CCA-13880; No of Pages 6 Clinica Chimica Acta xxx (2015) xxx–xxx

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Autoimmune peripheral neuropathies Pierre R. Bourque a, Jodi Warman Chardon a,b, Rami Massie c a b c

Division of Neurology, The Ottawa Hospital, 1053 Carling Avenue, Ottawa, ON K1Y 4E9, Canada Department of Genetics, The Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada

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Article history: Received 23 February 2015 Accepted 23 February 2015 Available online xxxx Keywords: Neuropathy Antiganglioside antibodies Guillain-Barré syndrome Myelin Multifocal motor neuropathy

a b s t r a c t Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood–nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies. © 2015 Elsevier B.V. All rights reserved.

Advances in pathophysiology, biomarkers and specific treatment approaches have transformed our understanding of immune disorders of the peripheral nervous system (PNS).The original syndromic classification simply categorizing acute (Guillain-Barré syndrome or GBS) and chronic (chronic inflammatory demyelinating polyradiculoneuropathy or CIDP) autoimmune neuropathies has been vastly expanded to include many subtypes. This article will review key clinical and laboratory aspects of GBS and CIDP subtypes, emphasizing the role of autoantibodies, notably against gangliosides, that show promise as potential biomarkers. Other forms of immune neuropathy, notably systemic vasculitis, presynaptic neuromuscular junction disorders and paraneoplastic neuropathy, are beyond the scope of this discussion. 1. The peripheral nervous system The PNS is composed of cranial nerves (with the notable exception of the optic nerve), nerve roots, plexuses and peripheral nerve branches, including the peripheral axons and ganglia of the autonomic nervous system. A fundamental histologic specificity is PNS myelination of

axons by Schwann cells. Along a single axon, the transition from oligodendroglia to Schwann cells, occurs within millimeters where cranial nerves arise from the brainstem and where spinal roots emerge from the spinal cord [1]. At a biochemical level, the most significant potential antigenic targets of the axonal membrane include gangliosides and ion channels. Sodium channels are largely limited to the region of the node of Ranvier, whereas potassium channels are concentrated in the paranodal regions (Fig. 1). PNS myelin is rich in proteolipids and specific proteins, and is formed of compact and non-compact domains. There are substantial differences in protein subtypes or proportions compared to the CNS myelin. Compact myelin, devoid of residual Schwann cell cytoplasm, forms the vast majority of PNS myelin. Its dominant protein subtypes are myelin protein zero (MPZ), myelin basic protein (MBP) and peripheral myelin protein-22 (PMP22). Non-compact myelin, localized in the paranodes and Schmidt-Lanterman incisures, is rich in myelinassociated glycoprotein (MAG), Connexin 32 and gangliosides. Interestingly, there has been little overlap between the preponderant antigenic determinants of inherited neuropathy and acquired immune neuropathy. Common forms of Charcot-Marie-Tooth disease

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Table 1 Immune neuropathy: clinical syndromes and main antibody associations. GBS syndromes AIDP

Axonal sensorymotor (AMSAN) Motor (AMAN) Sensory /ataxic Pharyngo-cervical-brachial Miller Fisher GBS/CMV infection CIDP syndromes CIDP MADSAM Multifocal motor neuropathy (MMN) Sensory/ataxic (CANOMAD) Gait ataxia with late onset polyneuropathy (GALOP) Distal acquired demyelinating symmetric (DADS) POEMS syndrome

No definite clinically-relevant antibody Non-specific Ab to Heparan sulfate, PMP22 or MPZ GM1, GD1a, GM1b, GalNAc-GD1a GM1/GaINac-GD1a complex, GD3 GD1b,other disialosyl epitopes, sulfatide GT1a, GQ1b GQ1b (occasionally GT1a) GM2

