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Journal of the Peripheral Nervous System 18:99112 (2013)

REVIEW

syndrome Update on Guillain-Barre


Simon Rinaldi
Nufeld Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Abstract

syndrome (GBS) has progressed substantially Understanding of Guillain-Barre and Strohl since the seminal 1916 report by Guillain et al . Although Guillain, Barre, summarised the syndrome based on observations of two French infantrymen, 2012 saw the beginning of an ambitious collaborative study designed to collect detailed data from at least 1,000 patients worldwide (IGOS, www.gbsstudies.org/about-igos). Progress has been made in many areas even since GBS was last reviewed in this journal in 2009. GBS subsequently received prominent attention in light of concerns regarding H1N1 inuenza vaccinations, and several large-scale surveillance studies resulted. Despite these developments, and promising pre-clinical studies, disease-modifying therapies for GBS have not substantially altered since intravenous immunoglobulin was introduced over 20 years ago. In other areas, management has improved. Antibiotic prophylaxis in ventilated patients reduces respiratory tract infection, thromboprophylaxis has reduced the risk of venous thromboembolism, and there is increasing awareness of the benet of high-intensity rehabilitation. This article highlights some of the interesting and thoughtprovoking developments of the last 3 years, and is based on a plenary lecture given at the 2012 Peripheral Nerve Society (PNS) meeting.

syndrome, neuroimmunology, neuropathy Key words: Guillain-Barre

Epidemiology
Most well-designed epidemiological studies of syndrome (GBS) return an annual inciGuillain-Barre dence of around 12 cases per 100,000. Nationwide hospital records from New Zealand were analysed from 1988 to 2010 to reveal an overall incidence of 2.32 cases per 100,000 per year. Interestingly, following a national programme aimed at reducing Campylobacter jejuni (C. jejuni ) contamination of poultry, the incidence of GBS also fell (Baker et al ., 2012). A shorter study from The Netherlands (19962008) returned a slightly lower annual incidence of 1.14/100,000, but here case records were manually reviewed by a neurologist (Van

der Maas et al ., 2011). The most impressive recent epidemiological data come from a comprehensive meta-analysis with strict inclusion criteria for quality, including the requirement for explicit use of an accepted case denition and review of the diagnosis by an expert (Sejvar et al ., 2011). The study encompassed 1,643 cases, 152.7 million person-years of follow-up, and conrms an increasing incidence with age and 1.8-fold excess of male cases. Regression equations were produced to allow an expected age-specic population incidence to be calculated (Fig. 1), and these equations are broadly in keeping with the oft quoted 1 in 1,000 lifetime risk of GBS.

H1N1/vaccination
Address correspondence to: Simon Rinaldi, PhD, Nufeld Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Tel:+44 1865 231912. E-mail: simon.rinaldi@ndcn.ox.ac.uk
2013 Peripheral Nerve Society

Some of the recent attention to GBS epidemiology has been driven by concerns regarding the possibility that H1N1 inuenza vaccine might trigger the disease, much in the way that the publication of the original 1978 GBS diagnostic criteria was precipitated by the
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syndrome Figure 1. Age-specic incidence of Guillain-Barre (GBS). The above graph has been generated from the agespecic regression equation (exp[12.0771 + 0.01813 (age in years)] 100,000) derived from a comprehensive metaanalysis of epidemiological studies ( Sejvar et al ., 2011). The upper line shows the annual incidence rate per 100,000, and the lower line shows the cumulative risk since birth per 1,000.

GBS itself can complicate inuenza infection. An earlier study of the UK General Practice Database looked at the excess risk of GBS in the 2 months following consultation for a number of other reasons, comparing 553 cases with 5,445 controls matched for age, sex, season, and GP clinic. Although consultation for inuenza like illness was associated with an approximately 18-fold increased chance of GBS diagnosis in the next 2 months (OR = 18.6, 95% CI: 7.546.4), consultation for inuenza vaccination was associated with no such risk, and in fact showed a nonsignicant trend towards being protective (OR = 0.16, 95% CI: 0.021.25) (Fig. 2) (Tam et al ., 2007).

