Michiaki Koga

Animal model of axonal Guillain‐Barré syndrome induced by sensitization with GM1 ganglioside

Some humans develop the axonal form of Guillain‐Barré syndrome after receiving bovine brain ganglioside. On sensitization with the ganglioside mixture, all of a group of rabbits injected developed high anti‐GM1 IgG antibody titers, flaccid limb weakness of acute onset, and a monophasic illness course. Pathological findings for the peripheral nerves showed predominant Wallerian‐like degeneration, with neither lymphocytic infiltration nor demyelination. IgG was deposited on the axons of the anterior roots, and GM1 was proved to be present on the axons of peripheral nerves. Sensitization with purified GM1 also induced axonal neuropathy, indicating that GM1 was the immunogen in the mixture. A model of human axonal Guillain‐Barré syndrome has been established that uses inoculation with a bovine brain ganglioside mixture or isolated GM1. This model may help to clarify the molecular pathogenesis of the syndrome and to develop new treatments for it.

Axonal Guillain-Barré syndrome: Relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan

To clarify the relations of the axonal form of Guillain‐Barré syndrome (GBS) to anti‐ganglioside antibodies and Campylobacter jejuni infection, 86 consecutive Japanese GBS patients were studied. Electrodiagnostic criteria showed acute inflammatory demyelinating polyneuropathy in 36% of the patients and acute motor axonal neuropathy (AMAN) in 38%. Frequent anti‐ganglioside antibodies were of the IgG class and against GM1 (40%), GD1a (30%), GalNAc‐GD1a (17%), and GD1b (21%). Identified infections were C. jejuni (23%), cytomegalovirus (10%), Mycoplasma pneumoniae (6%), and Epstein‐Barr virus (3%). There was a strong association between AMAN and IgG antibodies against GM1, GD1a, GalNAc‐GD1a, or GD1b. Almost all the patients with at least one of these antibodies had the AMAN pattern or rapid resolution of conduction slowing/block possibly because of early‐reversible changes on the axolemma. C. jejuni infection was frequently associated with AMAN or anti‐ganglioside antibodies, but more than half of the patients with AMAN or anti‐ganglioside antibodies were C. jejuni–negative. These findings suggest that the three phenomena “axonal dysfunctions (AMAN or early‐reversible conduction failure),” “IgG antibodies against GM1, GD1a, GalNAc‐GD1a, or GD1b,” and “C. jejuni infection” are closely associated but that microorganisms other than C. jejuni frequently trigger an anti‐ganglioside response and elicit axonal GBS. Ann Neurol 2000;48:624–631

Antecedent infections in Fisher syndrome A common pathogenesis of molecular mimicry

Objective: To assess the production mechanism of anti-GQ1b autoantibody in Fisher syndrome (FS). Methods: The authors conducted a prospective case-control serologic study of five antecedent infections (Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae) in 73 patients with FS and 73 sex- and age-matched hospital controls (HCs). Serologic evidence in FS patients of C. jejuni (21%) and H. influenzae (8%) infections was present significantly more often than in the HCs. None of the five pathogens examined was found in the 49 (67%) patients with FS. Anti-GQ1b IgG antibody was detected in most FS patients infected with C. jejuni or H. influenzae. Mass spectrometry analysis identified a C. jejuni strain (CF93-6) carrying a GT1a-like lipo-oligosaccharide (LOS) that had been isolated from an FS patient. Immunization of complex ganglioside-lacking knockout mice with the GT1a-like LOS generated IgG class monoclonal antibodies (mAbs) that reacted with GQ1b and GT1a. Thin-layer chromatography with immunostaining showed that anti-GQ1b mAb bound to the C. jejuni LOS (50% of the 20 FS-related strains) more commonly than in the Guillain–Barré syndrome (GBS)–related (7% of 70) or enteritis-related (20% of 65) strains. Anti-GM1 and anti-GD1a mAbs also reacted with the LOS from some FS-related strains (both 20%), but binding frequencies were higher in the GBS-related strains (74 and 57%). The GQ1b epitope was detected in 4 (40%) of the 10 FS-related H. influenzae strains but was absent in strains from patients with GBS (n = 4) and uncomplicated respiratory infections (n = 10). Conclusions: C. jejuni and H. influenzae are related to Fisher syndrome (FS) development, and production of anti-GQ1b autoantibody is mediated by the GQ1b-mimicking lipo-oligosaccharides on those bacteria. The causative agents remain unclear in the majority of patients with FS.

