C.W. Ang

Mild forms of Guillain-Barré syndrome in an epidemiologic survey in the Netherlands

Objective: Assessment of incidence rates of Guillain-Barré syndrome (GBS) in the Netherlands over a 10-year period; investigation of a relationship between possible seasonality in GBS and the occurrence of preceding infections; and determination of distinctive characteristics in patients with GBS who are only mildly affected (able to walk unaided at nadir). Method: Records of patients with GBS admitted between 1987 and 1996 from all 45 hospitals in the southwest Netherlands were evaluated, covering a population of 4.2 million inhabitants. Results: A total of 476 patients met National Institute for Neurological and Communicative Disorders and Stroke criteria for GBS. This resulted in a crude incidence rate (IR) of 1.18/100,000 inhabitants. This IR increased linearly with age (p < 0.001). Men were more frequently affected than women (p < 0.001). No seasonal preponderance for GBS, nor for any of the preceding infections, was found. Patients under 50 years of age (p < 0.001) and men (p = 0.01) were more frequently found in the mildly affected group. In both groups a preceding infection was reported in 70% of the cases. In the severely affected group, serologic evidence for infection with Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, or Mycoplasma pneumoniae was found more frequently than in the mildly affected group (41% versus 16%, p = 0.001). Conclusions: Overall IR in the Netherlands are similar to those found in other studies. The incidence increases linearly with age and men are more frequently affected than women. Distinctive characteristics for mildly and severely affected patients were found regarding age, sex, and preceding infections. This suggests that other infectious agents or host factors may be involved in mild forms of GBS.

Structure of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity and clinical features of Guillain-Barré and Miller Fisher patients

ABSTRACT Ganglioside mimicry in the lipopolysaccharide (LPS) fraction of Campylobacter jejuni isolated from Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) patients was compared with isolates from patients with an uncomplicated enteritis. The antibody response to C. jejuni LPS and gangliosides in neuropathy patients and controls was compared as well. LPS from GBS and MFS-associated isolates more frequently contained ganglioside-like epitopes compared to control isolates. Almost all neuropathy patients showed a strong antibody response against LPS and multiple gangliosides in contrast to enteritis patients. Isolates from GBS patients more frequently had a GM1-like epitope than isolates from MFS patients. GQ1b-like epitopes were present in all MFS-associated isolates and was associated with anti-GQ1b antibody reactivity and the presence of oculomotor symptoms. These results demonstrate that the expression of ganglioside mimics is a risk factor for the development of post-Campylobacter neuropathy. This study provides additional evidence for the hypothesis that the LPS fraction determines the antiganglioside specificity and clinical features in post-Campylobacter neuropathy patients.

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.

Cross-reactive antibodies against GM2 and CMV-infected fibroblasts in Guillain–Barré syndrome

Objective: To investigate whether anti-GM2 antibodies in patients with Guillain–Barré syndrome (GBS) are induced by molecular mimicry with cytomegalovirus (CMV). Background: Antibodies against ganglioside GM2 are frequently present in the serum from GBS patients with an antecedent infection with CMV. Methods: The authors detected inhibition of anti-GM2 reactivity after incubation of GM2-reactive serum samples with fibroblasts infected with a GBS-associated CMV strain. Control sera consisted of GQ1b-reactive samples, and control antigens included uninfected fibroblasts and fibroblasts that were infected with other herpes viruses. Results: Serum immunoglobulin M reactivity with GM2 was decreased in a dose-dependent manner after incubation with CMV-infected fibroblasts. Incubation of anti-GM2-positive serum samples with uninfected fibroblasts and fibroblasts infected with varicella zoster virus did not inhibit anti-GM2 reactivity, whereas this reactivity was slightly decreased after incubation with herpes simplex virus type 1 in one patient. Antibodies against ganglioside GQ1b did not react with CMV-infected fibroblasts. Conclusions: CMV-infected fibroblasts express gangliosidelike epitopes that recognize specifically anti-GM2 antibodies. These results support the hypothesis that antiganglioside antibodies in CMV-infected GBS patients are induced by molecular mimicry between GM2 and antigens that are induced by a CMV infection.

Guillain-Barré Syndrome- and Miller Fisher Syndrome-Associated Campylobacter jejuni Lipopolysaccharides Induce Anti-GM1 and Anti-GQ1b Antibodies in Rabbits

ABSTRACT Campylobacter jejuni infections are thought to induce antiganglioside antibodies in patients with Guillain-Barrésyndrome (GBS) and Miller Fisher syndrome (MFS) by molecular mimicry between C. jejuni lipopolysaccharides (LPS) and gangliosides. We used purified LPS fractions from fiveCampylobacter strains to induce antiganglioside responses in rabbits. The animals that received injections with LPS from GBS-associated strains developed anti-GM1 and anti-GA1 antibodies. Animals injected with LPS from one MFS-related C. jejuni strain produced anti-GQ1bantibodies. Rabbits that were injected with Penner O:3 LPS had a strong anti-LPS response, but no antiganglioside reactivity was observed. The antiganglioside specificity in the rabbits reflected the specificity in the patients from whom the strains were isolated. In conclusion, our results indicate that an immune response against GBS- and MFS-associated C. jejuni LPS results in antiganglioside antibodies. These results provide strong support for molecular mimicry as a mechanism in the induction of antiganglioside antibodies following infections.

