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Neuromuscular transmission is not impaired in axonal Guillain–Barré syndrome
  1. S Kuwabara1,
  2. N Kokubun2,
  3. S Misawa1,
  4. K Kanai1,
  5. S Isose1,
  6. K Shibuya1,
  7. Y Noto1,
  8. M Mori1,
  9. Y Sekiguchi1,
  10. S Nasu1,
  11. Y Fujimaki1,
  12. K Hirata2,
  13. N Yuki3
  1. 1Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
  2. 2Department of Neurology, Dokkyo Medical University, Tochigi, Japan
  3. 3Departments of Microbiology and Medicine, National University of Singapore, Singapore
  1. Correspondence to Professor Satoshi Kuwabara, Department of Neurology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; kuwabara-s{at}


Background Previous studies have shown that anti-GQ1b antibodies induce massive neuromuscular blocking. If anti-GM1 and -GD1a antibodies have similar effects on the neuromuscular junction (NMJ) in human limb muscles, this may explain selective motor involvement in axonal Guillain–Barré syndrome (GBS).

Methods Axonal-stimulating single-fibre electromyography was performed in the extensor digitorum communis muscle of 23 patients with GBS, including 13 with the axonal form whose sera had a high titre of serum IgG anti-GM1 or -GD1a antibodies.

Results All patients with axonal or demyelinating GBS showed normal or near-normal jitter, and no blocking.

Conclusion In both axonal and demyelinating GBS, neuromuscular transmission is not impaired. Our results failed to support the hypothesis that anti-GM1 or -GD1a antibody affects the NMJ. In GBS, impulse transmission is presumably impaired in the motor nerve terminal axons proximal to the NMJ.

  • Anti-GM1 antibody
  • anti-GD1a antibody
  • Guillain–Barré syndrome
  • acute motor axonal neuropathy
  • neuromuscular transmission
  • single-fibre electromyography
  • EMG
  • neuromuscular
  • neuropathy
  • neurophysiol
  • clinical

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Neurophysiological, pathological and immunological observations have shown that Guillain–Barré syndrome (GBS) is currently divided into the two major subtypes, acute inflammatory demyelinating polyneuropathy (AIDP, a classical demyelinating form) and acute motor axonal neuropathy (AMAN, an axonal variant).1 During the past 20 years, major advances have been made in understanding the immunopathogenesis of GBS, particularly in AMAN. Molecular mimicry of human gangliosides by the bacterial lipo-oligosaccharide has now been established as the cause of AMAN.2 Gangliosides GM1 and GD1a are the very likely antigenic targets of autoantibodies present in AMAN. Antibody binding to the nodes of Ranvier is thought to either interfere with ganglioside function or activate complement, causing axonal damage and thereby impaired action potential conduction.3

Clinical and electrophysiological investigations have shown that AMAN is characterised by pure motor neuropathy, but the basis of pure motor axonal involvement in AMAN is not clear, because both the motor and sensory nerve fibres similarly contain GM1 and GD1a.4 An attractive hypothesis for selective motor manifestation in AMAN is that antiganglioside antibodies affect the neuromuscular junction (NMJ). The presynaptic motor nerve terminal at the NMJ may be a prominent target because it is highly enriched in gangliosides and lies outside the blood–nerve barrier, allowing antibody access. The impaired neuromuscular synaptic transmission might contribute to the muscle weakness in AMAN patients. Experimental studies have shown that anti-GM1 and -GD1a antibodies bind to the presynaptic motor ending and activate complements, leading to formation of membrane attack complex, which causes intense neurotransmitter release and ultrastructural destruction, thereby blocking synaptic transmission at the NMJ.5–8

There is increasing evidence that anti-GQ1b antibodies causes functional and structural changes at the NMJ on mouse nerve–muscle preparations.6–8 Several studies showed both pre- and postsynaptic reversible blocking effects,8 whereas others demonstrated that anti-GQ1b antibodies induced massive irreversible quantal release of acetylcholine from nerve terminals, eventually causing neuromuscular blockade, described as α-latrotoxin-like effects.6 If anti-GM1 and -GD1a antibodies have similar effects on neuromuscular transmission, selective motor involvement can well be explained by dysfunction of the presynaptic motor axonal membrane at the NMJ.

Single-fibre electromyography (SFEMG) is the most sensitive in vivo measure of neuromuscular transmission, as established in myathenia gravis.9 To determine whether anti-GM1 or -GD1a antibodies are associated with neuromuscular transmission failure in human limb muscle, we prospectively performed SFEMG examination in consecutive patients with GBS, focussing on findings in patients with high-titre of serum IgG anti-GM1 or -GD1a antibodies.



