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. 2022 Jan 11;1(1):CD004429.
doi: 10.1002/14651858.CD004429.pub3.

Immunoglobulin for multifocal motor neuropathy

Stephen Keddie  1 , Filip Eftimov  2 , Leonard H van den Berg  3 , Ruth Brassington  4 , Rob J de Haan  5 , Ivo N van Schaik  2
Affiliations

Immunoglobulin for multifocal motor neuropathy

Stephen Keddie et al. Cochrane Database Syst Rev. .

Abstract

Background: Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated disorder characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation. It may cause prolonged periods of disability. Treatment options for MMN are few. People with MMN do not usually respond to steroids or plasma exchange. Uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin (IVIg). This is an update of a Cochrane Review first published in 2005, with an amendment in 2007. We updated the review to incorporate new evidence.

Objectives: To assess the efficacy and safety of intravenous and subcutaneous immunoglobulin in people with MMN.

Search methods: We searched the following databases on 20 April 2021: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP for randomised controlled trials (RCTs) and quasi-RCTs, and checked the reference lists of included studies.

Selection criteria: We considered RCTs and quasi-RCTs examining the effects of any dose of IVIg and subcutaneous immunoglobulin (SCIg) in people with definite or probable MMN for inclusion in the review. Eligible studies had to have measured at least one of the following outcomes: disability, muscle strength, or electrophysiological conduction block. We used studies that reported the frequency of adverse effects to assess safety.

Data collection and analysis: Two review authors independently reviewed the literature searches to identify potentially relevant trials, assessed risk of bias of included studies, and extracted data. We followed standard Cochrane methodology.

Main results: Six cross-over RCTs including a total of 90 participants were suitable for inclusion in the review. Five RCTs compared IVIg to placebo, and one compared IVIg to SCIg. Four of the trials comparing IVIg versus placebo involved IVIg-naive participants (induction treatment). In the other two trials, participants were known IVIg responders receiving maintencance IVIg at baseline and were then randomised to maintenance treatment with IVIg or placebo in one trial, and IVIg or SCIg in the other. Risk of bias was variable in the included studies, with three studies at high risk of bias in at least one risk of bias domain. IVIg versus placebo (induction treatment): three RCTs including IVIg-naive participants reported a disability measure. Disability improved in seven out of 18 (39%) participants after IVIg treatment and in two out of 18 (11%) participants after placebo (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.89 to 10.12; 3 RCTs, 18 participants; low-certainty evidence). The proportion of participants with an improvement in disability at 12 months was not reported. Strength improved in 21 out of 27 (78%) IVIg-naive participants treated with IVIg and one out of 27 (4%) participants who received placebo (RR 11.00, 95% CI 2.86 to 42.25; 3 RCTs, 27 participants; low-certainty evidence). IVIg treatment may increase the proportion of people with resolution of at least one conduction block; however, the results were also consistent with no effect (RR 7.00, 95% CI 0.95 to 51.70; 4 RCTs, 28 participants; low-certainty evidence). IVIg versus placebo (maintenance treatment): a trial that included participants on maintenance IVIg treatment reported an increase in disability in 17 out of 42 (40%) people switching to placebo and seven out of 42 (17%) remaining on IVIg (RR 2.43, 95% CI 1.13 to 5.24; 1 RCT, 42 participants; moderate-certainty evidence) and a decrease in grip strength in 20 out of 42 (48%) participants after a switch to placebo treatment compared to four out of 42 (10%) remaining on IVIg (RR 0.20, 95% CI 0.07 to 0.54; 1 RCT, 42 participants; moderate-certainty evidence). Adverse events, IVIg versus placebo (induction or maintenance): four trials comparing IVIg and placebo reported adverse events, of which data from two studies could be meta-analysed. Transient side effects were reported in 71% of IVIg-treated participants versus 4.8% of placebo-treated participants in these studies. The pooled RR for the development of side effects was 10.33 (95% CI 2.15 to 49.77; 2 RCTs, 21 participants; very low-certainty evidence). There was only one serious side effect (pulmonary embolism) during IVIg treatment. IVIg versus SCIg (maintenance treatment): the trial that compared continuation of IVIg maintenance versus SCIg maintenance did not measure disability. The evidence was very uncertain for muscle strength (standardised mean difference 0.08, 95% CI -0.84 to 1.00; 1 RCT, 9 participants; very low-certainty evidence). The evidence was very uncertain for the number of people with side effects attributable to treatment (RR 0.50, 95% CI 0.18 to 1.40; 1 RCT, 9 participants; very low-certainty evidence).

Authors' conclusions: Low-certainty evidence from three small RCTs shows that IVIg may improve muscle strength in people with MMN, and low-certainty evidence indicates that it may improve disability; the estimate of the magnitude of improvement of disability has wide CIs and needs further studies to secure its significance. Based on moderate-certainty evidence, it is probable that most IVIg responders deteriorate in disability and muscle strength after IVIg withdrawal. SCIg might be an alternative treatment to IVIg, but the evidence is very uncertain. More research is needed to identify people in whom IVIg withdrawal is possible and to confirm efficacy of SCIg as an alternative maintenance treatment.

