Treatment of patients with multifocal motor neuropathy with immunoglobulins in clinical practice: the SIGNS registry

Abstract

Objectives:

The management of patients with multifocal motor neuropathy (MMN) under everyday clinical conditions has been insufficiently studied. We therefore collected comprehensive observational data on patients with MMN who received intravenous (IV) or subcutaneous (SC) immunoglobulins (IGs) as maintenance therapy.

Methods:

This was a prospective, noninterventional study (registry) in neurological centres (hospitals and offices) throughout Germany.

Results:

As of 1 December 2015, 80 patients with MMN were included (mean age 55.4 ± 9.8 years, 67% males, mean disease duration 10.7 ± 10.2 years). The affected limb regions were predominantly distal muscle groups of the upper extremities. On the inflammatory neuropathy cause and treatment (INCAT) scale, 94% of the patients had some disability in the arms and 61% in the legs. At inclusion, 98.8% received IVIG and 1.3% SCIG. Substantial variation was observed between IVIG treatment intervals (every 0.7 to 17.3 weeks) and dosage (0.2–2.1 g/kg body weight received during a single administration; mean monthly dosage, 0.9 g/kg body weight). However, the mean monthly dosage was steady over time. At 1-year follow up, improvement was seen in muscle strength, INCAT and quality of life (QoL) scores (SF-36 questionnaire).

Conclusions:

The management of patients with MMN in everyday clinical practice demonstrates a wide range of absolute dosages and treatment intervals of IG, supporting the recommended practice of determining treatment dose on an individual patient basis. The improvements in muscle strength and reduction in disability, accompanied by increased QoL, strengthen the case for use of IG as a maintenance treatment for MMN.

Background

Multifocal motor neuropathy (MMN) is considered an acquired immune-mediated neuropathy characterized by exclusive involvement of peripheral motor nerves, asymmetric distribution and conduction block detected on neurophysiological examination. The clinical course is slowly progressive and can lead to severe disability. The diagnosis is made on the basis of clinical, electrodiagnostic and laboratory features, but is sometimes difficult in patients with atypical or overlapping presentations. Various sets of diagnostic criteria have been proposed for MMN [Van Den Berg-Vos et al. 2000; Olney et al. 2003; European Federation of Neurological Societies, 2010].

Several placebo-controlled trials have demonstrated the efficacy of high-dose intravenous immunoglobulin (IVIG) therapy for MMN [Azulay et al. 1994; Van Den Berg et al. 1995; Federico et al. 2000; Léger et al. 2001]. Although cyclophosphamide has also been described as effective in uncontrolled studies, IVIG is the preferred first-line treatment due to its solid safety profile. A meta-analysis by the Cochrane collaboration of four randomized controlled trials on IVIG for MMN, that included 34 patients in total, indicated a beneficial effect on muscle strength [Van Schaik et al. 2005]. These controlled trials of IVIG were the basis for regulatory approval of some IVIG preparations for the treatment of MMN [Elovaara et al. 2008; Stangel, 2010]. Although not approved, there are also several reports of successful treatment of MMN with subcutaneous immunoglobulins (SCIGs) [Eftimov et al. 2009; Harbo et al. 2009, 2010; Misbah et al. 2011]. The exact immunomodulatory mechanisms of action of IVIG (or SCIG) are not yet known, but it is thought that several immune system players are targeted, including B cells, T cells, macrophages, complement, cytokines or cellular adhesion molecules [Schwab and Nimmerjahn, 2013; Dalakas, 2014].

