European Journal of Neurology 2006, 13: 135140

Prediction of response to IVIg treatment in patients with lower motor neurone disorders
N. Strigl-Pilla, A. Konigb, M. Schrodera, H. Beranekb, B.G.H. Schosera, M. Spaetha, D. Pongratza a and W. Muller-Felber
a

Friedrich-Baur-Institute and bDepartment of Internal Medicine, Ludwig-Maximilians-University Munich, Munich, Germany

Keywords:

amyotrophic lateral sclerosis, IVIg, multifocal motor neuropathy, treatment

Received 5 August 2004 Accepted 19 January 2005

The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often dicult. To nd predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the rst and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.

Introduction
Multifocal motor neuropathy (MMN) was rst described in 1985 in four patients who suered from progressive weakness similar to motor neurone disorders (MND) [1]. The neurophysiological hallmarks were motor conduction blocks. In 1988 IgM antibodies to the GM1 ganglioside directed against glycolipids in the region of the nodes of Ranvier were found, suggesting an autoimmune process [2]. A recent report showed, that the increase of GM1 antibody titre in MMN is usually followed by an increase of the light chain (k lambda and j kappa) and the light chain ratio (k/j) of the antibody whereas in classical amyotrophic lateral sclerosis (ALS) the light chain ratio is normal [3]. MMN, originally related to chronic inammatory demyelinating polyneuropathy or MND is now considered as a separate entity. Typical ndings that conrm the diagnosis of MMN are conduction blocks. In contrast to other demyelinating neuropathies, there is
Correspondence: Prof. W. Muller-Felber, Friedrich-Baur-Institute, Ziemssenstr. 1 a, 80336 Munich, Germany (Tel.: ++49 89 51607470; fax: ++49 89 51602203; e-mail: wolfgang.mueller-felber@fbs.med. uni-muenchen.de).

no improvement or even worsening of MMN with steroids or plasmapheresis. In 1993 improvement of MMN following treatment with intravenous immunoglobulins (IVIg) was reported for the rst time [4]. In addition, an axonal motor neuropathy similar to MMN without conduction blocks was successfully treated by IVIg [5]. A study using a threshold tracking technique showed, that besides focal demyelination, axonal excitability changed signicantly and contributed to conduction failure. Furthermore, the axo-glial interaction was disturbed [6]. Pathologic alterations at the site of conduction block showed focal regions of bre loss, clusters of regenerating bres, and a low frequency of bre degeneration without onion bulbs or segmental demyelination. These changes were seen only in the motor bres of mixed nerves [7]. ALS starts with pure lower motor neurone disorder (LMND) in up to 20% of all cases. In a prospective, population-based study of ALS in Ireland, 52% of patients showed pure lower motor neurone signs at onset [8]. For that reason the major clinical problem is to nd those patients with LMND suitable for the expensive IVIg treatment. All criteria that have been proposed so far lack sucient sensitivity and specicity to predict response to treatment.

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The goal of this examination was to analyse clinical, serological and neurophysiological parameters that allow the prediction of successful IVIg treatment in patients with pure LMND.

Patients and methods

Between 1998 and 2002, 6495 patients were seen in our neuromuscular centre. Of these 40 patients were included in the study. The elected patients suered from pure LMND (nine females, 31 males) that is asymmetric limb weakness in the territory of more than one motor nerve without respiratory failure or cranial nerve aection. In all patients the duration of the disease before treatment was more than 1 year. All patients received IVIg treatment. The average age was 58 years (3375 years). Inclusion criteria were: isolated lesion of the motor neurone (i.e. clinical and neurophysiological signs of denervation without aection of the sensory nerves or upper motor neurone); progressive asymmetric weakness; electromyographical proof of a neurogenic lesion which was not related to a root compression, polyneuropathy or entrapment syndrome. Exclusion criteria were: respiratory involvement; lesion of the cranial-nerves; hyper-reexia or other signs of an involvement of the upper motor neurone; sensory impairment; neoplastic disorder; positive family history as to neuromuscular diseases; polyneuropathy. Positive GM-1 antibodies or the presence of a conduction block were not an imperative condition.
Study design

Intravenous immunoglobulins were given at 2 g/kg/ bodyweight over 5 days every 46 weeks. Every patient received at least two courses of IVIg. The average number of treatment courses was eight (range 243).
Examination before and during IVIg treatment