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Conflict of interest statement

Stephen Keddie: is employed by Barts and the Royal London NHS Trust and University College London Hospitals NHS trust bank for clinical neurology work. Dr Keddie's research is funded by a clinical training research fellowship awarded by the Association of British Neurologists and Guarantors of Brain. Dr Keddie is a neurology specialist registrar and manages patients with multifocal motor neuropathy.

Filip Eftimov: Dr Eftimov received support for printing of his thesis from Sanquin Bloedvoorziening (Dutch blood bank and IVIg manufacturer) and CSL‐Behring in 2014. He reports lecture fees from CSL‐Behring, Kedrion, and Grifols. Outside of the submitted work, as principal investigator of INCbase, he also reports investigator‐initiated grants from Kedrion, Terumo BCT, CSL‐Behring, and Takeda Pharmaceutical Company, and grants from ZonMw (Dutch governmental agency) and Prinses Beatrix Spierfonds (a Dutch charity). In addition, his institution has received fees from UCB Pharma, CSL‐Behring, and Takeda for advisory board membership. All grants and fees were paid to his institution. He is a member of the Cochrane Neuromuscular Editorial Board.

Leonard H van den Berg: has co‐ordinated one randomised controlled trial of IVIg in multifocal motor neuropathy, which is included in this review. He received remuneration for sitting on scientific advisory boards of Baxter and Biogen Idec. His institution has received financial support from Baxter for organisation of an multifocal motor neuropathy masterclass.

Ruth Brassington: none known. She is Managing Editor of Cochrane Neuromuscular. She relinquished editorial responsibility for the review after joining the author team.

Rob J de Haan: none known.

Ivo N van Schaik: chaired a steering committee for a CSL‐Behring study investigating the safety and efficacy of SCIg in chronic inflammatory demyelinating polyradiculoneuropathy and received departmental honoraria for serving on scientific advisory boards for CSL‐Behring and Kedrion. He received departmental research support from the Netherlands Organisation for Scientific Research and the Dutch Prinses Beatrix Fonds. All lecturing and consulting fees for INvS were donated to the Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders. INvS served on the editorial board of Cochrane Neuromuscular, was a member of the organising committee of the Inflammatory Neuropathy Consortium (INC), a standing committee of the Peripheral Nerve Society, and was a member of the Scientific Board of the Kreuth III meeting on the optimal use of plasma‐derived medicinal products, especially coagulation factors and normal immunoglobulins, organised under the auspices of the European Directorate for the Quality of Medicines & HealthCare (EDQM).

This review does not comply with the relevant Cochrane Conflicts of Interest policy, revised in 2014, which requires the majority of review authors to have no relevant conflicts of interest. The review will be updated a year after publication, when the review will comply with the policy.

Figures

1
1
Study selection flow chart.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Key: red (‐) = high risk of bias, yellow (?) = unclear risk of bias, green (+) = low risk of bias.
3
3
IVIg versus placebo. Proportion of participants with an improvement in disability as determined and defined by the study authors. In all forest plots, the 'Total' columns show the number of observations.
4
4
IVIg versus placebo. Proportion of participants with an improvement in muscle strength.
5
5
IVIg versus placebo. Change in mean muscle strength in participants without IVIg treatment at study entry.
6
6
IVIg versus placebo. Proportion of participants in whom at least 1 conduction block resolved after therapy.
1.1
1.1. Analysis
Comparison 1: IVIg versus placebo, Outcome 1: Proportion of participants with an improvement in disability as determined and defined by the study authors
1.2
1.2. Analysis
Comparison 1: IVIg versus placebo, Outcome 2: Proportion of participants with an improvement in muscle strength
1.3
1.3. Analysis
Comparison 1: IVIg versus placebo, Outcome 3: Change in mean muscle strength in participants without IVIg treatment at study entry
1.4
1.4. Analysis
Comparison 1: IVIg versus placebo, Outcome 4: Proportion of participants in whom at least 1 conduction block resolved after therapy
1.5
1.5. Analysis
Comparison 1: IVIg versus placebo, Outcome 5: Proportion of IVIg‐treated participants with an increase in disability during controlled IVIg withdrawal, as defined and determined by the study authors
1.6
1.6. Analysis
Comparison 1: IVIg versus placebo, Outcome 6: Proportion of IVIg‐treated participants with a decrease in muscle strength during controlled IVIg withdrawal, as defined and determined by the study authors
1.7
1.7. Analysis
Comparison 1: IVIg versus placebo, Outcome 7: Change in mean muscle strength in participants with IVIg treatment at study entry
1.8
1.8. Analysis
Comparison 1: IVIg versus placebo, Outcome 8: Proportion of participants with side effects attributable to treatment
2.1
2.1. Analysis
Comparison 2: IVIg versus SCIg maintenance, Outcome 1: Change in mean muscle strength in participants with IVIg treatment at study entry
2.2
2.2. Analysis
Comparison 2: IVIg versus SCIg maintenance, Outcome 2: Proportion of participants with side effects attributable to treatment
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to other published versions of this review

Van Schaik 2003
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