B. C. Jacobs

The spectrum of antecedent infections in Guillain-Barré syndrome: A case-control study

Objectives: To determine which antecedent infections are specifically associated with the Guillain-Barré syndrome (GBS). Background: Infections with many agents have been reported preceding GBS. Some infections are related to specific clinical and immunologic subgroups in GBS. Most agents were reported in case reports and uncontrolled small series of GBS patients only, and their relation to GBS and its subgroups remains unclear. Methods: A serologic study for 16 infectious agents in 154 GBS patients and 154 sex- and age-matched controls with other neurologic diseases. Acute phase, pretreatment samples were used from clinically well-defined GBS patients. The seasonal distribution of serum sampling in the GBS and control group was the same. Results: Multivariate analysis showed that in GBS patients, infections with Campylobacter jejuni (32%), cytomegalovirus (13%), and Epstein-Barr virus (10%) were significantly more frequent than in controls. Mycoplasma pneumoniae infections occurred more often in GBS patients (5%) than in controls in univariate analysis. Infections with Haemophilus influenzae (1%), parainfluenza 1 virus (1%), influenza A virus (1%), influenza B virus (1%), adenovirus (1%), herpes simplex virus (1%), and varicella zoster virus (1%) were also demonstrated in GBS patients, but not more frequently than in controls. C. jejuni infections were associated with antibodies to the gangliosides GM1 and GD1b and with a severe pure motor form of GBS. Cytomegalovirus infections were associated with antibodies to the ganglioside GM2 and with severe motor sensory deficits. Other infections were not related to specific antiganglioside antibodies and neurologic patterns. Conclusions: Recent infections with C. jejuni, cytomegalovirus, Epstein-Barr virus, and M. pneumoniae are specifically related to GBS. The variety of infections may contribute to the clinical and immunologic heterogeneity of GBS.

Cytomegalovirus infection and Guillain-Barre syndrome The clinical, electrophysiologic, and prognostic features

Guillain-Barre syndrome (GBS) is usually preceded by infections, in particular cytomegalovirus (CMV) and Campylobacter jejuni infection. We studied the clinical and electrophysiologic features of 20 CMV-associated GBS patients and compared the findings with earlier established data of C. jejuni-related GBS patients (n = 43) and of GBS patients without these infections (n = 71). The patients all participated in the Dutch GBS trial in which we compared the effect of intravenous immune globulins and plasma exchange. We demonstrate that CMV-related GBS patients have a different clinical pattern in comparison with the other two GBS groups. They are significantly younger, initially have a severe course indicated by a high frequency of respiratory insufficiency, and often develop cranial nerve involvement and severe sensory loss. This is in contrast to C. jejuni infection, which is associated with motor GBS. Both infections are associated with delayed recovery compared with the GBS patients without these infections. NEUROLOGY 1996;47: 668-673

Distinguishing acute-onset CIDP from fluctuating guillain-barré syndrome: A prospective study

Objective: The aim of the study was to provide criteria that can help to distinguish between GBS-TRF and A-CIDP in the early phase of disease. Background: The distinction between Guillain-Barré syndrome (GBS) with fluctuations shortly after start of treatment (treatment-related fluctuations, or GBS-TRF) and chronic inflammatory demyelinating polyneuropathy with acute onset (A-CIDP) is difficult but important because prognosis and treatment strategy largely differ. Methods: Patients with GBS (n = 170) were included in a prospective longitudinal study. Patients with GBS-TRF (n = 16) and patients with A-CIDP (n = 8) were analyzed and compared. Extended clinical data, biologic material, and electrophysiologic data were collected during 1 year follow-up. Results: The first TRF in the GBS-TRF group always occurred within 8 weeks (median 18 days; range 10–54 days) from onset of weakness. In the GBS-TRF group, 5 (31%) patients had a second TRF and none had more TRFs. At all timepoints, patients in the A-CIDP group were less severely affected than patients with GBS-TRF, did not need artificial ventilation, rarely had cranial nerve dysfunction, and tended to have more CIDP-like electrophysiologic abnormalities. More GBS-TRF patients were severely affected and more patients had sensory disturbances when compared to the GBS group without fluctuations. Conclusions: The diagnosis of acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP) should be considered when a patient thought to have Guillain-Barré syndrome deteriorates again after 8 weeks from onset or when deterioration occurs 3 times or more. Especially when the patient remains able to walk independently and has no cranial nerve dysfunction or electrophysiologic features likely to be compatible with CIDP, maintenance treatment for CIDP should be considered.

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.

Neuralgic amyotrophy and hepatitis E virus infection

Objective: To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from patients without an associated HEV infection. Methods: HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011–2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004–2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR). Results: Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome. Conclusions: Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms.

Multifocal motor neuropathy Association of anti-GM1 IgM antibodies with clinical features

Objective: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. Methods: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. Results: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. Conclusion: Anti-ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis.

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.

Pain in Guillain-Barre syndrome: a long-term follow-up study.

Background: Pain in Guillain-Barré syndrome (GBS) may be pronounced and is often overlooked. Objectives: To obtain detailed information about pain in GBS and its clinical variants. Methods: This was a prospective cohort study in 156 patients with GBS (including 18 patients with Miller Fisher syndrome [MFS]). We assessed the location, type, and intensity of pain using questionnaires at standard time points during a 1-year follow-up. Pain data were compared to other clinical features and serology. Results: Pain was reported in the 2 weeks preceding weakness in 36% of patients, 66% reported pain in the acute phase (first 3 weeks after inclusion), and 38% reported pain after 1 year. In the majority of patients, the intensity of pain was moderate to severe. Longitudinal analysis showed high mean pain intensity scores during the entire follow-up. Pain occurred in the whole spectrum of GBS. The mean pain intensity was predominantly high in patients with GBS (non-MFS), patients with sensory disturbances, and severely affected patients. Only during later stages of disease, severity of weakness and disability were significantly correlated with intensity of pain. Conclusions: Pain is a common and often severe symptom in the whole spectrum of GBS (including MFS, mildly affected, and pure motor patients). As it frequently occurs as the first symptom, but may even last for at least 1 year, pain in GBS requires full attention. It is likely that sensory nerve fiber involvement results in more severe pain.

Cytomegalovirus infections and anti-GM2 antibodies in Guillain-Barré syndrome.

To investigate whether antecedent cytomegalovirus (CMV) infections in patients with Guillain-Barré syndrome are associated with the presence of specific antiganglioside antibodies, acute phase serum samples from 130 patients with Guillain-Barré syndrome and 200 controls were tested. Anti-GM2 IgM antibodies were found more often in patients with Guillain-Barré syndrome with CMV infection (22%) than in patients without the infection (2%) (P = 0.003). CMV infections may elicit anti-GM2 antibodies in susceptible patients, which may contribute to the pathogenesis of Guillain-Barré syndrome associated with CMV.