Clinical features and response to treatment in Guillain‐Barré syndrome associated with antibodies to GM1b ganglioside

GM1b is a minor ganglioside in human peripheral nerves. Serum anti‐GM1b antibodies frequently are present in patients with Guillain‐Barré syndrome (GBS). In this collaborative study, we investigated the antecedent infections, clinical features, and response to treatment of GBS patients with anti‐GM1b antibodies. Of 132 GBS patients who participated in the Dutch GBS trial that compared the effect of intravenous immunoglobulins and plasma exchange, 25 (19%) patients had anti‐GM1b antibodies. IgM antibodies were present in 14, IgG antibodies in 15, and both isotypes in 4 patients. The 25 patients with anti‐GM1b antibodies had a clinical pattern distinct from that of the other 107 GBS patients. They more often had an episode of gastrointestinal illness and frequently showed serological evidence of recent infection by Campylobacter jejuni. The anti‐GM1b–positive subgroup was marked by more rapidly progressive, more severe, and predominantly distal weakness. Cranial nerve involvement and sensory deficits were less common in the patients with anti‐GM1b antibodies. The presence of anti‐GM1b antibodies was associated with slower recovery. The clinical manifestations predominantly were associated with anti‐GM1b antibodies of the IgG isotype. Fourteen (56%) of the 25 patients with anti‐GM1b antibodies also had anti‐GM1 antibodies. The group of patients with both antibodies was clinically more homogeneous and had a more rapidly progressive, pure motor neuropathy. The subgroup of anti‐GM1b–positive GBS patients responded well to treatment with immunoglobulins but not to plasmapheresis. The distinctive clinical features of the patients with anti‐GM1b antibodies show that acute motor neuropathy represents a specific subgroup within GBS and that recognizing these patients may have consequences as to the choice of therapy. Ann Neurol 2000;47:314–321

Comprehensive Analysis of Bacterial Risk Factors for the Development of Guillain-Barré Syndrome after Campylobacter jejuni Enteritis

BACKGROUNDnGuillain-Barre syndrome (GBS), a postinfectious autoimmune-mediated neuropathy, is a serious complication after Campylobacter jejuni enteritis.nnnMETHODSnTo investigate the bacterial risk factors for developing GBS, genotypes, serotypes, and ganglioside mimics on lipo-oligosaccharide (LOS) were analyzed in C. jejuni strains from Japanese patients.nnnRESULTSnStrains from patients with GBS had LOS biosynthesis locus class A more frequently (72/106; 68%) than did strains from patients with enteritis (17/103; 17%). Class A strains predominantly were serotype HS:19 and had the cstII (Thr51) genotype; the latter is responsible for biosynthesis of GM1-like and GD1a-like LOSs. Both anti-GM1 and anti-GD1a monoclonal antibodies regularly bound to class A LOSs, whereas no or either antibody bound to other LOS locus classes. Mass-spectrometric analysis showed that a class A strain carried GD1a-like LOS as well as GM1-like LOS. Logistic regression analysis showed that serotype HS:19 and the class A locus were predictive of the development of GBS.nnnCONCLUSIONSnThe high frequency of the class A locus in GBS-associated strains, which was recently reported in Europe, provides the first GBS-related C. jejuni characteristic that is common to strains from Asia and Europe. The class A locus and serotype HS:19 seem to be linked to cstII polymorphism, resulting in promotion of both GM1-like and GD1a-like structure synthesis on LOS and, consequently, an increase in the risk of producing antiganglioside autoantibodies and developing GBS.