Clinical Features
A number of series have examined some of the often neglected clinical features of GBS, most notably sensory disturbance and pain. An Indian study of 60 patients (Karkare et al ., 2011) found paraesthesia in 75%, but objective sensory loss in much smaller proportions pin prick, proprioception, and vibration were impaired in 13.3%, 23.3%, and 18.3% of cases, respectively echoing Guillains original assertion of paraesthesias with slight disturbance of objective sensation (Guillain et al ., 1916). Of course, GBS is most clearly characterised by disorders of motor function and abolition of the tendon reexes. Indeed, a signicant proportion of patients have a pure motor form of the syndrome without any notable sensory disturbance (20% of patients in the Indian series had neither clinical nor electrophysiological evidence of sensory disturbance). The reverse pattern (pure sensory GBS) is much more rarely seen (Oh et al ., 2001), and its very existence has sometimes been doubted (Windebank et al ., 1990). Nevertheless, if GBS is used as an umbrella term for a monophasic, post-infectious, immune-mediated disorder of the peripheral nervous system, and the absolute diagnostic requirement for motor dysfunction is not upheld, then pure sensory GBS does seem to be a valid entity. Pain is also a common feature, present in 50% of the Indian series and in 66% of 156 Dutch patients (Ruts et al ., 2010). Interestingly, pain often preceded weakness. Back pain affecting lumbar, intrascapular, and cervical regions was particularly prevalent in the acute phase, although pain in extremities was most frequent overall. The pain was substantial in many, with 86% reporting moderate to severe pain despite the use of analgesics. Treatment with methylprednisolone did not alter this. The same group also reported that the intra-epithelial nerve bre density as assessed by skin biopsy was signicantly lower in GBS patients with pain than those without pain (Ruts et al ., 2012),
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apparent aetiological association of some GBS cases with the 1976/7 swine u vaccine (Asbury , 1978). Neither the 2009 seasonal trivalent H5N1 vaccine nor the swine u monovalent H1N1 vaccine induced anti-ganglioside antibodies in mice or men (Yuki et al ., 2012), unlike the 1976/7 swine u vaccine and two other seasonal inuenza vaccines (1991/2 and 2004/5, neither associated with an apparent increased risk of GBS) (Nachamkin et al ., 2008). This provided some limited initial reassurance regarding the safety of the contemporary vaccines. Subsequently, a number of different surveillance studies, using both population level and self-controlled methodologies, returned broadly similar results with around 12 excess cases of GBS per million vaccine doses administered, no different to previous risk estimates for seasonal inuenza vaccine (Tokars et al ., 2012 ; Wise et al ., 2012 ; Yih et al ., 2012). One study showed an excess of 5 cases per million doses with the monovalent swine u vaccine vs. 1.1 cases per million with the trivalent seasonal vaccine. However, it is informative to note that the 95% condence intervals for these estimates overlap, and that the delayed production of the swine u vaccine meant that this was administered concurrently with an inuenza epidemic, whereas the seasonal immunisation programme started much earlier (Greene et al ., 2012). This small excess risk of GBS needs to be set against the potentially serious acute complications of inuenza infection itself. Out of approximately 6.6 million H1N1 cases in California in 2009, 2,069 patients required admission to intensive care or died from their illness, and 419 suffered acute neurological complications (including encephalopathy/encephalitis, seizures, and meningitis) (Glaser et al ., 2012). Indeed,

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(A)

(B)

syndrome (GBS) consultation to consultation for inuenza-like illness or inuenza Figure 2. Time from Guillain-Barre vaccination. (A) Patients presenting with GBS (light/blue bars) are signicantly more likely to have consulted with an inuenza-like illness in the previous 12 months when compared with matched control patients (dark/purple bars). (B) There is no signicant difference in the rates of GBS patients and controls consulting for inuenza vaccination in the period prior to GBS diagnosis, with a trend to suggest vaccination may be protective. Modied from the gure in Tam et al. ( 2007) under a Creative Commons Attribution Licence.

and observed damage to myelinated dermal bres in the presence of a mononuclear cell inltrate, further linking dysimmune pathology and neuropathic pain (Calvo et al ., 2012).