A total of 23 patients with GBS, who were seen at Chiba University Hospital or Dokkyo Medical University Hospital between 2007 and 2009, were studied. According to electrodiagnosic criteria,10 13 were diagnosed as having AMAN, and the remaining 10, AIDP. Fifteen age-matched healthy subjects served as normal controls, and 15 patients with myasthenia gravis with antiacetylcholine receptor antibody during the study periods, as disease controls. IgG antibodies against GM1, GM1b, GD1a and GalNAc-GD1a were measured with ELISA as described elsewhere 111 by one of the authors (NY) who was blinded to clinical and electrophysiological data. Sera for antiganglioside assay were obtained on the same day of electrophysiological examination.

All patients and normal subjects gave informed consent to the study procedures, which were approved by the Ethics Committee of Chiba University School of Medicine and Dokkyo Medical University.

Nerve-conduction studies and single-fibre electromyography

Electrodiagnostic studies were performed within 3 weeks after neurological onset. Routine motor nerve-conduction studies were performed in the median, ulnar, peroneal and tibial nerves, including F-wave analyses.

We used axonal stimulating SFEMG, because voluntary SFEMG can be done only if the patient is able to maintain a constant slight contraction, which is often difficult in GBS patients. Axonal-stimulating SFEMG was performed using a conventional EMG machine (Viking 4, Nicolet Biomedical Japan, Tokyo, Japan), as described elsewhere,12 13 in the right extensor digitorum communis (EDC) muscle, whereas a disposable concentric needle electrode was used for recordings.14 Intramuscular nerve stimulation was delivered using a needle cathode (Teflon-coated monopolar steel needle, Nicolet Biomedical Japan, Tokyo, Japan) at 10 Hz.

Jitter was expressed as the mean of the absolute consecutive differences (MCD) of the latency from the stimulus to the negative peak of the muscle action potential. Twenty different muscle action potentials were sampled, and a series of 100 responses was acquired from each muscle fibre. Single muscle action potentials with a rising time <0.5 ms and amplitude >0.2 mV were analysed. Special care was taken to avoid jitter/blocking due to near-threshold stimulation.14 The upper normal limit was 29 μs (normal mean+3SD) for the mean MCD of examined motor endplates, and 40 μs for MCD for individual endplates.


Clinical profiles and antiganglioside antibodies

During the study period, 13 patients (10 men and 3 women; mean age 40.1 years; range 25–70 years) were diagnosed as suffering AMAN, whereas the remaining 10 had AIDP (5 men and 5 women; mean age 46.9 years; range 28–72 years) (table 1). All AMAN patients showed pure motor neuropathy and had a high titre (>1:1000) of anti-GM1 or GD1a antibody. All 10 except one AIDP patient had motor-sensory polyneuropathy, and none of them had antiganglioside antibodies. At the peak of the disease, six of the 13 AMAN patients and six of the 10 AIDP patients were unable to walk independently, and were treated with intravenous immunoglobulin therapy (400 mg/kg/day for consecutive 5 days). The other patients able to walk received only conservative treatments. The recovery was good in all the patients, except an AMAN patient (no 13), who was still tetraplegic 12 months after onset.

Table 1

Clinical profiles and single-fibre electromyography results in patients with Guillain–Barré syndrome

Single-fibre electromyography

Table 1 shows SFEMG findings in 13 AMAN patients and 10 AIDP patients. All showed normal mean MCD of 20 endplate (<30 μs), whereas two AMAN patients (nos 5 and 10) and one AIDP patient (no 1) had border-zone abnormality (eg, endplate with MCD >40 μs was found for 15% (3/20) of the endplate (normal <15%)). None of the patients had endplates with blocking. Figure 1 shows the mean MCD in the normal controls, and patients with AMAN, AIDP or myasthenia gravis. The mean MCD (jitter) was significantly greater only in the myasthenia group (mean MCD, 48.6 μs; p<0.001; Mann–Whitney U test). The mean MCD was similar for the normal (18.0 μs), AMAN (19.2 μs) and AIDP (20.0 μs) groups.

Figure 1

Single-fibre electromyography findings recorded from the extensor digitorum communis in normal controls, and patients with acute motor axonal neuropathy (AMAN), acute inflammatory demyelinating polyneuropathy (AIDP) or myasthenia gravis (MG). The AMAN and AIDP groups show normal jitter (mean consecutive difference of muscle fibre action potentials on single-fibre electromyography). The MG group shows significantly increased jitter, compared with the other groups (p<0.001; Mann–Whitney U test).

