Human immune globulin infusion in the management of multifocal motor neuropathy

Figures & data

Table 1 Diagnostic clinical criteria for multifocal motor neuropathy

Primary clinical criteria: must be present for diagnosis	Secondary clinical criteria: support diagnosis	Exclusion clinical criteria: must be absent for diagnosis
Gradual or stepwise progressing focal, asymmetrical extremity weakness with involvement of at least two motor nerves for over 1 month. With involvement of one motor nerve, a diagnosis sometimes can be made	Mostly upper extremities involved Absent or diminished deep tendon reflexes in extremities affected	Upper motor neuron signs Notable involvement of cranial nerves
No sensory changes or loss though minimal loss of vibration sense in the lower extremities may occur	Sparing of cranial nerves Cramps and fasciculations in extremities affected Favorable response with increased strength and functionality to IVIG/SCIG therapy	Notable changes or loss of sensation Diffuse symmetrical weakness on initial presentation and early in disease course

Abbreviations: IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulins.

Figure 1 Proposed mechanism of IVIG within the classical complement pathway for treatment of multifocal motor neuropathy.

Abbreviations: IVIG, intravenous immunoglobulin; MAC, membrane attack complex.

Table 2 Summary of studies evaluating efficacy of IVIG/SCIG for treatment of MMN

Study examined	Patient number	Doses administered	Average follow-up period	Outcomes
Study A^Citation44	40 total 22 IVIG naïve (two lost to follow-up) 18 previously on IVIG	2 g/kg IVIG over 3–5 days initial treatment followed by maintenance dosing of 2 g/kg over 3–5 days if needed due to clinical worsening	Short term: <6 months Long term: 2.2 years	MRC scores improved (P<0.0001) in 14 (70%; 95% CI 0.46–0.88) of 20 treatment-naïve patients short term. Long term, only eight of 40 patients had sustained remission and 25 patients remained dependent on maintenance IVIG. CB decreased or were unchanged in 12 IVIG naïve patients and increased in two IVIG naïve patients. IVIG provided a significant short-term benefit but in the majority of patients maintenance dosing was required
Study B^Citation45	44 total	Randomized to double-blind placebo followed by a median dose of 1.2 g/kg IVIG every month infused over 5 days or less vs the same IVIG dosing followed by placebo each for 12 weeks. IVIG given for 12 weeks at start, end, and between double-blinded periods	After 12 weeks of either IVIG or placebo	MMG strength decreased in 31.38% during placebo and increased in 3.75% during IVIG (P=0.005). GND scores declined in 35.7% during placebo but not during IVIG. 69.0% of patients had to switch from placebo to open-label IVIG early due to worsening symptoms. IVIG improved disability and strength
Study C^Citation46	11 total	Initial treatment with IVIG (0.4 g/kg for 5 days) followed by an IVIG infusion (0.4 g/kg) every 1–7 weeks with an average dose of 7–48 g each week	4–8 years	MRC, handheld dynamometry, and GND scores increased significantly within 3 weeks starting IVIG therapy and declined significantly in follow-up but remained significantly increased at final follow-up as compared to scores prior to starting treatment. EDX performed annually showed a resolution of CB in six nerve segments but new CB in eight nerve segments. Remyelination or reinnervation occurred in 13 nerves and demyelination or axon loss occurred in 14 nerves during follow-up. IVIG maintenance treatment improved overall strength and disability but did not prevent decreases in muscle strength over time
Study D^Citation47	10 total	Initial dose 2 g/kg IVIG over 4–5 days then maintenance infusions (1–1.2 g/kg over 2–3 days) if worsening symptoms occurred. If patients experienced “end-of-dose” effects maintenance doses were increased to 1.5–2 g/kg over 3–4 days to stop progression	5–12 years	All ten patients responded to initial IVIG therapy with statistically significant improvements in MRC and RDS scores. At final follow-up, just two patients maintained maximum improvement achieved during therapy and eight showed a decline despite increased IVIG dosing. Decline began after 3–7 years (mean 4.8 years) of treatment. EDX CMAP reduction correlated with clinical decline (P<0.019). Efficacy of IVIG declined after several years and may have been correlated to worsening CB or axonal degeneration
Study E^Citation48	10 total	2 g/kg IVIG over 5 days monthly for 3 consecutive months followed by monthly maintenance therapy of 0.6–3.4 g/kg over 5 days. Maintenance therapy was increased or decreased by 0.4 g/kg every 4 weeks with clinical decline or improvement, respectively, until strength levels were stable	3.5–12 years	Statistically significant sustained improvement in MRC and RDS scores were seen in all patients while receiving IVIG. Significant improvements in CB and reinnervation were seen on EDX at final follow-up. Long-term IVIG therapy at higher maintenance doses improved outcomes as compared to results from studies using lower IVIG maintenance doses
Study F^Citation1	88 total	Initial dose of 2 g/kg IVIG over several days followed by variable doses of monthly maintenance treatments with median duration of 6 years (range 0–17 years) and median dose increases from 12 to 17 g/week	0–17 years (mean of 6 years)	Ninety-four percent responded to IVIG therapy: non-responders had longer disease duration before the first treatment (P=0.03). Seventy-six percent received IVIG maintenance treatment at the time of this study. The median maintenance dose increases over the years were statistically significant (P<0.01). Independent determinants of more severe weakness and disability were axon loss (P<0.001; P<0.0001) and longer disease duration without IVIG (P=0.03; P=0.07)
Study G^Citation54	9 total	Two groups randomized for a period equivalent to three IVIG doses to either IVIG at 1.2–2.1 g/kg over several days administered every 18–56 days or SCIG therapy of 12.8–24.8 g or 80–155 mL injected two to three times weekly. Groups then were switched	1–3 years	Dynamometric strength and quality of life as measured by SF-36 questionnaire were equally improved on IVIG and SCIG therapy. Strength was 3.6% (95% CI −3.6% to 10.9%) improved after SCIG vs 4.3% (−1.3% to 10.0%, P=0.86) after IVIG. No serious adverse events occurred with either therapy
Study H^Citation55	10 total	Two groups of five each randomized to either SCIG equivalent to 50% of their IVIG maintenance doses at 0.27–0.62 g/kg/month or SCIG equivalent to their IVIG maintenance doses at 0.61–1.1 g/kg/month. SCIG was given one to two times weekly	6 months	Of patients receiving 50% SCIG equivalent doses, one withdrew and four had significant decline in MRC scores. Of patients receiving equivalent SCIG doses, four of five maintained equal MRC scores. At higher doses, SCIG therapy maintained strength as well as IVIG
Study I^Citation57	1 total	IVIG 0.4 g/kg for 2 days every 3–4 weeks then transitioned incrementally to final dose of SCIG 25% greater than prior IVIG dose at 0.3125 g/kg weekly	6 months	Stable and increased MRC and modified RDS scores were noted after successful transition to SCIG therapy at final dose with stable IgG serum concentration at 21 g/L. Patient also reported to be living at home independently without any hospitalizations since switching to SCIG
Study J^Citation58	8 total	Total weekly SCIG dose calculated by dividing the average monthly IVIG dose (0.4 to 2 g/kg/month of IVIG) by 4. Patients were transitioned from IVIG to SCIG gradually. Week 1: SCIG dose at 25% of total calculated weekly SCIG dose. Week 2: SCIG dose at 50%. Week 3: Full calculated weekly SCIG dose. Continued 100% of the weekly dose until study end for 24 weeks. Weekly SCIG dose ranged from 100 to 488 mg/kg	6 months	Seven of eight patients were able to maintain trough IgG serum levels of 1,680 mg/dL (±5.0) on SCIG, comparable to trough IgG serum levels of 1,750 mg/dL (±4.9) measured before the last IVIG dose. SCIG preserved strength as measured by MRC sum scores (MRC score mean change: 0.4; 95% CI −4.50 to 5.00) and GND scores (Guy’s disability score mean change: 0.1; 95% CI 1.00–0.00). One patient unable to achieve trough IgG serum levels above 935 mg/dL declined and had to resume IVIG therapy with subsequent normalization of strength and trough IgG serum levels. Seven of eight patients successfully transitioned to SCIG without clinical decline and all elected to remain on SCIG therapy

