a has been tested in very limited numbers of people with MMN.
The efficacy of intravenous immunoglobulin (IVIg) has been suggested in an overwhelming number of open and uncontrolled studies including at least 100 people with MMN. To date three randomised controlled double‐blind trials of IVIg for treating MMN have been done (Azulay 1994; Federico 2000; Léger 2001). The ways by which IVIg exerts this beneficial effect in MMN are not clear, but various mechanisms of improvement after IVIg treatment have been suggested (Van Schaik 1994; Yu 1999). Studies in other diseases treated with IVIg have demonstrated that IVIg may inhibit auto‐antibody production, neutralize pathogenic antibodies, and decrease antibody‐dependent cellular cytotoxicity by blocking Fc‐receptors on macrophages (Kazatchkine 2001). Furthermore, peripheral blood from patients treated with IVIg shows increased CD8‐positive suppressor T‐cell function.
We will provide a systematic review of the randomised trials of IVIg for treating MMN.
Objectives
The objective is to review systematically the evidence from randomised controlled trials concerning the efficacy and safety of intravenous immunoglobulin in multifocal motor neuropathy.
Methods
Criteria for considering studies for this review
Types of studies
We will search for all randomised or quasi‐randomised (alternate or other systematic allocation) studies examining the effects of IVIg treatment in people with MMN.
Types of participants
Eligible studies will include unselected participants with definite or probable MMN according to the published criteria (Van den Berg‐V 2000a; Olney 2003). This is defined as a slowly or stepwise progressive asymmetric lower motor neuron syndrome with no bulbar or upper motor signs and evidence of definite or probable conduction block in motor nerves. Mild sensory symptoms are permitted as long as there are no sensory signs on examination and sensory nerve conduction studies are normal. Patients with upper motor neuron features or bulbar signs will be excluded. Other related conditions such as other neuropathies (diabetic, lead, porphyric, or vasculitic neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, Lyme neuroborreliosis, postradiation neuropathy, hereditary neuropathy with liability to pressure palsies, Charcot‐Marie‐Tooth disease, or paraproteinemic neuropathies) and myopathies (facioscapulohumeral muscular dystrophy, inclusion body myositis), will be excluded if indicated.
Types of interventions
We will consider any dose of immunoglobulin administered intravenously compared with placebo or any other treatment. All brands of IVIg will be included provided that the preparation has been produced according to the guidelines of the WHO (WHO 1982).
Types of outcome measures
PRIMARY OUTCOME MEASURE
Since different studies have used different disability scales, the primary outcome measure will be defined as the proportion of participants with a significant improvement in disability within one month after the last treatment and compared to baseline as determined and defined by the original authors. In each study the strictest available criteria to define 'significant' improvement will be used. As IVIg is thought to induce and maintain improvement in the majority of people with MMN, but does not eradicate the disease, patients have to be treated with periodic infusions for long periods of time. Outcome assessment within one month after the last IVIg treatment probably will reflect best the treatment responses of these patients.
SECONDARY OUTCOME MEASURES
Secondary outcome measures will be:
(1) the proportion of patients with a significant improvement of muscle strength as determined and defined by the original authors assessed within one month after the last treatment and compared to baseline;
(2) the mean change in muscle strength expressed as effect size assessed within one month after the last treatment and compared to baseline;
(3) the proportion of patients with a sustained significant improvement in disability as determined and defined by the original authors at 12 months or later;
(4) the proportions of patients in which at least one conduction block has resolved after therapy assessed within one month after the last treatment and compared to baseline;
(5) the frequency of adverse effects attributable to treatment during the whole study period.
Search methods for identification of studies
We will search the Cochrane Neuromuscular Disease Group trials register, MEDLINE (from 1990 to the present), EMBASE (from 1990 to the present), and ISI (from 1990 to the present) using the keywords and textwords: 'motor neuron disease', 'demyelinating neuropathy', 'motor neuropathy', 'multifocal motor neuropathy', 'multifocal demyelinating motor neuropathy', 'ganglioside GM1', 'nerve block', 'immunoglobulin', 'immunoglobulin G', 'intravenous drug administration'. The search will be restricted to articles published from 1990 onwards because to our knowledge IVIg was first used in MMN in 1990. A search of the references listed in the published studies, reviews, textbooks, and relevant conference proceedings will be performed. Investigators identified as active in the field will be contacted to identify unpublished or overlooked studies. Readers will be invited to suggest studies, particularly in other languages, which should be considered for inclusion when the review is updated.
OVID MEDLINE strategy
1. randomized controlled trial.pt.
2. randomized controlled trials/
3. controlled clinical trial.pt.
4. controlled clinical trials/
5. random allocation/
6. double‐blind method/
7. single‐blind method/
8. clinical trial.pt.
9. exp clinical trials/
10. (clin$ adj25 trial$).tw.
11. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$ or dummy)).tw.
12. placebos/
13. placebo$.tw.
14. random$.tw.
15. research design/
16. (clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
17. multicenter study.pt.
18. meta analysis.pt.