We did not perform radial nerve motor conduction studies. Instead, amplitudes of compound muscle action potential in median motor nerve studies were measured. The median (range) values of CMAP amplitude was 8.7 (5.6∼11.8) mV for the normal group, 3.7 (0.4∼5.8) mV for the AIDP group, 3.2 (0.8∼7.0) mV for the AMAN group and 8.0 (5.9∼10.9) mV for the MG group. The AIDP and AMAN group showed a significantly reduced CMAP amplitude, but more than 30% of motor axons were expected to be conductable. Therefore, it is unlikely that complete neuromuscular blocking occurred in these motor axons.


Our results showed that in patients with AMAN whose sera were positive for IgG anti-GM1 or -GD1a antibody, neuromuscular transmission in limb muscle assessed with SFEMG was almost normal. Two of the 13 AMAN patients showed a border-zone abnormality, but the entire lack of blocking suggests that AMAN patients do not have neuromuscular transmission failure, and muscle weakness in our AMAN patients cannot be explained by defect of neuromuscular transmission. Our findings, therefore, do not support the hypothesis that the presynaptic motor nerve terminal at the NMJ is a major target in AMAN. In addition, the present study revealed normal neuromuscular transmission in AIDP, as expected.

Whereas neuromuscular transmission in GBS has not been systematically examined, a previous study performed SFEMG in the EDC muscle of nine patients with GBS and showed increased jitter and intermittent blocking of muscle fibre action potentials to a varying degree in all patients, three of whom had anti-GM1 or -GD1a antibodies.15 These findings are entirely different from those in the present study that showed normal jitters and no blocking in almost of all the 23 patients with GBS. The reason for the discrepancy is unclear, but we speculated near-threshold stimulation in axonal stimulating SFEMG might result in pseudo-jitter and -blocking. If intramuscular axonal stimulation is not sufficiently suprathreshold, physiological jitter/blocking can occur in normal subjects,14 and this is a major pitfall of stimulating SFEMG, and sometimes difficult to resolve. During tetanic stimulation, axons undergo substantial membrane hyperpolarisation due to activation of the electrogenic sodium–potassium pump,16 and so it is necessary to further increase stimulus intensity during jitter measurements in stimulating SFEMG (unpublished data). To reach a conclusion as to whether SFEMG is abnormal in GBS, we performed a systematic examination including normal controls and positive controls (myasthenia gravis), as well as the larger number of GBS patients (n=23), compared with the previous study (n=7). As a result, we demonstrated normal neuromuscular transmission in GBS.

Experiments using mouse phrenic nerve-diaphragm preparations have led to conclusive results; anti-GQ1b sera cause presynaptic neuromuscular transmission failure, and this is presumably because GQ1b is prominently expressed at the motor nerve terminals of mouse phrenic nerves). Furthermore, a recent immunohistochemical study showed that GQ1b is expressed richly at the motor endplates of human extraocular muscles.17 These findings strongly suggest that in Fisher syndrome, the NMJ is presumably the major target of anti-GQ1b antibodies. However, our previous report has shown that Fisher syndrome patients with a high-titre anti-GQ1b antibody show normal SFEMG in the EDC muscle that was examined in the present study.13 The present study showed normal jitter and no blocking in a limb muscle of IgG anti-GM1 or -GD1a-positive GBS patients, and therefore does not support the view that the autoantibodies mainly affect the NMJ, leading to selective motor manifestation in axonal GBS. The possibility that neuromuscular transmission was completely blocked in some endplates, and therefore jitter/blocking could not be detected, cannot be excluded. However, we think that it is unlikely because of normal jitter and no blocking in all the endplates of the patients examined in this study.

The present study provides evidence that NMJ involvement is not responsible for pure motor manifestation in AMAN. Assuming that nerve conduction blocks preferentially occur near the motor nerve terminals,18 impulse transmission is impaired in terminal axons somewhat proximal to the NMJ. A recent report proposed that structural requirements of anti-GD1a antibodies determine their target specificity; the authors generated computer models of GD1a based on binding patterns of different GD1a-reactive monoclonal antibodies to different GD1a-derivatives.19 These modelling studies suggest that critical GD1a epitopes recognised by monoclonal antibodies are differentially expressed in motor and sensory nerves. The GD1a-derivative binding patterns of AMAN sera resembled those with motor-specific monoclonal antibodies. It is possible that both the fine specificity and ganglioside orientation/exposure in the tissues contribute to target recognition by antiganglioside antibodies and could be responsible for selective motor axonal injury in AMAN. Further studies will be required to elucidate the mechanism for pure motor axonal involvement in AMAN.



  • Funding This work was supported in part by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) (SK), and the Research Grant 16B-1 for Nervous and Mental Disorders (SK) from the Ministry of Health, Labour and Welfare of Japan.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Ethics Committee, Chiba University School of medicine and Dokkyo University.

  • Provenance and peer review Not commissioned; externally peer reviewed.