Anti-ganglioside antibodies profile in Guillain-Barré syndrome: Correlation with clinical features, electrophysiological pattern, and outcome
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_1226_15
Source of Support: None, Conflict of Interest: None
Background: Guillain-Barré syndrome (GBS) and its subtypes are associated with distinct anti-ganglioside antibodies. Hence, we aimed to determine the frequency of anti-ganglioside antibodies and its correlation with clinical features, electrophysiological patterns, and outcome in patients with GBS.
Keywords: Anti-ganglioside antibody, axonal, demyelination, Guillain–Barré syndrome, subtype
Guillain-Barré syndrome (GBS) is a (sub) acute immune-mediated inflammatory polyneuropathy. The most common subtypes of the GBS include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN).,,, Other rare variants have also been described such as acute pan-dysautonomia, paraparetic variant, ptosis without ophthalmoplegia, acute ophthalmoparesis, and facial diplegia or sixth nerve palsy with paraesthesias.,,, These subtypes are associated with distinct anti-ganglioside antibodies [Table 1].,,,,,,
Evidence shows that antiganglioside antibodies play an important role in the immunopathogenesis of GBS. Most common antibodies that are identified are against GM1, GD1a, GD1b, GT1a, and GQ1b gangliosides. One of the proposed mechanisms is molecular mimicry in which antecedent infection produces specific antibodies, which in turn cross-reacts with peripheral nerve components because of the sharing of cross-reactive epitopes. These antibodies can be directed against myelin or the axon. Antecedent infection with Campylobacter jejuni produces high titers of antibodies to GM1, GD1a, GalNAc-GD1a, and GD1b, which are strongly associated with the AMAN variant. Similar association with Campylobacter jejuni infection and antibodies to GQ1b ganglioside has been reported in Miller Fischer syndrome (MFS). Antibodies are more associated with the AMAN variant of GBS than with acute inflammatory demyelinating polyneuropathy (AIDP). Very few studies have addressed the outcome of GBS in relation to anti-ganglioside antibodies., In the present study, we aimed to determine the frequency of anti-ganglioside antibodies and the correlation of these antibodies with clinical features, electrophysiological patterns, and outcome in patients with GBS.
We collected the data retrospectively from the case records of patients diagnosed to have GBS during 2008–2013 at a tertiary care referral hospital in south India. The clinical diagnosis of GBS was made based on the National Institute of Neurological Disorders and Stroke (NINDS) criteria and that of MFS (GBS variant) as described by Miller Fisher in 1956. The following data were recorded – demographic data; preceding (if any) illness; neurological findings; and laboratory findings. The patients' disability at admission and at discharge were evaluated using Hughes functional grading scale. Outcome of patients at 6 months was divided into three categories: remained static, improved, or died.
Nerve conduction studies (NCS) were performed at admission and at 2 weeks of disease onset. NCS were performed on at least 4 motor (median, ulnar, common peroneal, and posterior tibial) and 3 sensory (median, ulnar, and sural) nerves using the conventional and standard techniques. The following parameters were noted: distal motor and sensory latencies, motor and sensory conduction velocities, compound muscle action potential (CMAP) amplitude, F latencies, temporal dispersion, conduction blocks, and sensory nerve action potential (SNAP) amplitude. The value of each variable was then compared with the upper or lower normal limits, as set by our laboratory. Later, all patients were classified as AIDP or AMAN based on the electrodiagnostic criteria of Ho et al. AMSAN was defined as per the criteria proposed by Feasby et al., and Rees et al. Patients whose NCS were not meeting the electrodiagnostic criteria of AIDP, AMAN orAMSAN were termed as being in the ‘unclassified’ category.
An enzyme-linked immunosorbent assay (ELISA) was used to detect the various types of anti-ganglioside antibodies in the serum samples of GBS patients. This was a qualitative test. Anti-immunoglobulin G (IgG) antibodies against the gangliosides GM1, GM2, GM3, GD1a, GD1b, GT1b, and GQ1b were assayed and analyzed.
Data were recorded on a predesigned proforma and managed using Microsoft Excel 2007 (Microsoft Corp, Redmond, WA). Descriptive statistics for the categorical variables were performed by computing the frequencies (percentages) in each category. Variables following normal distribution were summarized by mean and standard deviation (SD); the remaining variables were summarized as median [interquartile range (IQR)]. The association between two categorical variables was evaluated by the chi-square test. Student's t-test or Mann–Whitney U test, as appropriate, were used to compare continuous variables between the groups. All tests were two-tailed; a P value of <0.05 was considered as significant. Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) Version 20, (IBM SPSS Statistics, Somers NY, USA); and Statistical Analysis System (SAS), Version 8.2, (SAS Institute Inc., Cary, NC, USA).