Genetics
Two long appreciated facts about GBS strongly suggest that host factors inuence the chances of developing the condition. First, at most 1 in 1,000 people infected with C. jejuni develop GBS (McCarthy and Giesecke, 2001; Tam et al ., 2006), and a similar magnitude of risk has been estimated for cytomegalovirus infection (Orlikowski et al ., 2011). Although some strains of C. jejuni clearly have an increased risk of inducing GBS compared with others, these strains rarely induce GBS in those they infect. There have been individual reports of GBS occurring in single family members in the context of familial outbreaks of C. jejuni gastroenteritis. Intriguingly, antiganglioside antibodies were found in other family members as well as in the patients, although the patterns and titres of antibody positivity differed (Ang et al ., 2000 ; Hirano et al ., 2003). In the latter report, levels of soluble ICAM-1 were higher in the asymptomatic elder brother when compared with the symptomatic younger brother. No other differences were noted in either study.
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Second, the recurrence rate for GBS is usually quoted at around 5%, which is at least 50 times in excess of the risk in the background population. This was conrmed by a population-based Swedish study. In this series, 15 of 229 total GBS cases (6.6%) had at least one episode of recurrence. These patients tended to be younger at their rst presentation and have a shorter episode duration, dened as time from disease onset to a clinically stable phase after remission (Mossberg et al ., 2012). Despite these observations, a clear genetic risk factor for GBS has not yet been identied. Previous studies have found no association with HLA, T-cell receptor, CD14, or Toll-like receptor 4 (TLR4) polymorphisms (Ma et al ., 1998 ; Geleijns et al., 2004; 2005). A 2006 study reported an association between CD1a/CD1e polymorphisms and GBS risk (Caporale et al ., 2006), although concerns were raised regarding the statistical analysis used (Bang et al ., 2007), and a subsequent, larger study showed no such association (Kuijf et al ., 2008). Most recently, an attempt has been made to systematically assess the available data on the genetic risk factors for GBS. Studies without a casecontrol design, with evidence of heterogeneity, and where genotype frequencies were not available were excluded from analysis. Furthermore, only polymorphisms reported by three or more separate

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studies were included. In this way, Wu et al . evaluated six genetic variants of three candidate genes (TNF- , Fc R, and CD1), encompassing 1,590 GBS cases and 2,154 controls in total (Wu et al ., 2012). They conrmed that there was no evidence for an association with the CD1 polymorphisms discussed previously. Although the meta-analysis appears to have inappropriately included 46 patients with chronic inammatory demyelinating polyradiculoneuropathy (CIDP) from a 2007 study (De Angelis et al ., 2007), the conclusion would remain the same without these patients. Overall, only a 308AA polymorphism of the TNF- gene was signicantly associated with GBS. However, this association was not apparent within the sole included European study (Geleijns et al ., 2007). Furthermore, the largest Asian study showed that the association only held for axonal subtypes of GBS, and not the demyelinating type that dominates in Europe, suggesting one potential reason for this discrepancy (Jiao et al ., 2012). Other as yet unidentied genetic polymorphisms may inuence different aspects of the disease process aside from overall susceptibility. Indeed, earlier work has shown that polymorphisms in the mannosebinding lectin (MBL) gene alter serum levels and the activity of MBL, and that lower levels are associated with less severe GBS (Geleijns et al ., 2006). This presumably reects the involvement of MBL in the complement system and/or other immune processes. Nevertheless, this correlation is far from absolute, suggesting the involvement of other genes. It is also likely that, as has been found for IVIg responsiveness and TAG-1 in CIDP (Iijima et al ., 2009), certain polymorphisms will affect treatment responsiveness in GBS. Indeed, one presumes that the observed variations in delta-IgG measurements correlating with GBS prognosis (Kuitwaard et al ., 2009), as discussed later, are a result of genetic polymorphisms governing IVIg pharmacokinetics.

to question. Unlike experimental autoimmune neuritis (EAN) (Waksman and Adams, 1955), there has been no consistent detection of antibodies or T cells directed against myelin proteins in human GBS (Makowska et al ., 2008). Similarly, murine models of ganglioside antibody-mediated GBS usually require passive transfer of antibody produced in ganglioside-decient to ganglioside-overexpressing mice, along with the articial provision of a source of complement (Goodfellow et al ., 2005 ; Halstead et al., 2005a; 2008). Despite this, at least for particular disease subtypes, notably AMAN and Miller Fisher syndrome (MFS), a considerable body of evidence suggests that auto-reactive antiganglioside antibodies arise via a process of molecular mimicry following infection and drive complementmediated damage to the peripheral nervous system (Goodyear et al ., 1999 ; Perera et al ., 2007 ; Yuki , 2007 ; Yuki and Kuwabara, 2007).

