Hugh J. Willison

Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study

BACKGROUND Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome. METHODS In this case-control study, cases were patients with Guillain-Barré syndrome diagnosed at the Centre Hospitalier de Polynésie Française (Papeete, Tahiti, French Polynesia) during the outbreak period. Controls were age-matched, sex-matched, and residence-matched patients who presented at the hospital with a non-febrile illness (control group 1; n=98) and age-matched patients with acute Zika virus disease and no neurological symptoms (control group 2; n=70). Virological investigations included RT-PCR for Zika virus, and both microsphere immunofluorescent and seroneutralisation assays for Zika virus and dengue virus. Anti-glycolipid reactivity was studied in patients with Guillain-Barré syndrome using both ELISA and combinatorial microarrays. FINDINGS 42 patients were diagnosed with Guillain-Barré syndrome during the study period. 41 (98%) patients with Guillain-Barré syndrome had anti-Zika virus IgM or IgG, and all (100%) had neutralising antibodies against Zika virus compared with 54 (56%) of 98 in control group 1 (p<0.0001). 39 (93%) patients with Guillain-Barré syndrome had Zika virus IgM and 37 (88%) had experienced a transient illness in a median of 6 days (IQR 4-10) before the onset of neurological symptoms, suggesting recent Zika virus infection. Patients with Guillain-Barré syndrome had electrophysiological findings compatible with acute motor axonal neuropathy (AMAN) type, and had rapid evolution of disease (median duration of the installation and plateau phases was 6 [IQR 4-9] and 4 days [3-10], respectively). 12 (29%) patients required respiratory assistance. No patients died. Anti-glycolipid antibody activity was found in 13 (31%) patients, and notably against GA1 in eight (19%) patients, by ELISA and 19 (46%) of 41 by glycoarray at admission. The typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with Guillain-Barré syndrome and those in the two control groups (95%, 89%, and 83%, respectively). INTERPRETATION This is the first study providing evidence for Zika virus infection causing Guillain-Barré syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to prepare for adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome. FUNDING Labex Integrative Biology of Emerging Infectious Diseases, EU 7th framework program PREDEMICS. and Wellcome Trust.

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy

This multicenter, randomized, double‐blind, crossover trial compared a 6 week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over 1 to 2 days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty‐four of the thirty‐two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11‐point disability scale 2 weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = –0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after 2 weeks and improvement in disability grade after 6 weeks. Results may have been biased against IVIg by the 8 patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in 1 patient while on prednisolone and in none with IVIg.

Anti-GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barré syndrome

Immunopathological studies suggest that the target of immune attack is different in the subtypes of Guillain‐Barré syndrome (GBS). In acute motor axonal neuropathy (AMAN), the attack appears directed against the axolemma and nodes of Ranvier. In acute inflammatory demyelinating polyneuropathy (AIDP), the attack appears directed against a component of the Schwann cell. However, the nature of the antigenic targets is still not clear. We prospectively studied 138 Chinese GBS patients and found that IgG anti‐GD1a antibodies were closely associated with AMAN but not AIDP. With a cutoff titer of greater than 1:100, 60% of AMAN versus 4% of AIDP patients had IgG anti‐GD1a antibodies; with a cutoff titer of greater than 1:1,000, 24% of AMAN patients and none of the AIDP patients had IgG anti‐GD1a antibodies. In contrast, low levels of IgG anti‐GM1 antibodies (>1:100) were detected in both the AMAN and the AIDP forms (57% vs 35%, NS). High titers of IgG anti‐GM1 (>1:1,000) were more common in the AMAN form (24% vs 8%, NS). Serological evidence of recent Campylobacter infection was detected in 81% of AMAN and 50% of AIDP patients, and anti‐ganglioside antibodies were common in both Campylobacter‐infected and noninfected patients. Our results suggest that IgG anti‐GD1a antibodies may be involved in the pathogenesis of AMAN. Ann Neurol 1999;45:168–173

Miller Fisher syndrome is associated with serum antibodies to GQ1b ganglioside.

A recent report described serum anti-GQ1b ganglioside antibodies in Miller Fisher syndrome (MFS), a clinical variant of Guillain-Barré syndrome (GBS). Four consecutive cases of MFS all had high titre anti-GQ1b antibodies which were absent from all control sera including those of patients with GBS.

Monoclonal antibodies raised against Guillain-Barré syndrome–associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAbs that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

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

Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.

During recent years, novel insights in basic immunology and advances in biotechnology have contributed to an increased understanding of the pathogenetic mechanisms of immune‐mediated disorders of the peripheral nervous system. This increased knowledge has an impact on the management of patients with this class of disorders. Current advances are outlined and their implication for therapeutic approaches addressed. As a prototypic immune‐mediated neuropathy, special emphasis is placed on the pathogenesis and treatment of the Guillain–Barré syndrome and its variants. Moreover, neuropathies of the chronic inflammatory demyelinating, multifocal motor, and nonsystemic vasculitic types are discussed. This review summarizes recent progress with currently available therapies and—on the basis of present immunopathogenetic concepts—outlines future treatment strategies. Muscle Nerve 30: 131–136, 2004

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.

Motor nerve terminal degeneration provides a potential mechanism for rapid recovery in acute motor axonal neuropathy after Campylobacter infection

Article abstract-We investigated the possible mechanisms of paralysis and recovery in a patient with the acute motor axonal neuropathy (AMAN) pattern of the Guillain-Barre syndrome. The AMAN pattern of GBS is characterized clinically by acute paralysis without sensory involvement and electrodiagnostically by low compound motor action potential amplitudes, suggesting axonal damage, without evidence of demyelination. Many AMAN patients have serologic or culture evidence of recent Campylobacter jejuni infection. Pathologically, the most severe cases are characterized by wallerian-like degeneration of motor axons affecting the ventral roots as well as peripheral nerves, but some fatal cases have only minor changes in the roots and peripheral nerves, and some paralyzed patients with the characteristic electrodiagnostic findings of AMAN recover rapidly. The mechanism of paralysis and recovery in such cases has been uncertain. A 64-year-old woman with culture-proven Campylobacter upsaliensis diarrhea developed typical features of AMAN. She improved quickly following plasmapheresis. Her serum contained IgG anti-GM1 antibodies. The lipopolysaccharide of the organism bound peanut agglutinin. This binding was blocked by cholera toxin, suggesting that the organism contained the Gal(beta 1-3)GalNAc epitope of GM1 in its lipopolysaccharide. Motor-point biopsy showed denervated neuromuscular junctions and reduced fiber numbers in intramuscular nerves. In contrast, the sural nerve biopsy was normal and skin biopsy showed normal dermal and epidermal innervation. In AMAN the paralysis may reflect degeneration of motor nerve terminals and intramuscular axons. In addition, the anti-GM1 antibodies, which can bind at nodes of Ranvier, might produce failure of conduction. These processes are potentially reversible and likely to underlie the capacity for rapid recovery that characterizes some cases of AMAN. NEUROLOGY 1997;48: 717-724

Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain-Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.