During the study period (2008–2013), a total of 204 patients with GBS were studied, and 73 patients who underwent anti-ganglioside antibody testing were analysed; their male (n = 52) to female (n = 21) ratio was 2.5:1. The mean age at presentation was 37.6 ± 17.5 years (range: 2–79 years). Antecedent infection was present in 40 (54.8%) patients, and the mean gap between the antecedent infection and the disease-onset was 7.5 (range: 2–18) days. The antecedent infections included upper respiratory tract infection (URTI) (n = 21), gastroenteritis (GE) (n = 10), and nonspecific febrile illness (n = 40). The findings observed in these patients at the time of admission were quadriparesis in 67 (91.8%), paraparesis in 2 (2.7%), global areflexia/hyporeflexia in 73 (100%), sensory abnormalities in 36 (49.3%), facial nerve palsy in 31 (42.5%), dysautonomia in 16 (21.9%), bulbar palsy in 15 (20.5%), respiratory palsy requiring mechanical ventilation in 13 (17.8%), ataxia in 9 (12.3%), ophthalmoplegia in 4 (5.5%), and and nerve conduction study (NCS) suggestive of neuropathy in 69 (94.5%) patients. Based on the electrophysiological criteria, patients with GBS were classified as AIDP [n = 46 (63%)], AMAN [n = 15 (20.5%)], AMSAN [n = 5 (6.8%)], and unclassified [n = 3 (4.1%)]; NCS was normal in 4 patients who presented with the MFS phenotype. A total of 3 patients died. The median Hughes functional grade at the time of admission and at the time of discharge were 4 (3–4) and 3 (2–4), respectively.
Seventy-three patients underwent testing for the IgG anti-ganglioside antibodies. IgG anti-ganglioside antibodies were positive in 41 (56.2%) and negative in 32 (43.8%) patients. Eighteen patients were positive for the single type of IgG anti-ganglioside antibody, 5 patients showed positivity to two types of IgG anti-ganglioside antibodies, and 18 patients were positive for greater than two types of IgG anti-ganglioside antibodies. A comparison of the clinical characteristics and electrophysiological subtypes among the group of patients with IgG anti-ganglioside antibody-positive and -negative GBS are shown in [Table 2] and [Table 3], respectively. The median Hughes functional grade at the time of admission in patients with IgG anti-ganglioside antibody-positive and -negative GBS were 4 (3–4) and 4 (4–5), respectively (P = 0.065).
Among the patients who were anti-ganglioside antibody positive, the most frequent was IgG anti-GT1b antibody (25 patients, 34.2%), followed by IgG anti-GM2 (20 patients, 27.4%), IgG anti-GD1b (19 patients, 26.0%), and IgG anti-GM1 (18 patients, 24.6%) antibodies. IgG anti-GQ1b antibodies were also found in 16 patients (21.9%); however, they were present only in one (along with IgM anti-GQ1b antibody) out of the 4 patients with MFS. IgG anti-GD1a and anti-GM3 antibodies were present in 15 (20.5%) and 10 (13.7%) patients, respectively.
The most common IgG anti-ganglioside antibodies observed in the acute demyelinating variant were anti-GT1b (n = 13;17.8%), followed by anti-GM2 (n = 7), anti-GD1a (n = 7), anti-GD1b (n = 7), anti-GQ1b (n = 7), anti-GM1 (n = 6), and anti-GM3 (n = 3) antibodies; and in the acute axonal variant were anti-GM1 (n = 9; 12.3%), anti-GM2 (n = 9; 12.3%), anti-GD1b (n = 9; 12.3%), and anti-GT1b (n = 9; 12.3%) antibodies, followed by anti-GQ1b (n = 7), anti-GM3 (n = 6), and anti-GD1a (n = 5) antibodies. There were 4 patients with MFS, out of which only 2 patients were positive for IgG anti-ganglioside antibodies. The distribution of various IgG anti-ganglioside antibodies among different subtypes of GBS is shown in [Figure 1].
All patients with GBS received intravenous immunoglobulin (IVIg). Three (4.1%) patients died; all of them required mechanical ventilation and were negative for anti-ganglioside antibodies. A total of 5 (6.8%) patients were unable to walk independently (Hughes functional grade ≥3) at the end of 6 months from the disease onset. Two of them were positive for IgG anti-ganglioside antibodies and the other 3 were negative for these antibodies (P = 0.0625).