Abbreviations: IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulins; MMN, multifocal motor neuropathy; MRC, Medical Research Council Scoring for muscle strength; CB, conduction block; CI, confidence interval; MMG, mean maximal grip strength; GND, Guy’s Neurological Disability scores for upper extremities; EDX, electrodiagnostic studies; RDS, Rankin Disability Scale; CMAP, distal compound muscle action potential amplitudes.

LegerJMVialaKCancalonFIntravenous immunoglobulin as short- and long-term therapy of multifocal motor neuropathy: a retrospective study of response to IVIg and of its predictive criteria in 40 patientsJ Neurol Neurosurg Psychiatry2008791939618079302

 PubMed Web of Science ®Google Scholar

HahnAFBeydounSRLawsonVA controlled trial of intravenous immunoglobulin in multifocal motor neuropathyJ Peripher Nerv Syst201318432133024725024

 PubMed Web of Science ®Google Scholar

Van den Berg-VosRMFranssenHWokkeJHVan den BergLHMultifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatmentBrain2002125Pt 81875188612135977

 PubMed Web of Science ®Google Scholar

TerenghiFCappellariABersanoACarpoMBarbieriSNobile-OrazioEHow long is IVIg effective in multifocal motor neu-ropathy?Neurology200462466666814981195

 PubMed Web of Science ®Google Scholar

Van AsseldonkJTVan den BergLHKalmijnSAxon loss is an important determinant of weakness in multifocal motor neuropathyJ Neurol Neurosurg Psychiatry200677674374716705197

 PubMed Web of Science ®Google Scholar

CatsEAvan der PolWLPiepersSCorrelates of outcome and response to IVIg in 88 patients with multifocal motor neuropathyNeurology201075981882520805527

 PubMed Web of Science ®Google Scholar

HarboTAndersenHHessAHansenKSindrupSHJakobsenJSubcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trialEur J Neurol200916563163819236457

 PubMed Web of Science ®Google Scholar

EftimovFVermeulenMde HaanRJvan den BergLHvan SchaikINSubcutaneous immunoglobulin therapy for multifocal motor neuropathyJ Peripher Nerv Syst20091429310019691531

 PubMed Web of Science ®Google Scholar

DacciPRivaNScarlatoMSubcutaneous immunoglobulin therapy for the treatment of multifocal motor neuropathy: a case reportNeurol Sci201031682983120574753

 PubMed Web of Science ®Google Scholar

MisbahSABaumannAFazioRA smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-of-concept studyJ Peripher Nerv Syst2011162929721692906

 PubMed Web of Science ®Google Scholar