Patterns and serial changes in electrodiagnostic abnormalities of axonal Guillain–Barré syndrome

Background: In Guillain–Barré syndrome (GBS), anti-ganglioside antibodies are strongly associated with the acute motor axonal neuropathy (AMAN) form, but there are also cases of the demyelinating form of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) with anti-ganglioside antibodies. Objective: To elucidate the patterns and sequential changes in electrodiagnostic abnormalities of anti-ganglioside-positive GBS. Methods: Detailed serial electrodiagnostic findings were reviewed for 51 patients with GBS. Anti-ganglioside antibodies were measured by ELISA. Results: Antibodies to GM1, GM1b, GD1a, or GalNAc-GD1a were present in 25 patients. Of these, 12 (48%) showed the AMAN pattern, 5 (20%) the AIDP pattern, and 3 (12%) isolated F-wave absence in the first examination. All five patients with the AIDP pattern showed prolonged distal latencies, but three eventually showed the AMAN pattern or rapid normalization. The remaining two still had similarly prolonged distal latencies in weeks 4 to 6, but the serial changes were distinct from those in the anti-ganglioside-negative AIDP patients who showed progressive increases in distal latencies over 2 months after onset. Conclusions: Besides the simple axonal degeneration pattern, patients with anti-ganglioside-positive Guillain–Barré syndrome can show transient conduction slowing/block in the distal or proximal nerve segments, mimicking demyelination, but anti-ganglioside antibodies do not appear to be associated with acute inflammatory demyelinating polyneuropathy.

Campylobacter gene polymorphism as a determinant of clinical features of Guillain–Barré syndrome

Background: Ganglioside epitopes on Campylobacter jejuni are hypothesized as the key to the development and characterization of Guillain–Barré syndrome (GBS), but a comprehensive theory has yet to be established. A C jejuni gene, cst-II, involved in the biosynthesis of ganglioside-like lipo-oligosaccharide, shows a polymorphism (Asn/Thr51) that affects ganglioside epitopes. Objective: To examine the hypothesis that this polymorphism determines autoantibody reactivity, and thereby neurologic presentations in GBS. Methods: C jejuni isolates were collected from 105 GBS (including its variants) and 65 uncomplicated enteritis patients. The authors examined the frequency of cst-II and polymorphism (Asn/Thr51) in connection with the bacterial ganglioside epitopes, autoantibody reactivities against GM1, GD1a, and GQ1b, and patients’ neurologic findings. Results: Neuropathic strains more frequently had cst-II, in particular cst-II (Thr51), than did enteritic ones (85% vs 52%; p < 0.001). Strains with cst-II (Asn51) regularly expressed the GQ1b epitope (83%), whereas those with cst-II (Thr51) had the GM1 (92%) and GD1a (91%) epitopes. The presence of these bacterial epitopes in neuropathy patients corresponded to autoantibody reactivity. Patients infected with C jejuni (Asn51) more often were positive for anti-GQ1b IgG (56% vs 8%; p < 0.001) and had ophthalmoparesis (64% vs 13%; p < 0.001) and ataxia (42% vs 11%; p = 0.001). Patients who had C jejuni (Thr51) more frequently were positive for anti-GM1 (88% vs 35%; p < 0.001) and anti-GD1a IgG (52% vs 24%; p = 0.006) and had limb weakness (98% vs 71%; p < 0.001). Conclusions: The genetic polymorphism of C jejuni determines autoantibody reactivity as well as the clinical presentation of Guillain–Barré syndrome (GBS), possibly through modification of the host-mimicking molecule. The GBS paradigm is the first to explain the detailed pathogenesis of a postinfectious, autoimmune-mediated, molecular mimicry-triggering disorder.