19. Prospective Studies/
20. Intervention Studies/
21. Cross‐Over Studies/
22. Meta‐Analysis/
23. (meta?analys$ or systematic review$).tw.
24. control.tw.
25. or/1‐24
26. Animal/
27. Human/
28. 26 and 27
29. 26 not 28
30. 25 not 29
31. inflammatory demyelinating.tw.
32. (polyradiculoneuropath$3 or polyneuropath$3).tw.
33. Polyneuropathies/ or Polyradiculoneuropathy/
34. (polyneuritis or polyradiculoneuritis).tw.
35. 32 or 33 or 34
36. Chronic disease/ or "chronic disease".mp.
37. 31 and 35 and 36
38. cidp.tw.
39. 37 or 38
40. exp demyelinating diseases/
41. demyelinat$3.tw.
42. 40 or 41
43. (inflammatory adj5 neuropath$3).tw.
44. (inflammatory adj5 polyneuropath$3).tw.
45. 35 or 43 or 44
46. 36 and 42 and 45
47. 39 or 46
48. multifocal motor neuropath$.mp.
49. 47 or 48
50. exp Motor Neuron Disease/
51. (amyotrophic lateral sclerosis or motor neuron$1 disease$1 or motoneuron$1 disease$1).tw.
52. (mnd or als).tw.
53. 50 or 51 or 52
54. motor neuropath$.tw.
55. 49 or 53 or 54
56. ganglioside gm1.tw.
57. nerve block.mp. or exp Nerve Block/
58. exp Immunoglobulins/
59. immunoglobulin$.tw.
60. Injections, Intravenous/
61. intravenous.tw.
62. or/56‐61
63. 55 and 62
64. 55 and (56 or 57 or ((58 or 59) and (60 or 61)))
65. (immune adj3 globulin$).tw.
66. ivig.tw.
67. (immunoglobulins adj3 intravenous).mp.
68. 55 and (56 or 57 or 67 or 66 or 65 or (((58 or 59) and 60) or 61))
69. 30 and 68
Data collection and analysis
SELECTING TRIALS FOR INCLUSION
Two reviewers (IvS and LvdB) will independently review titles and abstracts obtained from literature searches. From the full texts, the reviewers will select the trials which meet the selection criteria for inclusion and grade their methodological quality. Reviewers will not be blinded to author and source institution. Disagreement will be resolved by consensus.
ASSESSMENT OF METHODOLOGICAL QUALITY
Methodological quality will take into account allocation concealment, a secure method of randomisation, patient blinding, observer blinding, explicit inclusion criteria, extent to which the study takes into account any imbalance in prognostically important variables present at the time of randomisation, and explicit outcome criteria. Quality indices will be graded A: adequate, B: unclear, if there was inadequate information to judge the index, and C: inadequate, if the index was inadequately addressed, and D: not done.
METHODS USED TO COLLECT DATA FROM INCLUDED TRIALS
Two reviewers will extract data independently using a data extraction tool. Disagreement will be resolved by consensus.
STATISTICAL ANALYSIS
For dichotomous data, such as the proportion of patients with a significant improvement in disability, we will calculate the relative risk for each study. To assess overall efficacy from all the studies, we will calculate pooled relative risk estimates. When chi‐square analysis shows our data to be heterogeneous, we will use the random effects model of DerSimonian and Laird (Ioannidis 1995). If no heterogeneity can be demonstrated, we will use a fixed effect model (Mantel‐Haenszel risk ratio method) (Rothman 1986). With regard to continuous data (changes in muscle strength), we will calculate weighted mean differences (WMD) if muscle strength assessment is sufficiently comparable between studies; if not, effect sizes will be calculated for each study. Effect size is defined as the mean change in score of the placebo group minus mean change in score of the treatment group, divided by the pooled standard deviation of the change in scores of the two groups. Means and standards deviations will be derived by calculation or extraction from the available data (all authors will be asked for the original data to enable effect size calculation). Individual WMD will be pooled using Review Manager 4.2 (RevMan). Individual weighted effect sizes will be pooled according to the method described in the Handbook of Research Synthesis (Shadish 1994). We will use 1/variance as the weights. The effect size calculations are not possible in RevMan and will be performed in the spreadsheet program EXCEL.
The results from the crossover trials will be analysed as if they had come from a parallel group trial assuming that no carryover effect had occurred. This means that the standard deviations of means and relative risks will be over‐estimated and thus crossover studies will be under‐weighted in the pooled results. This is not completely ideal but unavoidable if an effort is made to assess efficacy from all available studies. In the text, pooled relative risk estimates will be given separately for all studies and for the parallel design trials only. Furthermore, forest plot analysis will be done to reveal whether there are any differences between crossover and parallel group trials. The statistical uncertainty will be expressed with 95% confidence intervals.
If there is heterogeneity, we will investigate its source by repeating the analysis after elimination of trials which score less than A on each of the indices of quality, paying particular attention to allocation concealment.
DISCUSSION
Open and uncontrolled studies will be reviewed and discussed to assess the magnitude of publication bias. Adverse events of IVIg from the non‐randomised literature will be discussed in relation to the adverse events found in this review. The discussion will include a consideration of costs.