Disease induction
More generally, the primary importance of either the cellular or humoral immune system in initiating the disease process has long been debated. As long ago as 1949, attempts were made to clarify this using autopsy data, which suggested a humoral response preceding cellular inltration (Haymaker and Kernohan, 1949). The frequent detection of anti-ganglioside antibodies in axonal variants, only sporadic antibody detection in demyelinating disease, along with evidence of early cellular inltration in modern pathological AIDP specimens, has led to more recent speculation that AMAN is an antibody-driven disease, whereas in AIDP the cellular immune system is primarily involved (Hughes and Cornblath, 2005). With the realisation of increasingly diverse functions for T cells, B cells, and other immune effectors, it seems intuitive that both disease processes result from interactions between these different immunological components (Fig. 3). There is also increasing evidence that subtle differences in the infecting organism profoundly inuence the subsequent immune response. C. jejuni lipo-oligosaccharide (LOS) containing sialic acid signicantly increases the activation of dendritic cells compared with non-sialylated LOS, a process dependent on TLR4 (Kuijf et al ., 2010). This activation may also inuence the subsequent antibody response, which in GBS patients is often cross-reactive with sialylated C. jejuni LOS and self-ganglioside molecules (Goodyear et al ., 1999). Sialylation modulates the phagocytosis and tissue destination of C. jejuni (Huizinga et al ., 2012). It increases the production of the IL-6 and IL-10 cytokines by macrophages and dendritic cells in vitro, and the production of IFN- and IFN- in vivo, which might be expected to lead to polarisation of the immune response, as
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Pathophysiology
Unravelling the ner details of the pathophysiology of GBS and integrating these into an overall disease mechanism have proved problematic. One major confounding factor is that there are clearly at least two pathologies that result in a clinical diagnosis of GBS demyelinating pathology with acute inammatory demyelinating polyradiculoneuropathy (AIDP) and axonal pathology with acute motor axonal neuropathy (AMAN). Furthermore, it is not always possible to accurately separate even these major GBS subtypes using standard clinical and electrophysiological assessments, as further discussed below. The applicability of animal models to the human disease is also open

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syndrome (GBS) pathogenesis. (1) The disease process begins with Figure 3. Postulated mechanism of Guillain-Barre infection. In this case, Campylobacter jejuni is used as an exemplar. (2) In one paradigm, the initial immune encounter is with antigen-presenting cells (APCs, which may be macrophages or dendritic cells). The particular sialic acid moiety displayed by C. jejuni determines a specic Siglec receptor interaction, which following (3) activation of T cells by APCs promotes either a (4) Th1- or (5) Th2-type response. Glycolipid antigens can be presented to natural killer T (NKT) cells via CD1d molecules on dendritic cells. Each response has its own cytokine signature, as shown. The Th1 response is cellular, and the activated T cell must (6) cross the blood-nerve barrier (BNB) to exert pathological effects. Upregulation of M -integrin, an ICAM-1 ligand, may be involved, as might the physical action of matrix metalloproteinases (e.g., MMP-9). Once inside the peripheral nervous system, the polarised Th1 cell (7) recruits and activates macrophages, neutrophils, and possibly other effector cells via the secretion of cytokines such as TNF- and IFN- . The cells are misdirected to (8) cause damage to peripheral nervous tissue via the action of agents such as MMP-2, 9 and nitrous oxide, rather than targeted to solely respond to similar structures found on the initial infectious agent. In the humoral hypothesis, (9) the initial immune response is mediated by B cells. Lipo-oligosaccharide (LOS) may cross-link the B-cell receptor directly, or following processing and presentation via an intermediary APC. B-cell activation can occur both (10) with or (11) without T-cell help. Both T-cell-dependent and -independent activation can result in class switching to IgG. The secreted antibody binds to both (12) the initial microbial antigen and (13) cross-reacts with similar epitopes in the peripheral nervous system (PNS). Antigen binding can activate the complement cascade (14), resulting in membrane attack complex deposition into the cellular membrane. Additionally, (15) complement activation and the process of opsonisation may promote and direct a cellular inltrate. Antibodies may also directly perturb the function of nerves and/or their regeneration independent of complement. Macrophage and APC images modied from http://en.wikipedia.org/wiki/Image: Hematopoiesis_%28human%29_diagram.png, A. Rad, under the terms of a Creative Commons Attribution-Share Alike 3.0 Unported licence.

well as an enhancement of B-cell receptor activation, immunoglobulin production, and isotype switching (Huizinga et al ., 2012). Indeed, whether monosialylated or disialylated LOS is encountered can in itself profoundly inuence the subsequent immune response. It is established that infection by C. jejuni with 2,3 monosialyltransferase activity is more likely to result in the
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production of antibodies directed against GM1 and GD1a and thus induce AMAN. In contrast, C. jejuni with 2,8 bifunctional sialyltransferase activity induces anti-disialylosyl antibodies such as GQ1b and gives rise to MFS ( Koga et al., 2005 ; Koga and Yuki, 2007). It is now additionally apparent that monosialylated LOS preferentially interacts with sialoadhesin (Heikema et al ., 2010), a member of the Siglec family of