Although the short-term benefit of IVIG treatment for MMN is unequivocal and can even be used as a diagnostic criterion in atypical cases, the data on long-term IVIG treatment are limited. Often, muscle strength declines despite treatment, and an increase in IVIG dose is necessary [Terenghi et al. 2004]. Furthermore, due to the low incidence of the disease, observational data on the presentation and management of patients with MMN in clinical practice are usually limited to small cohorts and retrospective analyses [Cats et al. 2010; Cocito et al. 2014]. Thus, we aimed to systematically collect prospective data in the context of a large longitudinal observational study under everyday clinical conditions. The SIGNS study focuses on the utilization of immunoglobulin (IG) preparations and clinical outcomes across a broad spectrum of centres and indications, respectively, and includes a specific module on patients with MMN. The aim was to describe the clinical properties of a large German cohort of MMN patients, their management and treatment in everyday clinical practice and their quality of life (QoL). In addition, we sought to compare these with published data from other cohorts.

Methods

Study design

SIGNS (assessment of IG treatment in a long-term noninterventional study) is an ongoing prospective, observational study (registry type), with consecutive inclusion of eligible patients [Kirch et al. 2012]. The study is performed in agreement with the Declaration of Helsinki in its latest revision, and according to the principles of good epidemiological practice. The study was approved by the ethics committee of the Medical Faculty of the Technical University of Dresden, and further local ethics committees in Germany. Patients were only included if they provided written informed consent. All patient data are processed in a pseudonymized format; that is, only the treating physician knows the identity of his or her individual patient. The ClinicalTrials.gov identifier is NCT01287689.

Currently, 88 centres throughout Germany are taking part in the study. These include university hospitals, community hospitals and office-based physicians.

Patients and parameters

Documentation of patients with MMN started in September 2010. Patients of either gender and of any age group were eligible for documentation if they received any IG preparation as long-term therapy or as newly initiated therapy for neurological autoimmune disease. In addition, primary and secondary immunodeficiencies were documented in the registry [Kirch et al. 2010, 2012]. Visits were scheduled every 6 months, and the intended observation period was at least 2 years per patient.

Information was collected on application route [subcutaneous (SC) or intravenous (IV)] and dosage of IGs, frequency of IG administrations and days of treatment with IG. Information on MMN was collected using the protocol of Cats and colleagues as a template [Cats et al. 2010], with additional information on previous (tentative) diagnoses, electrophysiology and nerve conduction. The diagnostic criteria applied as per protocol were those proposed by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) issued in 2006 [European Federation of Neurological Societies/Peripheral Nerve Society, 2006].

Data were collected on disease duration, time to diagnosis, clinical symptoms, neurological function, physical function using the inflammatory neuropathy cause and treatment (INCAT) disability scale, QoL and stabilization or progression of symptoms over time. Muscle strength was assessed according to Medical Research Council (MRC) criteria [Kleyweg et al. 1991]. The following muscles were assessed on both sides: upper arm abductors, elbow flexors, wrist extensors, hip flexors, knee extensors and foot dorsal flexors. In our study, scores were collected as 0–3 (combined integers), 4 and 5. Thus, an MRC sum score as published in some recent publications [Eftimov et al. 2009; Markvardsen et al. 2013] was not computed.

As an activity and participation measure, the INCAT disability score [Hughes et al. 2001] was applied to capture daily activities such as doing and undoing buttons and zips, washing and brushing hair, using knife and fork together and handling coins. The leg scale measures problems with walking, taking into account the use of aids. The INCAT scales range from 0 (no signs of disability) to 5 (most severe disability score), with separate subscores generated for arm and leg disability. The overall INCAT score is the sum of the two scores.

For the assessment of QoL, the Short Form 36-item (SF-36) [Ware and Sherbourne, 1992], EQ-5D [Fahrenberg et al. 2000], life satisfaction (LFZ) [Greiner et al. 2005] and WHO-5 questionnaires (see http://www.cure4you.dk/354/index.php?a=e2&ei=4151) were administered. These questionnaires have been validated in a German version and are generic, that is, can be used across various indications or diseases. Questionnaires were (and are planned to be in the future) completed at least once a year to allow for longitudinal analyses. Diaries, in which patients were asked to document their exercise activities, nonpharmacological treatments and any medical treatments undertaken, were handed out to the patients every 6 months.