Infections and course of disease in mild forms of Guillain–Barré syndrome

ObjectiveTwenty-eight percent of patients with the Guillain–Barré syndrome remain able to walk unaided. Studying patients with the mild form of Guillain–Barré syndrome can further contribute to knowledge of the spectrum of the syndrome and explore whether this subgroup may need treatment with IV immunoglobulin. MethodsPatients fulfilling the National Institute of Neurologic and Communicative Disorders and Stroke criteria for Guillain–Barré syndrome were included in a nationwide survey over a 2-year period. Clinical characteristics and serum samples were collected prospectively. In addition, a questionnaire was completed concerning the course and outcome of the disease. ResultsA total of 139 patients were included. Nineteen of the patients (14%) included were mildly affected, and 120 (86%) were severely affected. Infections with Epstein–Barr virus were found more frequently in mildly affected patients (p = 0.02). Antiganglioside antibodies were less frequently found in the mildly affected patients (p = 0.03). The degree of severity of the disease between mildly and severely affected patients was different on the day of admission (p < 0.01). Thereafter, the groups showed a remarkably similar rate of progression. Thirty-eight percent of mildly affected patients report problems in hand function and an inability to run at 3 and 6 months (all women, p = 0.02). ConclusionThe difference in severity of Guillain–Barré syndrome seems to be determined in an early phase of the disease. Preceding infections and antiganglioside antibodies may influence the initial immune attack, determining the severity of the disease. The presence of residual signs in patients with mild disease may advocate the use of early treatment in mildly affected patients.

Cross-reactive anti-galactocerebroside antibodies and Mycoplasma pneumoniae infections in Guillain–Barré syndrome

Anti-galactocerebroside (GalC) antibodies are reported to be present in GBS patients with preceding Mycoplasma pneumoniae (MP) infection. We investigated the presence of anti-GalC reactivity in serum of a large group of GBS patients using ELISA and compared this with healthy controls and individuals with an uncomplicated MP infection. Anti-GalC antibody reactivity was present in 12% of the GBS patients. Furthermore, anti-GalC antibodies were associated with MP infections, a relatively mild form of the disease and demyelinating features. Anti-GalC antibodies cross-reacted with MP antigen. In conclusion, anti-GalC antibodies in GBS patients may be induced by molecular mimicry with MP.

Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy

Antibody reactivity to GA1, GM1, GM2, GD1a, GD1b, and GQ1b gangliosides was measured in 87 patients with polyneuropathy associated with monoclonal gammopathy (60 IgM, 25 IgG, 2 IgA) and 42 control patients with monoclonal gammopathy without polyneuropathy (21 IgM, 21 IgG). Of these 87 patients, 30% had anti-myelin-associated glycoprotein antibodies and 15% had antiganglioside antibodies. Antiganglioside antibodies were significantly associated with demyelinating neuropathy and with IgM monoclonal gammopathy. Anti-GD1b and anti-GQ1b antibodies were significantly associated with predominantly sensory ataxic neuropathy.

Campylobacter jejuni lipopolysaccharides from Guillain–Barré syndrome patients induce IgG anti-GM1 antibodies in rabbits

Abstract Lipopolysaccharides (LPS) from Campylobacter jejuni strains isolated from patients with Guillain–Barre syndrome (GBS) display molecular mimicry with GM1. We immunized rabbits with C. jejuni LPS from GBS-associated strains containing a GM1-like epitope. All animals produced high titre anti-LPS antibodies that were cross-reactive with GM1. We conclude that C. jejuni strains from GBS patients are able to induce antibodies that cross-react with gangliosides and LPS. This study further confirms the role of molecular mimicry in the induction of anti-ganglioside antibodies in GBS patients.

Gastroenteritis-associated Guillain–Barré syndrome on the Caribbean Island Curaçao

Background: The number of patients with Guillain–Barré syndrome (GBS) who have been observed in Curaçao, the Netherlands Antilles, may be increasing. Methods: Clinical and serologic data were obtained from records of patients admitted between 1987 and 1999 and fulfilling National Institute of Neurological and Communicative Disorders and Stroke criteria for GBS. When possible, serum and stool samples were collected. The results were compared with a large Dutch epidemiologic study. Results: The authors identified 49 patients, an overall crude incidence rate (IR) in Curaçao of 2.53/100,000 inhabitants (95% CI 1.87 to 3.35) (Dutch study 1.18, rate ratio (RR) of 2.14, p < 0.001). The IR in Curaçao increased from 1.62 in 1987 to 1991 to 3.10 in 1992 to 1999, RR 5.22 (95% CI 2.48 to 10.2, p = 0.02). The IR showed a curvilinear shape within a year. In comparison with the Dutch group, patients from Curaçao had a more severe course of the disease, with a mortality rate of 23% (3.4% in the Dutch group, p < 0.001), a higher percentage of preceding gastroenteritis (p < 0.001), and less sensory involvement (p < 0.001). In 8 of 10 serum samples, evidence was found for a recent infection with Campylobacter jejuni. Conclusions: The authors found a steady increase in incidence of GBS over the years in association with a more pronounced seasonal preponderance and a more severe course. The clinical characteristics suggest a role for C jejuni.