Before treatment was started, the examination of the cerebrospinal uid was performed in all patients. Magnetic resonance imaging (MRI) was performed to exclude compression of the spinal cord and of the nerve roots. MRI of the lumbar or cervical plexus was not performed. Previous to IVIg and before each treatment period a detailed clinical, laboratory and neurophysiological analysis by experienced neurologists was performed using a standardized protocol. Muscle strength was examined bilaterally according to the Medical Research Council (MRC) Score [9]. Activities of daily living were

assessed by the Neuromuscular Symptom Score (NSS) [10]. Patients were divided into a responder and nonresponder group after the second course of treatment: Positive response was dened as a lasting improvement in the NSS and/or in the neurological testing by means of the MRC Score at the third examination when compared with the rst one. A non-response was dened as a worsening of the NSS and/or of the MRC-Score. In the NSS 14 items which describe activities of daily living were taken into account (i.e. for example opening of bottles or jam glasses, buttoning up, binding shoelaces). Each item can be answered in four ways: very restricted, moderately restricted, little restricted or normal (points 0, 1, 2, 3). Besides a worsening of the neurological status or appearance of new symptoms such as upper motor signs, involvement of cranial nerves, or of the respiratory system was dened as a non-response. For determining the patients global assessment of the treatment, patients were asked about subjective improvement after each treatment period, using a semi-quantitative 3-point scale (worse, unchanged, improved). The electromyographic examination was performed with concentric needle electrodes (Medtronic Keypoint, Copenhagen, Denmark). Proximal as well as distal muscles of each limb were examined. Pathological spontaneous activity (PSA) was described semiquantitatively (0 absent to +++ profuse PSA). Duration, amplitude and recruitment pattern of the motor unit action potentials were recorded. Motor neurography was performed with surface stimulation and registration electrodes. The motor nerve conduction velocities (NCV) and distal motor latencies of the ulnar, median, radial, tibial and peroneal nerve were bilaterally recorded in the proximal, middle, and distal part. NCV and compound muscle action potentials (CMAP) were measured (baseline to peak). Care was taken to perform all measurements at 32C. A conduction block was dened as a reduction of the area under the CMAP for more than 50% or a reduction of the amplitude >50%. F-wave latencies and persistence were recorded at the abductor pollicis brevis, abductor digiti minimi, and extensor digitorum brevis muscle. To exclude entrapment syndromes inching of the nerve was performed at common entrapment sites (elbow, head of the bula). Sensory NCV and sensory nerve action potentials (SNAP) of the median, ulnar, supercial radial, and sural nerves were registered on both sides. Prior to treatment creatinekinase (CK) levels, GM1and asialo-GM1 antibody titres were examined.

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Measurements of GM1- and asialo-GM1 antibody titres

Table 1 Characteristics of the patients before treatment Number of patients Responders Non-responders (%) (%) P-value

Antibody titres were measured by a commercial laboratory (Institute of Clinical Chemistry, Hospital Lippe-Lemgo, Germany, K.H. Muller and Dr W. Siede). A commercially available enzyme immunoassay (Buhlmann Laboratories, Switzerland) was used.
Statistical analysis

Parameter Sex Male Female Weakness Prox. and distal distal Creatinekinase (U/l) >80 <80 GM1 antibody titre Positive (IgM > 5950 BTU) Negative Low titre Acute or chronic denervation Generalized denervation (a non-paretic limb affected) Local No Conduction block Yes No Upper limb Lower limb Upper and lower limb

13 (42) 5 (56) 6 (24) 12 (80) 5 (21) 13 (81) 3 (100) 7 (33) 8 (57) 0 (0) 11 (52) 7 (78) 11 7 9 1 2 (65) (30) (75) (25) (100)

18 (58) 4 (44) 19 (76) 3 (20) 19 (79) 3 (19) 0 (0) 14 (67) 6 (43) 10 (100) 10 (48) 2 (22) 6 16 3 3 0 (35) (70) (25) (75) (0)

0.4697

0.0006

Statistical analysis was performed by a statistician (H.B., co-author) who used the BioMedical Computer Program (BMDP, Department of Biomathematics, School of Medicine, University of California, Los Angeles, CA, USA). To compare clinical, laboratory and electrophysiological ndings between the responders and non-responders, the KruskalWallis H-test for continuous variables (rank variance analysis) and the chi-squared test (multifactorial analysis of frequency tables) for categorical variables were used. A P < 0.05 was considered to be signicant.