Data entry and statistical analysis

Data were entered in an online electronic data capture system. During data entry, automatic plausibility checks were performed for completeness and accuracy. Data were checked by statistical methods centrally on a quarterly basis and, if required, queries were sent to the centres. Monitoring visits for source data verification were performed in randomly selected centres. Cut off for the present analysis was 1 December 2015.

Descriptive statistics (mean and standard deviation, or median and range) were used for continuous variables. Categorical variables were described as counts and percentages of subjects. Statistical analyses were performed using IBM SPSS Statistics Version 19.0.

Results

In the SIGNS registry, 23 centres included 81 patients with MMN (range, 1–18 per centre), between September 2010 and December 2015. Of those, one patient with Lewis–Sumner syndrome (or MADSAM) was excluded. The mean observation duration of the analysed 80 MMN patients was 20.9 ± 11.5 months.

Diagnostic criteria for MMN

The MMN diagnosis of physicians was not adjudicated by a third party, as it was the purpose of the study to document diagnostic procedures and patient management under real-life conditions. Nerve conduction was reported in only 91% of the included patients, and not all fulfilled the EFNS/PNS criteria for conduction block, however, some fulfilled the criteria partially and the patients without conduction block had a positive clinical response to IgG and thus were regarded as MMN patients in line with the findings of Delmont and colleagues [Delmont et al. 2006].

Patient characteristics

The characteristics of patients with MMN at inclusion are displayed in Table 1. More male (54) than female (26) patients were documented. The mean age of the MNN patients at inclusion into the study was 55.4 ± 9.8 years. Mean disease duration was 10.7 ± 10.2 years. There was a substantial time lag, ranging from 0 to 57 years, with a mean of 4.4 years, between the occurrence of first symptoms and the diagnosis of the disease. The initial (suspected) diagnosis was MMN in 42 cases (57.5%), motor neuron disease or amyotrophic lateral sclerosis (ALS) in eight patients (11.0%), ‘motor neuropathy’ in five patients (6.8%), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in four patients (5.5%), radiculopathy in three patients (4.1%) and other diseases in the remaining patients (15.1%), including Lewis–Sumner Syndrome (MADSAM), neuroborreliosis, sensorimotor neuropathy, sulcus ulnaris syndrome, hereditary neuropathy and polyneuropathy (Table 2).

Table 1.

Characteristics of multifocal motor neuropathy (MMN) patients at inclusion.

Characteristic	SIGNS (n = 80)	Dutch cohort (n = 88)*
Age (years) at inclusion	55 (range 29–76)	52 (range 27–78)
Sex ratio, male: female	54 (67.5%): 26 (32.5%)	64 (73%): 24 (27%)
Body mass index, kg/m2	26.1 ± 3.8	nr
Symptom/disease duration at inclusion (years)	8.6 (range 0.1–60)	11 (range 2–43)
Age (years) at symptom onset	45 (range 17–69)	40 (range 22–66)
Disease duration since diagnosis (years)	6.3 (range 0–27)	nr

Values are mean ± standard deviation or percentages, if not specified otherwise.

nr, not reported.

^*Source: Cats et al. [2010].

Table 2.

Initial diagnosis.

	SIGNS (n = 73/80)	Dutch cohort (n = 88)*
Initial diagnosis	n (%)	n (%)
MMN	42 (57.5)	31 (35)
Motor neuron disease	8 (11.0)	28 (32)
Mononeuropathy	5 (6.8)	11 (13)
Polyneuropathy	3 (4.1)	13 (15)
Radiculopathy	3 (4.1)	2 (2)
CIDP	4 (5.5)	1 (1)
Hereditary neuropathy	1 (1.4)	1 (1)
Minor stroke	0	1 (1)
Other**	7 (9.6)	0

^*Source: Cats et al. [2010].

^**Including ganglionitis (shoulder), Guillain–Barré syndrome, Lewis–Sumner syndrome (MADSAM), neuroborreliosis, sensorimotor neuropathy, sulcus ulnaris syndrome (n = 2).

