In our study, 36 of total 63 patients were diagnosed as AMAN (57.1%) and 27 patients were diagnosed as AIDP (42.9%). RCF was observed in 14 out of 36 (38.9%) in AMAN and 5 out of 27 (18.5%) in AIDP. AIDP patients with anti-ganglioside antibody were 5 out of 17 (29.4%). Onset age of AIDP-RCF was significantly lower than that of AIDP-nRCF and it was similar with AMAN-RCF. Diarrhea was more frequent in AIDP-RCF and AMAN than in AIDP-nRCF as preceding infection. HFGSs at 1 month and at 6 months after the onset were significantly lower in AIDP-RCF than in AMAN-nRCF and it was similar with AMAN-RCF. However, there were no significant differences in frequency of anti-ganglioside antibody status among the groups.
GBS subtypes are mainly classified into AIDP and AMAN based on electrodiagnostic studies. In AIDP, demyelination impairs the transmission of impulses along nerve fibers by changing the properties of the paranodal and internodal membranes. As the demyelinating changes take place, the current becomes insufficient to depolarize the node to a threshold, resulting in conduction failure/block, conduction velocity reduction, and temporal dispersion[17]. The pathophysiology of AIDP suggests that the production of autoantibodies by preceding infection and the activity of complement complexes results in the demyelination of peripheral nerves. However, the causative autoantibody for AIDP has not yet been identified[18]. In AMAN, the infecting organisms probably share homologous epitopes with an axon in the node of Ranvier of the peripheral nerves, reflecting molecular mimicry, and the immune responses cross-react with the nerves, causing axonal degeneration[19]. Gangliosides represent major target antigens of axonal GBS. The complement system is activated when IgG antibodies bind to gangliosides located at a node of Ranvier, where GM1 and GD1a are strongly expressed. Axonal degeneration proceeds by forming a membrane attack complex on the axolemma of motor fibers, resulting in the disappearance of voltage-gated sodium channels and the detachment of paranodal myelin loops[20, 21]. Anti-ganglioside antibody binding to the nodal axolemma leads to dysfunction of voltage-gated sodium channel clusters and disruption of paranodal axon–Schwann cell adhesion, resulting in conduction failure/blockage. If an autoimmune attack is aborted, axonal degeneration does not progress and nodal function rapidly recovers, which represents the pathomechanism of RCF[22, 23]. RCF in AMAN has been considered a sign of nodopathy and has a favorable prognosis[24]. Many previous reports have suggested that AMAN without RCF has the worst prognosis in GBS[10, 13], similar to the results of our study.
The term nodo-paranodopathy was suggested to characterize neuropathies related to autoantibodies based on a common pathogenic mechanism of dysfunction at the node of Ranvier, resulting in a pathophysiological continuum from transitory nerve conduction failure to axonal degeneration[25]. Some common beliefs, such as conduction failure and conduction velocity slowing, are associated only with demyelinating neuropathies and may be misleading in the interpretation of electrophysiological results in disorders affecting the nodal region. Uncini et al. have suggested that temporal dispersion helps to distinguish conduction failure in demyelinating neuropathy from conduction failure in nodopathy[5]. Remyelination following acute demyelination or ongoing demyelination is characterized by the desynchronization of conduction among fibers, which induces temporal dispersion and decreases CMAP amplitude due to the cancellation effect of opposing phases of a single motor unit potential. Nonetheless, conduction failure in nodopathy may be reversed without a temporal dispersion. Conduction velocity slowing is thought to be characteristic of demyelinating neuropathy, but partial inactivation of the sodium channel reduces the conduction velocity in nodopathy and improves in parallel with the resolution of conduction failure[5].
In our study, conduction failure without temporal dispersion was identified in some patients who were classified as having AIDP in an initial electrodiagnostic study and conduction failure disappeared within a short period of time without temporal dispersion in the serial NCS. We classified these patients as having AIDP with RCF. Uncini et al. set new criteria based on the results of Hadden[26] and Rajabally’s criteria[1], and the new criteria had intermediate features of two previous electrostatic criteria for GBS[6]. In the criteria by Uncini et al., RCF was defined as distal CMAP amplitude > 150% of that in first NCS, without evidence of increased distal CMAP duration (≤ 120%), or a proximal CMAP to distal CMAP amplitude ratio increase of 0.2 or more compared to the first NCS, without temporal dispersion or improvement of isolated F-wave absence without delayed latencies, in at least two nerves. In this study by Uncini et al., RCF in the presence of other demyelinating features occurred in 8/53 patients (15%) with a diagnosis of AIDP, similar to our results. In our study, 5/27 patients (18.5%) were classified into the AIDP-RCF group. A previous study by Chan et al. suggested tentative criteria for the recognition of early RCF on serial NCS based on the current electrodiagnostic criteria for GBS[7]. They correlated RCF with subtype classification according to traditional criteria (Ho[12] and Hadden’s criteria[26]) for GBS using serial NCS within 10 weeks of disease onset[7]. The criteria for the presence of early RCF in a nerve were i) 50% increase in amplitude of distal CMAP or sensory nerve action potentials or ii) resolution of proximal motor conduction block with accompanying decrease in distal latencies or CMAP duration or increase in conduction velocities. In the initial NCS of 82 patients, 60, 9, and 13 were classified into the AIDP, AMAN, and equivocal groups, respectively. Although they reported that 37 (45%) of 82 patients had early RCF, they did not analyze the frequency of RCF in AMAN or AIDP groups, respectively.