0.0002

0.0424 0.0630 0.0010

0.0019 0.0313

Results
The cerebrospinal uid (CSF) was examined in all patients. 33 patients showed a normal cerebrospinal uid (15 responders, 18 non-responders); six showed a protein elevation <100 mg/dl (three responders, three nonresponders); one non-responder showed a protein elevation of 126 mg/dl. Immunoglobulin synthesis in the central nervous system or an increase of cell account of the CSF was not found. Sensory NCV and sensory nerve action potentials were normal in all patients. Characteristics of the patients before treatment are shown in Table 1. In total 18 patients responded to IVIg treatment (42% responder) and 22 did not (58% non-responder). Nineteen non-responders received more than two courses of IVIg. The age of onset was not dierent between both groups (responder: 56.9 years, range 3476, non-responder: 58.5 years, range 3375). In our patients, the interval between the onset of the clinical symptoms and the beginning of the treatment was at mean 4.8 years (range 113 years). The duration of symptoms before the onset of treatment was longer in responders (6.0 years, range 111) than in non-responders (3.7 years, range 113 ). Gender did not inuence the response to treatment: 58% of the men and 44% of the women did not prot (P 0.4697). At the beginning of IVIg treatment, weakness was localized distally in 15 patients (two lower limbs, eight upper limb, ve upper and lower limb) and distally as well as proximally in 25 patients. Of the patients with

distal and proximal weakness 76% did not prot. Of the patients who suered only from distal weakness 20% did not respond (P 0.0006). The mean levels of CK were signicantly higher in the non-responders (230 U/l) when compared with the responders (86 U/l). Of the patients with an abnormal CK-level (normal range <80 U/l) 21% responded to treatment, whereas 81% of patients with normal CKlevels responded to treatment (P 0.0002). Of all patients 7.5% had a high titre of GM1 antibodies (IgM > 5950 BTU). All these patients responded to therapy. Of the patients with negative antibody titre 33% responded and 57% with low titre (P 0,0630). Asialo-GM1 antibodies were screened in 83% of the patients. Fifty-four per cent with positive asialoGM1 antibody titre and 56% with negative titre were responders (P 0.9122). Of all patients 25% showed electromyographic signs of denervation exceeding the clinical aected muscles. All these patients were non-responders to IVIg. In the group without generalization of electromyographic changes (no PSA or local PSA only), 12 patients were non-responders (40%). Of the patients without PSA 78% responded to IVIg (P 0.0019). A conduction block was found in 43% of all patients. Sixty-ve per cent of the patients with conduction

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10 9 8

Responders Non-responders

to the course of the disease. Five of them received additional immunosuppressive therapy.

Number of patients

7 6 5 4 3 2 1 0 0 1 2 3 4 5

Discussion
In contrast to disorders such as ALS and spinal muscular atrophy, MMN responds to immunomodulating treatment with IVIg. Unfortunately, there are no widely accepted criteria which permit a clear distinction between these disorders, especially in the early course of the disease. Several groups have tried to dene clinical, laboratory, and neurophysiological criteria [1113]. The aim is to give the very expensive IVIg treatment to all who need it, without wasting medical resources on those patients who will not respond to them. Though most authors suggest that the presence of a conduction block is mandatory for the diagnosis of MMN, recent studies have raised concerns that by a strict application of this criterion some treatable patients would be excluded from treatment [5,14]. High titre ganglioside antibodies are rather specic but lack sensitivity. It is currently estimated that only 50% of patients with treatable motor neuropathy have these antibodies [15]. Consequently, we performed a prospective study with 40 consecutive patients suering from pure lower motor neurone disease that received repeated courses of IVIg treatment. Inclusion criteria were based on clinical ndings, only. The repeated response to treatment was used as a gold standard to distinguish between MMN and other forms of MND. The purpose of the study was to dene a better set of criteria to predict the response to IVIg treatment. In our study there was no single clinical, neurophysiological or laboratory parameter which allows to select only those patients who might respond to treatment. Nevertheless, there is one parameter which predicts a non-response to treatment: patients with a generalization of electromyographic signs of denervation beyond the clinical involved site did not respond to treatment. This indicates that in treatable multifocal motor neurone disease, in contrast to spinal muscular atrophies or ALS there is no subclinical denervation preceding the onset of symptoms. To our knowledge there are no data in the literature concerning the spatial distribution of electromyographic ndings in this group of patients. Most reports describe neurophysiological changes in MMN, including an exhaustive discussion about the denition and relevance of conduction blocks [13,16,17]. Certainly the existence of a denite conduction block is a major criterion for MMN; in our study a signicant correlation could be demonstrated between response to treatment and existence of a conduction block which was dened by restrictive criteria.