MMN, multifocal motor neuropathy; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy.

The first symptom was most often: reduced grip strength of the hand (35.6%), weak dorsiflexion of the foot (23.3%) or weakness of the finger extensors (11.0%) (Table 3).

Table 3.

First symptoms.

Symptoms	SIGNS (n = 73/80)	Dutch cohort (n = 88)*
	n (%)	n (%)
Reduced grip strength hand	26 (35.6)	22 (25)
Reduced dexterity hand	6 (8.2)	18 (21)
Extension weakness of fingers	8 (11.0)	14 (16)
Weakness adduction upper arm	2 (2.7)	4 (5)
Femoral weakness	3 (4.1)	0
Weak dorsiflexion of foot (foot drop)	17 (23.3)	28 (32)
Reduced mobility toes	2 (2.7)	2 (2)
Other	8 (11.0)	0
Unknown	1 (1.4)	0

^*Source: Cats et al. [2010].

The majority of patients had up to three affected limb regions at inclusion (Table 4). Muscle weakness was reported in 80.0%, muscle atrophy in 60.0%, limited endurance in 52.5%, muscle twitching 38.8% and muscle cramps in 33.8% of patients.

Table 4.

Number of affected limbs at inclusion.

Affected limb regions*	SIGNS (n = 63/80)	Dutch cohort (n = 88)**
Number	n (%)	n (%)
0 (only hands)	8 (12.7)	–
1	11 (17.5)	12 (14)
2	17 (27.0)	15 (17)
3	9 (14.3)	13 (15)
4	2 (3.2)	19 (22)
5	3 (4.8)	12 (14)
6	4 (6.3)	11 (13)
7	3 (4.8)	2 (2)
8	6 (9.5)	4 (5)

^*Maximum eight regions: upper arm and lower arm on both sides; upper leg and lower leg on both sides.

^**Source: Cats et al. [2010].

As sensory symptoms are absent in MMN, most patients had no sensory abnormalities (78.8%). Only few had formication (2.5%), an electrifying sensation (3.8%), pins and needles (2.5%), and some, a numbness (15.0%).

Nerve conduction was documented in 73 of the 80 included patients. Conduction block was reported in 54 patients (74%). In 41 of these (75.9%) (Table 5), the conduction block was assessed according to EFNS/PNS criteria.

Table 5.

Results of nerve conduction tests at inclusion.

		n	%
MMN diagnosis	MMN with conduction block	54	74.0
	MMN without conduction block	19	26.0
	Total	73	100.0
MMN with conduction block (n = 54) diagnosed according to EFNS/PNS criteria	No	9	16.7
	Yes	41	75.9
	nr	4	7.4

Data on nerve conduction studies were reported in 73 of the 80 included patients.

MMN, multifocal motor neuropathy; nr, not reported; EFNS, European Federation of Neurological Societies; PNS, Peripheral Nerve Society.

The majority of MMN patients were categorized as stable with deficits at the beginning of the study (n = 58, 79.4%). Fewer patients were progressive or relapsed (n = 7, 9.6%) or stable with no deficits while undergoing treatment (n = 5, 6.8%).

Muscle strength and disability

In the detailed analysis of muscle strength according to MRC criteria (Figure 1), available for 63 patients, normal strength was observed in one patient, reduced strength in the arms in 47 patients (78.3%), in the hands in 57 patients (90.5%) and in the legs in 34 patients (56.7%).

Figure 1.

Muscle strength according to Medical Research Council (MRC) criteria.

BL, baseline.

On the INCAT disability scale, 5.6% of the patients had no limitations in the arms and 38.9% had none in the legs (Figure 2). A substantial proportion of patients (24.3%) had improved at 1 year in the INCAT score compared with baseline, while 54.1% remained unchanged. In the improved patients, the INCAT score was mostly reduced by 1 point (16.2%), or by 2, 3, or even 5 points, respectively (2.7% each, Table 6).