It has been proposed that anti-ganglioside antibodies contribute to the immunopathogenesis of GBS and certain other inflammatory neuropathies. Arguments against the importance of these antibodies in GBS have been raised because anti-ganglioside antibodies such as IgM anti-GM1 are also observed in apparently healthy individuals and in patients with multifocal motor neuropathy with conduction block other than GBS.,, The mechanism by which anti-ganglioside antibodies production is triggered is not very well known. However, it has been proposed that production of anti-ganglioside antibodies may be triggered by viruses or bacteria through a molecular mimicry mechanism or epitope sharing., Anti-ganglioside antibodies bind to the nodal axolemma or the paranodal myelin, thus leading to axonal degeneration or demyelination. Research has shown that the clinical features of GBS and its subtypes are closely associated with some specific anti-ganglioside antibodies.,, Four gangliosides – GM1, GD1a, GT1a, and GQ1b – described in GBS differ with regard to the number and position of their sialic acids, in which M, D, T, and Q represent mono-, di-, tri-, and quadri-sialosyl groups, respectively. IgG anti-ganglioside antibodies to GM1 and GD1a are more commonly associated with AMAN, AMSAN, and acute motor conduction block neuropathy, but not with AIDP., Motor and sensory nerves express similar quantities of GM1 and GD1a; however, their expression within various tissues may differ. It has been suggested that IgG anti-GD1a antibodies bind to the motor nerve terminals where the blood nerve barrier is deficient and cause pure motor neuropathy. This could explain the preferential motor axon injury seen in AMAN.
Worldwide, the positivity of anti-ganglioside antibodies in patients with GBS has ranged from 37–78%.,,,,, The explanation for this wide variation in the frequencies of positivity of anti-ganglioside antibodies among various countries may be the differences in the methodology of assays used by different laboratories;, or, may be the differences in the number of patients recruited in each study. In our study, 56% of the patients with GBS were found to be positive for anti-ganglioside antibodies, which is almost similar to the results observed in a previous study. The common anti-ganglioside antibodies in our study were IgG anti-GT1b (34.2%), followed by IgG anti-GM2 (27.4%), IgG anti-GD1b (26.0%), IgG anti-GM1 (24.6%), IgG anti-GQ1b (21.9%), IgG anti-GD1a (20.5%), and anti-GM3 (13.7%). In our study, we found that IgG anti-ganglioside antibodies were significantly positive (P = 0.0169) with the AMAN subtype of GBS compared to the other subtypes of GBS. The frequency of positivity with IgG anti-GM1 and anti-GD1b antibodies was high in the AMAN variant compared to the other anti-ganglioside antibodies. IgG anti-ganglioside antibodies against GQ1b are associated with ophthalmoplegia and ataxia, and have been considered to be amongst the possible markers of MFS; they are often cross-reactive with GT1a.,,, Although the association between MFS and anti-GQ1B antibodies is well-known, we found it to be positive in only 1 out of 4 patients. A monospecific anti-GT1a antibody without GQ1b reactivity is associated with bulbar palsy in patients with GBS. Similarly, monospecific IgG anti-GD1b antibodies without GM1 cross-reactivity are associated with sensory ataxia.,
The presence of anti-ganglioside antibodies in AIDP is not common. However, one study showed that, in AIDP, antiganglioside antibodies against GM3, GD3, and GT3 can be seen, which may produce an inhibitory effect on the spontaneous muscle action potential at the neuromuscular junctions. In the present study, we found the highest positivity of IgG anti-GT1b antibodies (n = 13, 17.8%), the significance of which is unknown. In some patients with GBS, antibodies are not reactive toward a single ganglioside, as observed in the present study. Instead, the antibodies react toward a complex of ganglioside antigens made up of two different gangliosides. This may be due to a new conformational epitope formed by these glycolipids.,
Some studies,,, found significant correlation between antecedent infections, clinical features, severity of disease, and anti-ganglioside antibodies, and very few studies,, observed no such correlation. In the present study, an antecedent history of nonspecific febrile illness, an antecedent history of upper respiratory tract infection (URTI), the presence of dysautonomia, and the requirement of ventilatory support correlated significantly (P < 0.05) with the absence of IgG anti-ganglioside antibodies [Table 2], and there was no correlation between the disease severity and antibody status (P = 0.065). Considering the outcome, the number of deaths (3 patients), and the number of patients who were unable to walk independently (Hughes functional grade ≥3) at the end of 6 months (5 patients) were more in the IgG anti-ganglioside antibody-negative group; however, this difference did not reach statistical significance (P > 0.05). A similar finding of a poor outcome was observed in the previous studies; however, the number of patients were too small to draw any statistically valid conclusions.,
In conclusion, the frequency of anti-ganglioside antibodies in our cohort of patients with GBS was 56%, with the IgG anti-GT1b antibody being the most common antibody. The anti-ganglioside antibodies were significantly positive in the AMAN subtype of GBS. The disease severity does not correlate with the antibodies, although it was observed that the absence, and not the presence, of antibody was associated with antecedent URTI, dysautonomia, and requirement of ventilatory support. Moreover, the presence of anti-ganglioside antibodies was not useful in predicting the outcome and prognosis.
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[Table 1], [Table 2], [Table 3]