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immunomodulatory receptors displayed by antigenpresenting cells. This interaction favours a Th2-type response, with increased production of IL-4 and related cytokines, promoting B-cell/humoral activity. In contrast, disialylated LOS favourably binds Siglec7, results in greatly increased production of IFN- , driving a Th1 (macrophage/cellular) response (Bax et al ., 2011). The above observations highlight the way in which the initial encounter with the innate immune system can modulate the subsequent adaptive response. Further support for the role of the innate immune system in GBS has come from studies showing upregulation of TLR mRNA in the acute phase of the disease. Nevertheless, the upregulation of TLR2, 4, and 6 mRNA negatively correlated with disease severity in one study (Gries et al ., 2012), whereas in another higher levels of TLR2, 4, and 9 expression were positively associated with disability score (Wang et al ., 2012). The reason for this difference is unclear. Both studies involved patients early in the disease course, employed identical severity scales, and used similar methodology to assess expression levels, although RNA was extracted from whole blood in one study and from peripheral blood mononuclear cells in the other. It may be that geographical differences in the proportion of patients with different GBS subtypes are responsible for the apparent discrepancy, rather than subtle differences in methodology, although the latter cannot be completely discounted. Suppressing one aspect of the immune response does not necessarily result in improved outcomes. Mice lacking IFN- , and hence having a much attenuated Th1 response, develop more severe EAN than controls (Zhang et al ., 2012). This result is difcult to resolve with previous observations of EAN in rats, which was augmented by recombinant IFN- and attenuated by IFN- -neutralising antibodies (Hartung et al ., 1990). Of course, certain immunological responses may be reparative, suppressing one facet of immunity may enhance another (particularly Th2 and Th17 when Th1 is suppressed), and there is a long history conrming the difculty in transferring results across species and from models to diseases. In keeping with the typical disease course of GBS, inammatory cytokines TNF- , IL-1 , and the matrix metalloproteinase 9 (MMP-9) are raised in the active phase of the disease, but fall back to below control levels in recovery (Nyati et al ., 2010). The way in which these molecules t into the overall disease process and the mechanisms by which they are subsequently downregulated are yet to be established. The MMPs might either act as myelinolytic agents, be involved in the disruption on the blood-nerve barrier, or both. This latter outcome
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is a pre-requisite for a systemically activated immune response to access the peripheral nervous system (PNS), except perhaps at some non-privileged sites. Yosef and Ubogu demonstrated that mononuclear cells from untreated GBS patients upregulate ICAM-1 ligands, such as M -integrin. Neutralising M -integrin/ICAM-1 antibodies also reduced GBS mononuclear leukocyte transmigration in a model system of the BNB with much greater potency than the pooled immunoglobulins found in intravenous immunoglobulin preparations (IVIg, the established treatment for GBS) (Yosef and Ubogu, 2012). This resonates with the differential levels of the soluble ICAM-1 (sICAM-1) decoy receptor molecule observed in the brothers with and without GBS following C. jejuni infection (Hirano et al ., 2003). In this case report, sICAM-1 levels were much higher in the asymptomatic brother, the suggestion being that sICAM-1 interferes with integrin-mediated leukocyte adhesion to the endothelium and thus modulates the immune response. A large cohort study previously noted that higher levels of sL-selectin were associated with better outcome, but did not report a similar association for sICAM-1 (Hadden et al ., 2001). In summary, following infection the nature of the immune response is governed by both host and pathogen factors. There is evidence of early activation of innate immunity which then guides the adaptive response. On one side a predominantly cellular response results, and on the other B cells are activated without T-cell help, but synergistic action is also possible.