Figure 2.

Degree of disability on the INCAT scale in MMN patients documented in SIGNS.

INCAT, inflammatory neuropathy cause and treatment.

Arm disability

0 No upper limb problems

1 Symptoms, in one or both arms, not affecting the ability to perform any of the following functions: doing all zips and buttons; washing or brushing hair; using a knife and fork together; handling small coins

2 Symptoms, in one arm or both arms, affecting but not preventing any of the abovementioned functions

3 Symptoms, in one arm or both arms, preventing one or two of the abovementioned functions

4 Symptoms, in one arm or both arms, preventing three or all of the functions listed, but some purposeful movements still possible

5 Inability to use either arm for any purposeful movement

Leg disability

0 Walking not affected

1 Walking affected, but walks independently outdoors

2 Usually uses unilateral support (stick, single crutch, one arm) to walk outdoors

3 Usually uses bilateral support (sticks, crutches, frame, two arms) to walk outdoors

4 Usually uses wheelchair to travel outdoors, but able to stand and walk a few steps with help

5 Restricted to wheelchair, unable to stand and walk a few steps with help

Source: Merkies et al. [2002].

Table 6.

Changes on the INCAT disability scale at 1 year compared with inclusion: (a) in categories; (b) in points.

(a)

		n	%
Arm	Worsening	7	18.9
	Unchanged	25	67.6
	Improvement	5	13.5
	Total	37	100.0
Leg	Worsening	24	64.9
	Unchanged	8	21.6
	Improvement	5	13.5
	Total	37	100.0
INCAT total	Worsening	8	21.6
	Unchanged	20	54.1
	Improvement	9	24.3
	Total	37	100.0

(b)

			n	%
Arm	Worsening	+1	6	85.7
		+2	1	14.3
	Unchanged	0	25	100.0
	Improvement	−3	1	20.0
		−2	2	40.0
		−1	2	40.0
	Total	−3	1	2.7
		−2	2	5.4
		−1	2	5.4
		0	25	67.6
		+1	6	16.2
		+2	1	2.7
Leg	Worsening	+1	11	45.8
		+2	9	37.5
		+3	4	16.7
	Unchanged	0	8	100.0
	Improvement	−2	2	40.0
		−1	3	60.0
	Total	−2	2	5.4
		−1	3	8.1
		0	8	21.6
		+1	11	29.7
		+2	9	24.3
		+3	4	10.8
Change INCAT total score	Worsening	+1	6	75.0
		+3	1	11.1
		+4	1	11.1
	Unchanged	0	20	100.0
	Improvement	−5	1	11.1
		−3	1	11.1
		−2	1	11.1
		−1	6	66.7
	Total	−5	1	2.7
		−3	1	2.7
		−2	1	2.7
		−1	6	16.2
		0	20	54.1
		+1	6	16.2
		+3	1	2.7
		+4	1	2.7

Treatment at inclusion and after 1 year

The great majority of patients (63, or 79%) had already been on IG maintenance therapy for at least 3 months; only 16 (20%) were on newly initiated therapy. At inclusion, all 80 patients were treated with 6 different IV preparations (in 64%, Kiovig, which was approved for this indication in Germany in 2011) and 1 SC preparation (Table 7).

Table 7.

Immunoglobulins at inclusion and at 1-year follow up.

Treatment characteristic	Baseline (n = 80*)	1-year follow up (n = 59)
	n (%)	n (%)
Newly initiated treatment (treatment duration < 3 months after entry)	16 (20.3%)	–
Maintenance treatment	63 (79.7%)	–
Mean treatment duration at inclusion (months ± SD)	23.3 ± 29.8	–
IVIG preparation
Kiovig	51 (63.7%)	37 (62.7%)
Gamunex 10%	10 (12.5%)	7 (11.9%)
Intratect	3 (3.8%)	3 (5.1%)
Octagam 5%	2 (2.5%)	1 (1.7%)
Octagam 10%	1 (1.3%)	0
Privigen	12 (15.0%)	7 (11.9%)
SCIG preparation
Hizentra 20%	1 (1.3%)	1 (1.7%)
Subcuvia 16%	0	1 (1.7%)
Treatment interruption	–	2 (3.4%)
IG prescribed at:
Hospital based	17 (21.3%)	6 (10.2%)
Outpatient clinic	35 (43.8%)	24 (40.7%)
Office based	26 (32.5%)	25 (42.4%)
Other institution	2 (2.5%)	4 (6.8%)