Two patterns of clinical recovery in Guillain-Barré syndrome with IgG anti-GM1 antibody

Objective: To investigate the prognostic value of anti-GM1 antibody. Background: Whether anti-GM1 antibody is a marker of poor prognosis due to axonal degeneration in Guillain-Barré syndrome (GBS) is a matter of controversy. Methods: The clinical recovery of 41 consecutive GBS patients was analyzed. Results: The Hughes functional grading scores were similar at the peak, and 1, 3, and 6 months after onset for the groups of patients with (n = 19) and without (n = 22) immunoglobulin (Ig) G anti-GM1 antibodies. However, the anti-GM1-positive group included significantly higher proportions of patients with poor recovery (inability to walk independently at 6 months, 5 of 19 versus 0 of 22; p = 0.01) and those with a markedly rapid recovery (improvement by two or more Hughes grades within a month, 9 of 19 versus 4 of 22; p = 0.05). The positivity of IgG anti-GM1 antibody correlated well with the electrodiagnosis of the acute motor axonal neuropathy pattern but was not always associated with poor prognosis. Anti-GM1-positive patients showed two different patterns of clinical recovery-their conditions improved slower or faster than those of the anti-GM1-negative patients, most of whom had acute inflammatory demyelinating polyneuropathy. Conclusions: Anti-GM1 antibody is not always a marker of poor prognosis and, besides axonal degeneration, early reversible effects other than demyelination could be part of the pathophysiology of Guillain-Barré syndrome with IgG anti-GM1 antibody.

Rapidly progressive, predominantly motor Guillain-Barré syndrome with anti-GalNAc-GD1a antibodies

Objective: To investigate the presence of anti-GalNAc-GD1a antibodies in patients with Guillain-Barré syndrome (GBS) and to determine the relation of anti-ganglioside antibodies with clinical features. Background: The GBS is heterogeneous with regard to clinical manifestations, antecedent infections, and the presence and specificity of anti-ganglioside antibodies. Recently, antibodies to minor gangliosides have been identified in serum from GBS patients. Methods: The authors used ELISA to detect anti-ganglioside antibodies in 132 GBS patients and then correlated results with a database containing information on antecedent infections and clinical parameters. Results: Anti-GalNAc-GD1a antibodies could be detected in 19 (14%) GBS patients. The presence of anti-GalNAc-GD1a antibodies was related to antecedent Campylobacter jejuni infection (p < 0.001). GBS patients with anti-GalNAc-GD1a antibodies had a rapidly progressive, more severe, and predominantly distal weakness. Furthermore, they had less sensory loss, paresthesia, and cranial nerve involvement. In most patients, this reactivity was independent of reactivity to GM1. Dividing patients into separate groups based on their reactivity to GalNAc-GD1a and GM1 enabled the authors to delineate more homogeneous subgroups with regard to clinical features. Conclusions: This study provides further evidence for the hypothesis that antecedent infections and the specificity of subsequent anti-neural antibody responses determine the clinical manifestations in GBS patients.

Does Campylobacter jejuni infection elicit “demyelinating” Guillain–Barré syndrome?

Background: Campylobacter jejuni enteritis is the most common antecedent infection in Guillain–Barré syndrome (GBS). C. jejuni-related GBS is usually acute motor axonal neuropathy (AMAN), but previous reports described many cases of the demyelinating subtype of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) after C. jejuni infection. Objective: To investigate whether C. jejuni infection elicits AIDP. Methods: In 159 consecutive patients with GBS, antibodies against C. jejuni were measured using ELISA. Antecedent C. jejuni infection was determined by the strict criteria of positive C. jejuni serology and a history of a diarrheal illness within the previous 3 weeks. Electrodiagnostic studies were performed weekly for the first 4 weeks, and sequential findings were analyzed. Results: There was evidence of recent C. jejuni infection in 22 (14%) patients. By electrodiagnostic criteria, these patients were classified with AMAN (n = 16; 73%) or AIDP (n = 5; 23%) or as unclassified (n = 1) in the first studies. The five C. jejuni-positive patients with the AIDP pattern showed prolonged motor distal latencies in two or more nerves and had their rapid normalization within 2 weeks, eventually all showing the AMAN pattern. In contrast, patients with cytomegalovirus- or Epstein–Barr virus-related AIDP (n = 13) showed progressive increases in distal latencies in the 8 weeks after onset. Conclusion: Patients with C. jejuni-related Guillain–Barré syndrome can show transient slowing of nerve conduction, mimicking demyelination, but C. jejuni infection does not appear to elicit acute inflammatory demyelinating polyneuropathy.