Antibodies/antigens
Once activated, the immune response needs to exert its end effects on the PNS for GBS to result. Most recent studies have focused on the effector mechanisms of the anti-ganglioside antibodies, notwithstanding the potential contribution of the cellular response already discussed. A substantial body of previous experimental evidence attests to the fact that the anti-ganglioside antibodies cause both structural and functional disruption to the peripheral nervous system (Willison et al ., 1993 ; Roberts et al ., 1994; Plomp et al ., 1999 ; Halstead et al., 2004; 2005b;Goodfellow et al ., 2005 ; Buchwald et al ., 2007 ; Susuki et al ., 2007). It has more recently been appreciated that both anti-GD1a and anti-GM1 antibodies can also interfere with regeneration following injury. Anti-GD1a antibodies inhibit neurite outgrowth via activation of the RhoA/ROCK pathway, a process dependent on binding to complex gangliosides in the neuronal cell membrane but independent of the presence of Schwann cells (Zhang et al ., 2011). Anti-GM1 antibodies can

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syndrome (GBS). A representative 28 10 Figure 4. Example glycolipid complex binding reactivities in Guillain-Barre combinatorial glycoarray is shown, which has been probed with serum from a Western European patient with GBS. The antigen spotted at each grid location is revealed by combining the row and column headings given in the key below. The line of x across the centre of the membrane represents the negative control spots (methanol only spotted). The left most column and upper most row contain single antigens only. Thus, locations (9,7) and (7,9) contain GA1 : GM3 complexes (red circles). These are bound without any detectable reactivity to either single GA1 (,9) or GM3 (,7), so-called complex-enhanced binding. Sulfatide : Asialo-GM1 complexes (yellow circles) were frequently bound at high intensity and in a complex-enhanced fashion by GBS-associated sera in this study (Rinaldi et al., 2011). As is also demonstrated in this example, binding to a wide range of other glycolipid complexes was often seen. Key: (1) sphingomyelin, (2) phosphatidylserine, (3) globoside, (4) CTH, (5) SGPG, (6) GM2, (7) GM3, (8) GD2, (9) Asialo-GM1, (10) GalC, (11) LM1, (12) GM1, (13) GD1a, (14) GD1b, (15) GD3, (16) GQ1b, (17) GT1b, and (18) sulfatide.

also block NGF-driven neurite outgrowth and appear to reduce Trk-neurotrophin auto-phosphorylation while causing the redistribution of Trk protein from the raft to non-raft fraction (Ueda et al ., 2010). The pathophysiological effects of anti-ganglioside antibodies at the NMJ are ameliorated by rapid antibody internalisation. This process is cholesterol dependent and leaves the ganglioside on the cell surface (Fewou et al ., 2012). Conversely, the nodes of Ranvier are susceptible to complement and calpain-mediated disruption of nodal protein architecture and function following exposure to anti-GD1a antibodies (McGonigal et al ., 2010). Interestingly, distal nodes appear more accessible for GD1a binding and conduction failure can occur without loss of structural integrity, providing some pointers towards the pathophysiology of subtypes of AMAN associated with rapid clinical recovery. The pathogenic potential of anti-ganglioside antibodies also appears to be critically dependent on certain aspects of their ne specicity. Only the GM1 antibody titre as assessed by a cell-based assay correlated with disease severity, in contrast to titre assessed by ELISA (Lardone et al ., 2010). This is consistent with the prior observation that some anti-GM1 antibodies are prevented from binding and exerting pathological effects in living membranes because of an inhibitory inuence exerted by other, neighbouring gangliosides (most notably GD1a in this study) (Greenshields et al ., 2009). Indeed, this effect was rst noticed in melanoma cells over 20 years ago (Lloyd et al ., 1992).
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Glycolipid complexes
In contrast, it is now appreciated that certain antibodies fail to bind single gangliosides in isolation, but can bind in the additional presence of a second type of ganglioside. These have been termed ganglioside complex (GSC) antibodies, and have been found in up to 20% of GBS cases from Japan ( Kaida et al., 2004; 2007). More recently, antibodies to the GM1 : galactocerebroside complex have been widely detected in Scottish patients with multifocal motor neuropathy (Galban-Horcajo et al ., 2012). In work as yet only published in abstract form, we have found that antibodies to single gangliosides are found in around 80% of axonal but only 12% of demyelinating Western European GBS cases using a glycoarray methodology ( Rinaldi et al., 2009; 2012). Using glycolipid complexes, the detection rate in demyelinating cases is increased to over 60% (Rinaldi et al ., 2011), although the range of glycolipid complexes targeted by the antibody response is diverse (Fig. 4). Evidence is emerging to show that at least some anti-ganglioside complex antibodies can induce pathogenic effects (Zitman et al ., 2011). These observations give a further hint to more extensive involvement of the humoral immune response in AIDP than has sometimes been suggested. It is an intriguing possibility that antiglycolipid complex antibodies may explain some of the so far incomplete serologicalclinical associations and other pathophysiological inconsistencies in GBS. It also seems hopeful that glycolipid complex assays will have much greater utility as diagnostic or prognostic biomarkers than standard, single ganglioside tests.