^*For one patient, previous treatment was unknown.

IG, any immunoglobulin (intravenous or subcutaneous); IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin.

On average, MMN patients received IVIG at a mean monthly (4-week) dose of 0.9 g/kg body weight (BW) (median 0.7 g/kg BW: minimum 0.1 g/kg BW, maximum 2.9 g/kg BW). The mean IG application interval was 4.8 weeks (median 4.0 weeks: minimum 0.7 weeks, maximum 17.3 weeks). The absolute dosage per infusion cycle was 0.8 ± 0.5 g/kg BW, range 0.2– 2.1, median 0.7 and interquartile range 0.4–1.0. Thus, dosage varied substantially among patients (Figures 3a and 4b). While in 63.9% of MMN patients there was no dose change between baseline and 1 year, in selected patients there were substantial changes (−70% to ⩾100%). Nevertheless, compared with baseline, at 1 year the median dose had hardly changed, though the variance in dosing decreased. Average doses (and dosing intervals) were stable during the follow-up period (Figure 4).

Figure 3.

IV Dosing of intravenous immunoglobulin (IVIG) preparations in patients with MMN at baseline and at follow up.

(a) Per patient.

IVIG, intravenous immunoglobulin; BW, body weight.

Each line represents an individual patient.

(b) In dosage categories.

IVIG dosage at inclusion:

0.9 ± 0.7 g/kg BW/4 weeks, range 0.1–2.9, median 0.6 [interquartile range (IQR), 0.3–1.3].

IVIG dosage at 1 year:

MMN: 0.9 ± 0.7 g/kg BW/4 weeks, range 0.1–3.0, median 0.6 (IQR, 0.4–1.3).

MMN, multifocal motor neuropathy; IQR, interquartile range.

Figure 4.

Dosing changes at 1-year follow up compared with at inclusion.

Values are %.

Only five patients received further immunosuppressive or immunomodulatory treatment in addition to IgG (one patient had cyclophosphamide until 6 months, one patient had cyclophosphamide until year 1, one patient had steroids until 18 months, one patient started tocilizumab at 1 year and one patient started cyclophosphamide at 1.5 years). All other patients did not receive further add-on therapy even in the case of clinical deterioration.

Nonpharmacological therapy

According to patient diaries, a majority of patients who filled out the questionnaires did physical exercise or sports on a regular basis. For example, in the first 6 months after inclusion, 39 of 46 (85%) of the MMN patients, and in months 7–12, 26 of 32 (81%) patients reported regular exercise. Prescribed nonpharmacological interventions addressing the neurological disease mostly consisted of physiotherapy (52%).

Quality of life

On the EQ-5D, the mean index was 0.8 ± 0.2. The overall state of health on the 100-point visual analogue scale was 38.4 ± 19.7. Further, QoL was assessed with the SF-36 in eight main domains as shown in Figure 5. Compared with an unselected sample of the German general population, QoL of patients with MMN was reduced in all domains, in particular ‘social functional capability’, ‘physical functional capability’ and ‘physical role function’. On average, QoL as measured by SF-36 was 38.6 ± 10.9 on the physical scale and 44.4 ± 10.6 on the mental scale; at 1 year, the values were 39.1 and 47.1, respectively.

Figure 5.

Quality of life in Short Form-36 at the time of inclusion.

Higher values indicate better status, range [0–100].

Norm control from German representative sample for normative comparison.

