Bart C. Jacobs

Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an important cause of acute neuromuscular paralysis. Molecular mimicry and a cross-reactive immune response play a crucial part in its pathogenesis, at least in those cases with a preceding Campylobacter jejuni infection and with antibodies to gangliosides. The type of preceding infection and patient-related host factors seem to determine the form and severity of the disease. Intravenous immunoglobulin (IVIg) and plasma exchange are effective treatments in GBS; mainly for practical reasons, IVIg is the preferred treatment. Whether mildly affected patients or patients with Miller Fisher syndrome also benefit from IVIg is unclear. Despite medical treatment, GBS often remains a severe disease; 3-10% of patients die and 20% are still unable to walk after 6 months. In addition, many patients have pain and fatigue that can persist for months or years. Advances in prognostic modelling have resulted in the development of a new and simple prognostic outcome scale that might also help to guide new treatment options, particularly in patients with GBS who have a poor prognosis.

Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis.

Guillain–Barré syndrome (GBS) is a potentially life-threatening postinfectious disease characterized by rapidly progressive, symmetrical weakness of the extremities. About 25% of patients develop respiratory insufficiency and many show signs of autonomic dysfunction. Diagnosis can usually be made on clinical grounds, but lumbar puncture and electrophysiological studies can help to substantiate the diagnosis and to differentiate demyelinating from axonal subtypes of GBS. Molecular mimicry of pathogen-borne antigens, leading to generation of crossreactive antibodies that also target gangliosides, is part of the pathogenesis of GBS; the subtype and severity of the syndrome are partly determined by the nature of the antecedent infection and specificity of such antibodies. Intravenous immunoglobulin and plasma exchange are proven effective treatments but many patients have considerable residual deficits. Discrimination of patients with treatment-related fluctuations from those with acute-onset chronic inflammatory demyelinating polyneuropathy is important, as these conditions may require different treatments. Novel prognostic models can accurately predict outcome and the need for artificial ventilation, which could aid the selection of patients with a poor prognosis for more-individualized care. This Review summarizes the clinical features of and diagnostic criteria for GBS, and discusses its pathogenesis, treatment and prognosis.

Miller Fisher anti-GQ1b antibodies : α-latrotoxin-like effects on motor end plates

In the Miller Fisher syndrome (MFS) variant of the Guillain‐Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti‐GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti‐GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin α‐latrotoxin at the mouse NMJs, implying possible involvement of α‐latrotoxin receptors or associated downstream pathways. By using complement‐deficient sera, the effect of anti‐GQ1b antibodies on NMJs was shown to be entirely dependent on activation of complement components. However, neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti‐GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action. Ann Neurol 1999;45:189–199

The crucial role of Campylobacter jejuni genes in anti-ganglioside antibody induction in Guillain-Barre syndrome

Molecular mimicry of Campylobacter jejuni lipo-oligosaccharides (LOS) with gangliosides in nervous tissue is considered to induce cross-reactive antibodies that lead to Guillain-Barre syndrome (GBS), an acute polyneuropathy. To determine whether specific bacterial genes are crucial for the biosynthesis of ganglioside-like structures and the induction of anti-ganglioside antibodies, we characterized the C. jejuni LOS biosynthesis gene locus in GBS-associated and control strains. We demonstrated that specific types of the LOS biosynthesis gene locus are associated with GBS and with the expression of ganglioside-mimicking structures. Campylobacter knockout mutants of 2 potential GBS marker genes, both involved in LOS sialylation, expressed truncated LOS structures without sialic acid, showed reduced reactivity with GBS patient serum, and failed to induce an anti-ganglioside antibody response in mice. We demonstrate, for the first time, to our knowledge, that specific bacterial genes are crucial for the induction of anti-ganglioside antibodies.

Guillain-Barré syndrome

Guillain-Barré syndrome is the most common and most severe acute paralytic neuropathy, with about 100,000 people developing the disorder every year worldwide. Under the umbrella term of Guillain-Barré syndrome are several recognisable variants with distinct clinical and pathological features. The severe, generalised manifestation of Guillain-Barré syndrome with respiratory failure affects 20-30% of cases. Treatment with intravenous immunoglobulin or plasma exchange is the optimal management approach, alongside supportive care. Understanding of the infectious triggers and immunological and pathological mechanisms has advanced substantially in the past 10 years, and is guiding clinical trials investigating new treatments. Investigators of large, worldwide, collaborative studies of the spectrum of Guillain-Barré syndrome are accruing data for clinical and biological databases to inform the development of outcome predictors and disease biomarkers. Such studies are transforming the clinical and scientific landscape of acute autoimmune neuropathies.