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(B)

(A)

(C)

Figure 5. Conduction block without demyelination. (A) Conduction block can occur without other neurophysiologic features of demyelination, manifesting as a drop in CMAP amplitude on (P) proximal as opposed to (D) distal stimulation. (B) Reversible conduction failure. In some cases, a rapid return of conduction is seen, with the (P) proximal CMAP amplitude returning to normal. This occurs faster than can be explained by remyelination, suggesting that the block was due to a functional impairment of conduction rather than structural damage or demyelination. (C) Length-dependent conduction failure. Alternatively, if the distal parts of axons degenerate following proximal injury, then CMAP amplitude on (D) distal stimulation will also fall. Note that in both examples, the result is an equalisation of proximal and distal CMAP amplitudes within the same study at the latter time point. Valid comparisons of amplitudes between studies, and thus distinguishing (B) from (C), may be more difcult in practice.

Diagnostics
GBS remains a largely clinical diagnosis, with supportive evidence coming from analyses of cerebrospinal uid content, and nerve conduction studies/electromyography (NCS/EMG).

Nerve conduction studies/electromyography


Several different sets of electrodiagnostic criteria have previously been proposed for GBS. These initially stressed the importance of detecting nerve conduction slowing as evidence of a demyelinating process (Asbury and Cornblath, 1990). Following the description of axonal GBS subtypes (McKhann et al ., 1993), these criteria were re-evaluated (Meulstee and , 1995 ; Hadden et al ., 1998). In these van der Meche series of largely Western GBS patients, demyelinating pattern electrophysiology was dominant, being found in 60%69% of cases following initial examination. The proportion of demyelinating pattern cases either increased on retesting at 4 weeks or declined only slightly. More recently, increasing attention has been paid to the pattern of reversible conduction failure (RCF), whereby conduction block and/or
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slowing rapidly resolves without the development of temporal dispersion or other features of demyelination (Kuwabara et al ., 1998), and length-dependent conduction failure, whereby the initial fall in proximal to distal CMAP amplitude is superseded by a globally reduced amplitude. A serial study of 55 Italian patients found that the proportion of axonal cases increased from 18% to 38% on retesting, largely because of the identication of these patterns in patients initially categorised as AIDP (Uncini et al., 2010; Uncini and Kuwabara, 2012). The authors hypothesise that RCF is the correlate of conduction failure without structural damage seen in the ganglioside antibody/node of Ranvier injury model under calpain inhibition (McGonigal et al ., 2010). If the pathological process is arrested at this stage then rapid recovery is possible, whereas if subsequent axonal degeneration occurs then recovery would be much slower. In this paradigm, each of these outcomes is associated with a particular progressive change in the electrophysiology (Fig. 5). On occasion, the initial NCS in GBS can be normal, even if F-wave measurements are used to assess conduction over the entire length of the nerve. It has now been shown that measurement of the motor root

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conduction time (calculated from the F-wave latency and the latency of stimulation from a magnetic coil at the level of the seventh cervical vertebra) is more sensitive than any other electrophysiological measure in and Nurlu, 2011). in the rst week of illness (Temuc

this agent, the comparator group was treated with corticosteroids, which may themselves be deleterious in GBS (Hughes and van Doorn, 2012), and as yet no further studies have been performed.

Pre-clinical studies
A number of different agents have recently been trialled successfully in a variety of model systems, most often rat experimental autoimmune neuritis (EAN). Notwithstanding the difculties in translating such ndings into clinically effective therapies, these results are encouraging. Glatiramer acetate reduces EAN severity in rats when administered intraperitoneally, although the mechanism of this effect is not entirely clear (Aronovich et al ., 2012).The novel fusion molecule quinpramine (incorporating imipramine and quincarine) reduces cellular inltration, reduces proliferation and MHC class II expression on antigen-presenting cells, and prevents sciatic nerve demyelination in a similar EAN model (Meyer zu Horste et al ., 2011). Both this agent and the Rho-kinase inhibitor fausadil (Pineda et al ., 2011) are effective when given as either preventative therapy or after the onset of the experimental disease. Fausadil was investigated because of the known benet of Rho/Rhokinase inhibition in models of CNS demyelination, where it reduces T-cell proliferation and shifts the cytokine prole towards a Th2 pattern. In light of recent observations suggesting that activation of RhoA pathways inhibits axonal regeneration (Zhang et al ., 2011), there is reason to hope that Fausadil might benecially modulate both the inammatory and recovery phases of GBS. An anti-GD3 anti-idiotype antibody (BEC2) was investigated as a treatment for GBS-like motor dysfunction induced by GD3-LOS immunisation of rats. Given as the GD3 antibody titre begins to rise (8 weeks into this model), BEC2 reduced the titre compared with control animals at later time points, maintained nerve conduction velocities, reduced demyelination, and improved rotarod performance (Usuki et al ., 2010). The authors of this study suggest that ganglioside mimics might be effective therapy in GBS. A note of caution seems appropriate here given that previous observed associations between exogenous ganglioside administration and the induction of GBS led to the withdrawal of these treatments in the late 1980s and early 1990s (Figueras et al ., 1992 ; Landi et al ., 1993).