The current state of health, according to question 12 on the SF-36, was categorized by the majority of patients as good or moderate (27% and 48%, respectively, Figure 6a). At 1 year, in response to the question ‘Compared with one year ago, how would you rate your health in general now?’, 50% of the patients considered themselves as stable, while 30% of patients stated improvement and 20% reported deterioration (Figure 6b).

Figure 6.

Global health as measured with the Short Form-36.

(a) At baseline: ‘In general, would you say your health is?’.

For comparison, values derived from the German population for this question are displayed [Morfeld et al. 2005]. For the German version of the SF-36, translation of this question deviates from the original English version; shown here are back-translated German answer categories.

(b) At follow up: ‘Compared with one year ago, how would you rate your health in general now?’.

Values are %.

Discussion

This analysis of the SIGNS study provides current insights regarding the characteristics and management of patients with MMN on IG as maintenance therapy, as documented by experienced neurologists throughout Germany.

Demographic data and disease characteristics

We collected a set of data similar to that of a nationwide Dutch cross-sectional study on 88 patients with MMN performed in 2007 [Cats et al. 2010]. In both studies, there were more men than women; however, our study did not include all patients in Germany and thus the data do not match an exact epidemiological or demographic group. Nevertheless, the similarity in gender distribution, mean age and similar disease duration suggests that we investigated a representative patient population. The differential diagnosis of MMN appears to pose problems for primary care physicians, as both in SIGNS and in the abovementioned Dutch study, a considerable portion of patients initially were given other diagnoses (42% and 35%, respectively). In both studies, reduced grip strength of the hand (SIGNS, 35.6%; Dutch, 25%) and weak dorsiflexion of the foot (SIGNS, 23.3%; Dutch cohort, 32%) were noted as the two most frequent symptoms at onset. Thus, clinical presentation was relatively homogenous, with the onset of disease often asymmetric, predominantly in distal muscle groups and with upper extremities more often affected than lower extremities in terms of weakness [Dimberg, 2009, Cats et al. 2010].

Treatment

IG is recommended as a first-line therapy for MMN to improve muscle strength [Van Schaik et al. 2006]. In Germany, more than 15 different IG preparations for IV and SC use are available; however, only one IVIG preparation (Kiovig) has been approved for MMN. The data in SIGNS indicate that a substantial portion of patients are treated ‘off label’, that is, with IG preparations that have not received approval as treatments for MMN. On the one hand, this is due to the fact that at the beginning of recruitment for the study, no IG preparation had specifically been licensed for MMN, and patients continued on the preparation that they were being treated with before approval. On the other hand, it seems that preparations might be considered interchangeable by physicians with regard to treatment efficacy.

It is recommended that dosing and administration intervals of IG be individually titrated [EFNS, 2010]. In a recent randomized study by Hahn and colleagues, the mean monthly IG dose was 1.2 ± 0.5 g/kg BW [Hahn et al. 2013]. In SIGNS, dosing patterns vary substantially (between 0.1 and > 0.9 g/kg BW per 4 weeks), reflecting individualized treatment regimens. It is notable that dosing remained constant or was only slightly changed in the majority of patients over the course of 1 year. Notably, authors of a retrospective study found reliably good short-term response to IVIG, but declining effectiveness in long-term follow up of patients [Léger et al. 2008], that was confirmed by other studies [Van Den Berg-Vos et al. 2002; Terenghi et al. 2004], while in another study their IgG effectiveness persisted [Vucic et al. 2004]. In our study, IgG treatment was stopped in only one patient who did not have a clinical benefit from the treatment. All other patients required further infusions that were decided on clinical grounds since they got worse when the infusions were delayed. However, the average follow up of 1.5 years may be too short to finally assess the long-term response to IVIG.

Overall, the SIGNS data from everyday practice show that IGs are administered as recommended by international guidelines on an individual basis [EFNS, 2010].