A clinical prognostic scoring system for Guillain-Barré syndrome.

BACKGROUND Guillain-Barré syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a highly variable clinical course and outcome. We aimed to develop and validate a scoring system based on clinical characteristics in the acute phase of GBS to predict outcome at 6 months. METHODS We studied patients with GBS who were unable to walk independently. A derivation set included 388 patients from two randomised controlled trials and one pilot study. Potential predictors were assessed for their association with the inability to walk independently at 6 months. A simple clinical scoring system was developed on the basis of regression coefficients of predictors in a multivariable logistic regression model. Model performance was quantified with respect to discrimination (area under receiver operating characteristics curve, AUC) and calibration (graphically). We validated our scoring system in a set of 374 patients from another randomised trial. FINDINGS We included three variables that were predictive of poor outcome at 6 months in our model: age, preceding diarrhoea, and GBS disability score at 2 weeks after entry. Scores ranged from 1 to 7, with three categories for age, two for diarrhoea, and five for GBS disability score at 2 weeks. Predictions corresponding to these prognostic scores ranged from 1% to 83% for the inability to walk independently at 6 months. Predictions agreed well with observed outcome frequencies (adequate calibration) and showed a very good discriminative ability (AUC 0.85) in both data sets. INTERPRETATION A simple scoring system for patients with GBS, based on three clinical characteristics, accurately predicts outcome at 6 months. The system could be used to counsel individual patients and identify high-risk groups to guide future trials.

Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria

Guillain-Barré syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-Barré syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with Guillain-Barré syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53 years (interquartile range 36-66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients during follow-up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in 95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/μl) was found in 15%, and none had more than 50 cells/μl. An increased cerebrospinal fluid protein concentration was found only in 64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88% after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59% fulfilled the current criteria for a distinct subtype of Guillain-Barré syndrome. Patients with a complete data set (335) were classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2 in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key diagnostic features of Guillain-Barré syndrome in the current cohort study, can be used to improve the sensitivity of the diagnostic criteria.

Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome.

Intravenous immunoglobulin (IVIg) is the first choice treatment for Guillain‐Barré syndrome (GBS). All patients initially receive the same arbitrary dose of 2g per kg body weight. Not all patients, however, show a good recovery after this standard dose. IVIg clearance may depend on disease severity and vary between individuals, implying that this dose is suboptimal for some patients. In this study, we determined whether the pharmacokinetics of IVIg is related to outcome in GBS.

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

Structural characterization of Campylobacter jejuni lipooligosaccharide outer cores associated with Guillain-Barré and Miller Fisher syndromes

ABSTRACT Molecular mimicry between lipooligosaccharides (LOS) of Campylobacter jejuni and gangliosides in peripheral nerves plays a crucial role in the pathogenesis of C. jejuni-related Guillain-Barré syndrome (GBS). We have analyzed the LOS outer core structures of 26 C. jejuni strains associated with GBS and its variant, Miller Fisher syndrome (MFS), by capillary electrophoresis coupled with electrospray ionization mass spectrometry. Sixteen out of 22 (73%) GBS-associated and all 4 (100%) MFS-associated strains expressed LOS with ganglioside mimics. GM1a was the most prevalent ganglioside mimic in GBS-associated strains (10/22, 45%), and in eight of these strains, GM1a was found in combination with GD1a mimics. All seven strains isolated from patients with ophthalmoplegia (GBS or MFS) expressed disialylated (GD3 or GD1c) mimics. Three out of 22 GBS-associated strains (14%) did not express sialylated ganglioside mimics because their LOS locus lacked the genes necessary for sialylation. Three other strains (14%) did not express ganglioside mimics because of frameshift mutations in either the cstII sialyltransferase gene or the cgtB galactosyltransferase gene. It is not possible to determine if these mutations were already present during C. jejuni infection. This is the first report in which mass spectrometry combined with DNA sequence data were used to infer the LOS outer core structures of a large number of neuropathy-associated C. jejuni strains. We conclude that molecular mimicry between gangliosides and C. jejuni LOS is the presumable pathogenic mechanism in most cases of C. jejuni-related GBS. However, our findings suggest that in some cases, other mechanisms may play a role. Further examination of the disease etiology in these patients is mandatory.