Imaging
Magnetic resonance imaging is usually performed in GBS to rule out other potential causes of the clinical presentation, especially myelopathy. Over the last 2 years, a handful of small case series have looked at positive imaging ndings, which may be suggestive of GBS. The most often reported nding is greater enhancement of the anterior compared with posterior roots of the cauda equina, but other patterns of root and cranial nerve enhancement have also been reported (Smith et al ., 2010 ; Yikilmaz et al., 2010; Zuccoli et al ., 2011). Whilst the sensitivity of some of these appearances may be high, the specicity is as yet undened.

Treatment
In some areas, management of GBS has improved. Antibiotic prophylaxis in ventilated patients reduces respiratory tract infection (Liberati et al., 2009), and routine thromboprophylaxis has reduced the risk of venous thromboembolism (Gaber et al ., 2002). However, despite the progress detailed above, translation to novel disease modifying therapies has been slow.

Clinical trials
A handful of studies have investigated different non-pharmacological interventions in the care of GBS patients. Evidence now exists to demonstrate that higher intensity rehabilitation produces greater functional improvement than lower intensity rehabilitation, and also reduces disability in the later stages of recovery (Khan et al ., 2011). Unfortunately, a programme of yogic relaxation was not shown to be effective in this regard (Sendhilkumar et al ., 2012). A Dutch study revealed that patients in centres practicing selective decontamination of the digestive tract spent a shorter time being mechanically ventilated (Bos Eyssen et al ., 2011). Whether this represents an effect of this particular intervention, or reects some other differences in practices between the centres, remains to be seen. The 2011 Cochrane review of pharmacological treatment other than corticosteroids, intravenous immunoglobulin, and plasma exchange for GBS (Hughes et al ., 2011) identied one low-quality study investigating the benet of the Thunder God Vine, tripterygium polyglycoside (Zhang et al ., 2000). Although there was a suggestion of slight benet with
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High-quality studies from the Dutch Guillain-Barre study group have allowed the development of scoring systems, which robustly predict long-term outcome

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and the requirement for ventilatory support as early as the rst day of hospital admission ( Walgaard et al., 2010; 2011). The scales have not only immediate clinical utility as a simple means of better counselling patients regarding their expected disease course but will also aid in the future selection of patients who may most benet from experimental adjunctive therapies. In a similar vein, the same group also made an intriguing observation that a lower increment in serum IgG levels following IVIg treatment (delta IgG) correlates with a slower recovery of unaided walking (Kuitwaard et al ., 2009). This gives further support to the idea that a standard IVIg dose is not appropriate for all GBS patients, and forms a part of the underlying rationale for a study assessing the benet of a second IVIg dose (International Second Immunoglobulin Dose in GBS patients with poor prognosis, I-SID, see http://www.trialregister.nl/trialreg/admin/rctview.asp? TC=3281). It is interesting to note, however, that those patients who went on to have a low delta IgG already had signicantly more severe disease at baseline prior to IVIg being administered. It may be that a low delta IgG is a marker of some aspect of the disease process, which itself confers a poor prognosis, and this may not necessarily be countered by higher or further doses of IVIg. Even with modern standards of medical and supportive care, GBS remains fatal in around 4% of cases. Furthermore, the long-term deleterious effects of the condition are increasingly recognised. A year after onset, 40% of patients have not recovered full strength, 16% are unable to walk independently, 38% need to change their employment, and a similar proportion experience ongoing pain (Rajabally and Uncini , 2012).

Conclusion
Even in the short period covered by this update, there have been signicant developments in our understanding of GBS. With many lines of scientic endeavour now converging on the clinical disease, and the beginning of an unprecedented international collaboration, the eld remains vibrant and exciting and as we approach the centenary of Guillain, Barre, Strohls original description.

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