Muscle strength and disability

Severe limitation in muscle strength (score 0–3 on the MRC scale) was the exception in our patient population. IG treatment improved muscle strength (MRC) and reduced disability (INCAT) in most patients after 1 year. Weakness is the only determinant of disability in MMN, and improving strength will improve disability [Van Schaik et al. 2006]. The INCAT score, which we used similarly to other trials in patients with immune neuropathies [Hughes et al. 2008], has some shortcomings. These include the failure to properly capture limitations due to proximal arm weakness or fatigue (which lowers content validity), or heavy-item weighting due to the inclusion of only two functions [Breiner et al. 2014]. Among the strengths of the INCAT are the ease of administration, attention to both upper and lower limb dysfunction, good reliability and high responsiveness to change [Breiner et al. 2014]. Our data demonstrate that most patients with MMN are stable or improve after long-term treatment with IG.

QoL

On the SF-36, one of the most widely used generic instruments, patients presented with values of 40 to 67 in the 8 different domains, which represents substantially impaired QoL and functionality in comparison with normal samples derived from a German population [Morfeld et al. 2005] (see also http://www.sf-36.org/research/sf98norms.pdf). Nevertheless, almost one third of the patients rated their overall health as ‘good’. It should be noted that satisfaction with health does not mean absence of disease; that may explain why many patients with neurological autoimmune diseases do not differ much from individuals in the general population in this respect [Bellach, 2000]. Thus, although many patients with MMN have an impaired QoL, most are nevertheless satisfied with their treatment and their overall condition, in spite of persistent neurological disability. This underscores the fact that even though the treatment may not lead to a full recovery, maintenance IG therapy is important for the sake of upholding QoL.

Methodological considerations

The current SIGNS registry is prospective and recruits consecutive patients, aiming to reduce selection bias. It applies various measures for quality assurance, the most important being systematic plausibility checks, queries based on statistical checks (e.g. on outlier values), as well as on-site monitoring with systematic comparisons between study data and patient files.

The main limitations of this study are those inherent in any registry. Given that this is an observational, nonrandomized study, different biases can obscure true causal association [Delgado-Rodriguez and Llorca, 2004]. Clinical decisions by the treating physicians may assign patients to different IG preparations (or other drugs) based on disease severity, disease duration, presence of comorbidities and other factors. This can potentially introduce allocation or channelling bias and confound the association between treatment and outcomes. In our registry, there is no re-evaluation of patients, which may result in some inclusion of patients with unconfirmed diagnoses. Also, in the Dutch study of Cats and colleagues, the application of different diagnostic criteria would have led to the noneligibility of approximately 15% of patients [Cats et al. 2010].

Data on neurophysiology were incomplete in our study and the follow-up examinations were neither mandatory nor standardized as a follow-up examination. Thus, data on conduction block in the follow-up examinations are few and were not included in the analysis due to too many data lacking.

However, as mainly specialist centres are involved, the quality of diagnosis should be high, and indeed is based on established criteria in the great majority of cases. Still, the inclusion of expert centres might not reflect the true picture of MMN management in Germany (especially in small centres). Also, extrapolation of the results to other, especially non-European, countries may only be made with caution. Information on side effects (other than serious adverse drug reactions) was not collected, so no statement can be made about the tolerability of IG preparations in the described setting.

Even taking all these limitations in account, our study confirms the presentation and diagnostic difficulties observed in other patient populations [Cats et al. 2010]. This delays treatment and probably also leads to a higher proportion of patients with permanent axonal damage and neurologic disability. Thus, early diagnosis and treatment of MMN is warranted, as our data show that maintenance therapy can halt or even improve both muscle strength and QoL.

Conclusion

In conclusion, the results of this analysis confirm the previously reported phenotype of MMN under clinical practice conditions. Most patients with MMN are treated with an individualized regimen in dosing and interval as recommended by international guidelines. The improvements in muscle strength and reduction in disability, accompanied by increased QoL, further strengthen the case for use of IG as maintenance treatment for this indication.