Rajabally et al. suggested modified criteria for classifying patients with GBS. However, these criteria could not confirm reversible conduction failure/block in the initial stage of GBS. In fact, Although approximately 50–65% of patients are initially suggested that they have demyelinating features, some of these cases are often changed into axonal neuropathy with initial conduction failure[21]. The importance of serial NCS for a proper diagnosis is stressed. Uncini et al. suggested that serial NCS is needed for the accurate classification of GBS subtypes, and temporal dispersion is a main feature of demyelinating GBS[6]. We conducted serial NCS in all enrolled patients and finally made a diagnosis after having checked the results of all serial NCS. In addition, we classified the RCF groups in AMAN and AIDP based on the results of serial NCS.
AMAN was observed more frequently than AIDP in our study and it is consistent with a previous report from China[10]. In this previous study, AMAN patients represented 55.8%, AIDP patients represented 21.2%, and patients classified into the equivocal group that did not fit into AIDP or AMAN group represented 13.5% of the cohort. Although patients with equivocal NCS findings were excluded from our study, AMAN was the most common subtype of GBS, accounting for more than half of the total number of patients. AIDP is the most common subtype of GBS in Western countries, while some reports from Eastern Asia, Southern Asia, Latin America, and the Middle East have demonstrated that AMAN is the most common subtype of GBS[11–15]. The incidence of GBS subtypes varies depending on the region[15]. These differences, depending on geographic location, are known to be linked to the presence of a preceding infection. Previous studies have suggested that AMAN is the most common subtype of GBS and may be related to preceding infections, such as gastrointestinal infection with Campylobacter jejuni[13].
Diarrhea is often preceded by C. jejuni infection in AMAN, and anti-ganglioside antibodies against GM1 and GD1a are frequently detected. Ogawara et al. reported that anti-C. jejuni-positive patients showed a significantly higher percentage of AMAN than the C. jejuni-negative patients (70% of C. jejuni-positive patients had AMAN type), and 80% of patients with AMAN had IgG antibodies to GM1, GD1a, GalNAc-GD1a, or GD1b[27]. In our present study, diarrhea was significantly more frequent in AMAN and AIDP with RCF than in AIDP without RCF as a preceding infection. In addition, the presence of anti-ganglioside antibody revealed a tendency for higher positivity in AMAN and AIDP with RCF than in AIDP without RCF, but there was no significant difference. Testing for anti-ganglioside antibodies is important because they are related to the pathomechanism of GBS. A recent cohort study from China analyzed the relationship between immune-mediated peripheral neuropathy and serum levels of anti-ganglioside IgG and IgM antibodies[28]. In this cohort, 42.4% patients were positive for at least one of the anti-ganglioside antibodies, and the sensitivity and specificity of the diagnostic test for GBS was 42% and 76%, respectively. The sensitivity of the anti-ganglioside antibody detection method can be elevated if ganglioside complexes are detected rather than each type of ganglioside[3, 29]. In our study, we used immunoblotting methods for each type of ganglioside, which might have caused relatively low sensitivity and no statistical differences in anti-ganglioside antibody status among the groups.
Our study had a number of limitations. First, the number of subjects in our study was relatively small, and the study was carried out at a single tertiary center. In particular, the number of patients in the AIDP with RCF group was five, which was insufficient to represent the clinical manifestations of the patients in that group. Second, to date, no criteria or definitions have been presented for RCF in AIDP. In the present study, RCF observed in AIDP was defined as conduction failure without temporal dispersion with other demyelination features in the initial NCS that disappeared in serial NCS; however, definition of RCF in AIDP may be controversial in terms of timing. We suggest that it is necessary to consider the definition of the timing of RCF or the remyelination process in AIDP. Third, testing for antiganglioside antibodies is critical in terms of the pathomechanism of GBS. However, there were no significant differences in anti-ganglioside antibody status among the groups in our study. More meaningful results can be obtained among the groups if additional tests for C. jejuni are conducted.
The current electrodiagnostic criteria for GBS can be used to classify GBS into AIDP, AMAN, and AMAN with RCF but have not suggested a classification of AIDP with RCF. However, some patients had RCF with demyelinating features in the initial NCS and presented different clinical features and prognoses from typical AIDP. A previous review by Yuki reported a study in which C. jejuni-related GBS patients were classified as having AMAN (n = 16) or AIDP (n = 5) or were unclassified (n = 1) in the first electrodiagnostic test[30]. Five C. jejuni-positive patients with the initial AIDP subtype showed prolonged motor distal latencies in two or more nerves. However, these changes rapidly normalized within 2 weeks. The author suggested that patients with C. jejuni-related GBS can show transient slowing of nerve conduction, mimicking demyelination, which is called a pseudo-demyelinating feature in AMAN[30]. However, there currently remain no electrodiagnostic criteria for classifying RCF in AIDP.
In conclusion, RCF in AIDP can be observed and is comparable with AMAN with RCF in terms of clinical features. AIDP with RCF may be a manifestation of nodopathy. The current dichotomous electrodiagnostic criteria, classifying demyelinating and axonal neuropathy, are not sufficient to define the presence of nodopathy. Further studies are required to revise the electrodiagnostic criteria for GBS.