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Léger MMN IVIg

Intravenous immunoglobulin therapy in multifocal motor neuropathy: A double-blind, placebo-controlled study

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Year of Publication: 2001

Authors: Jean-Marc Léger, Bénédicte Chassande, Lucile Musset, ..., Nicole Baumann

Journal: Brain

Citation: Brain 2001;124:145-153

Link: https://doi.org/10.1093/brain/124.1.145

Clinical Question

Is intravenous immunoglobulin (IVIg) effective in treating multifocal motor neuropathy (MMN) with persistent conduction block?

Bottom Line

IVIg is significantly more effective than placebo in MMN. At month 4, 78% of IVIg-first patients responded versus 22% of placebo-first patients (P=0.03). Self-evaluation scores showed significant improvement with IVIg. Prior IVIg exposure enhanced subsequent response. Anti-GM1 antibody titres did not correlate with treatment response, though patients with high titres (>3200) were more likely to respond.

Major Points

  • First adequately powered double-blind, placebo-controlled trial of IVIg in MMN with crossover design
  • 19 patients enrolled: 10 IVIg-naïve (Group 1) and 9 previous IVIg responders (Group 2)
  • Primary endpoint: Significant difference in responder rate at month 4 (7/9 IVIg-first vs 2/9 placebo-first; P=0.03)
  • Self-evaluation score showed significant improvement with IVIg (median change -7) vs placebo (median change 0)
  • MRC score improved significantly in IVIg patients but difference vs placebo was not statistically significant
  • Previously treated patients (Group 2) showed higher response rates than treatment-naïve patients
  • Electrophysiological studies did not show significant differences between groups in motor parameters
  • 4/5 patients with high anti-GM1 titres (>3200) responded to IVIg, but titres did not change significantly with treatment
  • Non-responders to placebo who crossed to IVIg showed subsequent response (5/7 patients)
  • IVIg efficacy maintained over 6-month treatment period

Design

Study Type: Randomized, double-blind, placebo-controlled trial with crossover

Randomization: 1

Blinding: Double-blind (patients and assessors blinded)

Enrollment Period: December 1995 to October 1997

Follow-up Duration: 7 months

Centers: 1

Countries: France

Sample Size: 19

Analysis: Fisher's exact test for responder rates; median differences with 95% CI for clinical scores; intention-to-treat analysis

Inclusion Criteria

  • Adults ≥18 years
  • Clinical and electrophysiological diagnosis of MMN with persistent conduction block
  • Group 1: Never treated with IVIg, continuously progressive neuropathy for ≥2 months
  • Group 2: Previous IVIg responders with recurrent symptoms after successful treatment
  • No immunosuppressors within 2 months before inclusion
  • No IVIg within 3 months before inclusion

Exclusion Criteria

  • Severe concurrent medical condition causing neuropathy or interfering with treatment
  • Pregnancy
  • Age <18 years

Arms

FieldIVIgControl
InterventionEndobulin 5% lyophilized (Baxter) 500 mg/kg/day for 5 consecutive days, once monthly for 3 months1% human albumin lyophilized, same dosing schedule as IVIg
Duration3 months initial; responders continued 3 more months3 months initial; non-responders crossed to IVIg

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Responder rate at month 4 (responder = ≥1 MRC point improvement in 2 affected muscles PLUS ≥1 point improvement in 2 daily activities)Primary0.03
Change in MRC score (baseline to month 4) | IVIg-first: Median change +3 (95% CI: 2-13); significant; Placebo-first: Median change +3 (95% CI: -1 to 10); not significant; Difference: 95% CI: -2 to 9; not significantSecondaryNS
Change in self-evaluation score (baseline to month 4) | IVIg-first: Median change -7 (95% CI: -14 to -1); significant improvement; Placebo-first: Median change 0 (95% CI: -3 to 3); not significant; Difference: -7 (95% CI: -12 to -3); significantSecondary<0.05
Reduction in conduction block severity at month 4 | IVIg-first: 4/9 (44%) patients; Placebo-first: 2/9 (22%) patientsSecondaryNS
Response by group | Group 1 (IVIg-naïve): 4/9 responded to IVIg, 2/9 responded to placebo, 3/9 no response to either; Group 2 (prior responders): 8/9 responded to IVIg, 0/9 responded to placeboSecondary
HeadacheAdverseIVIg: 3 patients; Placebo: 0 patients
FlushingAdverseIVIg: 1 patient; Placebo: 0 patients
ShiveringAdverseIVIg: 2 patients; Placebo: 0 patients
FeverAdverseIVIg: 1 patient; Placebo: 0 patients
Cold feetAdverseIVIg: 0 patients; Placebo: 1 patient
Visual blurAdverseIVIg: 2 patients; Placebo: 0 patients
EczemaAdverseIVIg: 1 patient; Placebo: 0 patients
Withdrawals due to AEsAdverseNone

Subgroup Analysis

Anti-GM1 antibody analysis: 5/18 patients had significantly high titres (>3200) at baseline. Of these, 4/5 responded to IVIg. However, anti-GM1 titres did not change significantly during treatment and were not correlated with clinical improvement. No IgG anti-GM1 antibodies were detected in any patient.

Criticisms

  • Small sample size (n=19) limits statistical power
  • Single-center study limits generalizability
  • Crossover design complicates interpretation of month 7 outcomes
  • MRC score (primary clinical measure) did not show significant between-group difference
  • Heterogeneous population (mixed IVIg-naïve and previously treated patients)
  • Self-evaluation scale not validated standardized instrument
  • Long disease duration (mean 9 years) may limit treatment response
  • 2/9 placebo patients showed spontaneous improvement confounding interpretation
  • Electrophysiological outcomes not significantly different between groups
  • No long-term follow-up beyond 7 months

Funding

Assistance Publique-Hôpitaux de Paris (CEDIT) with support from Immuno AG (now Baxter AG); BIOMED contract (INCAT) of the European Community

Based on: Léger MMN IVIg (Brain, 2001)

Authors: Jean-Marc Léger, Bénédicte Chassande, Lucile Musset, ..., Nicole Baumann

Citation: Brain 2001;124:145-153

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