Score
Figure 1 Scoring of the responders and non-responders.

blocks and 30% of the patients without a conduction block responded to treatment (P 0,0313). Seventyve per cent of the patients with a conduction block exclusively of the upper limbs responded to therapy and only 25% of the patients with a conduction block of the lower limbs. Both patients with conduction blocks of upper and lower limbs proted. We computed a scoring system with the ve parameters which diered signicantly between responders and non-responders (CK level, localization of weakness, acute or chronic denervation of a limb without clinical signs, GM1 antibody titre, conduction block). We gave one point for each of the following conditions: normal CK level; distal weakness; electromyographic signs of denervation only in clinical aected limbs; IgM-GM1 antibody titre >5950 BTU; existence of a conduction block. Therefore a maximal score of 5 could be achieved. No non-responder obtained more than two points and no responder less than two points. Seven nonresponders and ve responders got two points (30% of all patients) (Figure 1).
Follow-up of the non-responders

Five patients were lost to follow-up. One patient showed progression of weakness and signs for the rst motor neurone. Two patients showed a progression of weakness without signs for the rst motor neurone. Seven patients died of respiratory failure. Seven patients showed neither progression nor improvement of the paresis. The diagnosis of them is still unclear.
Follow-up of the responders

Four were lost to follow-up. In the remaining 14 responders the dosage of IVIg was adapted according

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Nevertheless, if we had used the presence of a conduction block as main inclusion criterion for IVIg treatment, 30% of all treatable patients (responders without conduction block) would have been remained untreated. On the other hand 35% of patients with a conduction block did not respond to treatment. In patients without conduction blocks, Ellis et al. [14] found a response to treatment in four of 10 patients and Katz et al. [5] in three of six treated patients. Divergent to this, in studies with patients who have conduction blocks about 30% of patients [12,18] did not respond to treatment. Similar to our ndings, this indicates that in quite a considerable number of patients a conduction block is of limited value for the decision to treat with IVIg. Elevated CK levels make a success doubtful, but do not exclude it. Of the patients with elevated CK levels 79% did not respond to treatment. The mean CK values diered signicantly between responders and nonresponders. Similar ndings have been reported by van den Berg-Vos et al. [12]. In this study, 30% of responders and 83% of non-responders had elevated CK levels. Earlier studies have shown that especially patients with ALS show elevated CK levels [19]. The only single parameter that highly correlated with a positive response to treatment in our study was an elevated GM1 antibody titre. All patients which had a high titre of GM1 antibodies responded to treatment. In clinical practice, the major problem is, that only a minority of treatable patients show highly elevated antibody titres, whereas the majority has normal titres or unspecic low titre. In our study only three patients had high titres of GM1 antibodies, another 14 patients had unspecic low to moderate titres. Previous studies have shown a wide range in the number of patients with GM1 antibodies. Between 22% [20] and 79% of patients [21] had elevated titres. According to Pestronk and Choksi [2], the rate of patients with positive titres can be increased up to 85% by using a modied assay. This nding was not conrmed by Carpo et al. [22]. In order to improve the detection rate of treatable patients without an excessive increase in costs due to large number of non-responders, we propose a scoring system that combines clinical, laboratory and neurophysiological data. By the use of this system all responders could be identied. Every patient which got 2 or more points should be treated with IVIg. Nevertheless a grey zone exists in our scoring system at a score of 2 points. Twelve patients got 2 points. Five of them were responders (28% of all responders), seven were non-responders (32% of all non-responders). However, all 15 patients with a score of 0 or 1 were identied as non-responders and 72% of patients who got 2 or more points responded. For that reason no

Table 2 Conduction block or score: Comparison of hypothetical treatment decisions Hypothesis CB responder Absent CB non-responder Score 01 non-responder Score 35 responder Hypothesis correct 27 (67.5%) Patients 11 Responders 16 Non-responders 28 (70%) Patients 15 Non-responders 13 Responders Hypothesis wrong 13 (32.5%) Patients 6 Non-responders with CB 7 Responders without CB 12 (30%) Patients 5 Responders: Score 2 7 Non-responders: Score 2

potential responder remained untreated, if a score of above two points was used as criterion. If we had used the criteria suggested by van den BergVos (inclusion criterion: conduction block) 30% of treatable patients would have been missed (seven responders of the 23 patients without conduction block) and 35% non-responders with conduction block would have been treated (six non-responders of the 17 patients with conduction block) (Table 2). This indicates that the use of conduction block criteria results in a considerable overlap between responders and non-responders. Our score helps to reduce this grey zone. The number of responders, which would not get treatment, because they do not have a conduction block, can be reduced from 30% (responders without conduction block) to zero (all responders got 2 or more points). The number of nonresponders can be reduced from 35% (non-responders with conduction block) to 28% (seven non-responders with 2 points in the group of patients with 2 or more points). This indicates, that our scoring is able to increase the number of treatable patients and to reduce the number of non-responders without the risk of excessive costs by unjustied treatment.

Acknowledgements
The study was supported by the Fordan Stiftung and by the Friedrich-Baur-Stiftung.

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