None identified None identified IgM GM1 (also asialo GM1, GM2, GD1a or NS6S) IgM GD1b and other disialosyl epitopes Sulfatide, Galopin (CNS white matter antigen) IgM gammopathy, MAG, sufatide IgG or IgA lambda gammopathy, ↑VEGF levels

have been associated with mutations in genes coding for PMP22, MPZ, Connexin 32 and other structural proteins. In contrast, immune mediated neuropathies have so far been more closely associated with antibodies that recognize gangliosides, much less frequently myelin proteins, with the exception of MAG. Gangliosides are glycosphingolipids present in large amounts on the plasma membranes, anchored in the lipid bilayer by a ceramide moiety and exposed to the extracellular space and hence accessible to the immune system [2]. In addition to ceramide, gangliosides contain an oligosaccharide (for the majority, a glucose molecule attached to a combination of galactose and N-acetylgalactosamine) with one or more sialic acids linked to the sugar chain. In the accepted ganglioside nomenclature, the first letter, G, stands for ganglioside, while the second letter refers to the number of sialic acid residues – M = 1, D = 2, T = 3,

Q = 4. The following number refers to the number of complete tetrasaccharide chains and the final lower-case letter to its isomeric position (Fig. 2). In addition, several other glycolipids are sulfated, the most common being sulfatide, and represent another potential immunogenic target. Gangliosides act as receptors, receptor modulators or signaling molecules. 2. Mechanisms of PNS autoimmune attack The PNS, like the CNS, is relatively isolated from the systemic circulation by the blood–nerve barrier. The chief structural determinant of this filter for large molecules (including antibodies) is the presence of tight junctions between endoneurial capillary endothelial cells and between the perineurial cells that ensheath individual nerve fascicles. The blood–nerve barrier is more permeable in proximal (spinal roots) and distal (neuromuscular junction) segments of the PNS. Similar to immune disorders in the CNS such as multiple sclerosis, cellular and humoral immune responses can still successfully target relatively shielded PNS antigens. The initial step in immunopathogenesis is postulated to involve molecular mimicry and antigen processing at a systemic level. This leads to activation of autoreactive T cells, which penetrate the blood–nerve barrier with the help of cell adhesion molecules [3]. At the level of the endoneurium, T cells may directly execute the cytotoxic attack, or recruit local macrophages through the production of cytokines and chemokines. Some immune neuropathies may be mediated directly by systemic B-cell production of autoreactive antibodies that are able to traverse a leaky blood–nerve barrier. At the endoneurial level, such antibodies may produce either a direct humoral, complement-mediated attack, or recruit macrophages expressing Fc receptors. The pathophysiology of immune neuropathies is often described as “axonal” or “demyelinating”. This distinction was formerly based on nerve biopsies, which almost exclusively were limited to the sural nerve, chosen because of ease of access and low procedural morbidity. Sural nerve specimens represent a very selective sampling of a purely cutaneous distal nerve branch, devoid of motor axons. Most modern evaluations of immune neuropathy rely instead on nerve conduction studies. Axonal loss is inferred if the predominant abnormality is

Fig. 1. Panel A shows the proposed immune attack in AIDP. Autoantibodies are suspected to bind to myelin antigens and activate complement.The formation of a membrane attack complex (MAC) on the outer surface of Schwann cells leads to vesicular degeneration, with subsequent removal of myelin debris by macrophages. Panel B shows a different pathogenesis proposed for AMAN. Anti-GM1 or anti-GD1a antibodies are shown binding to the nodal axolemma. This may affect voltage-gated sodium (Nav) channels. Additional disruption of paranodal myelin may also contribute to conduction failure. Macrophages may subsequently invade the periaxonal space [5].

Please cite this article as: Bourque PR, et al, Autoimmune peripheral neuropathies, Clin Chim Acta (2015), http://dx.doi.org/10.1016/ j.cca.2015.02.039

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Fig. 2. Gangliosides associated with potentially pathogenic antibodies autoantibodies [2].

reduction of motor or sensory potential amplitude. In contrast, demyelination is reflected in prominent slowing of conduction velocity or focal conduction block. A wide sampling of nerve conduction studies is required to determine if there is diffuse or distally accentuated neuropathy, selective involvement of motor or sensory axons, unifocal or multifocal conduction block, and involvement of proximal nerve segments. Compared to demyelinating neuropathies, axonal neuropathies identified on nerve conduction studies were originally expected to have a poorer prognosis, based on inferences made from classical studies of nerve trauma. This traditional binary subdivision has been questioned recently with the proposal of a new pathophysiological entity, nodo-paranodopathy [4]. This would explain how some acute neuropathies, previously classified as axonal, and may have an excellent prognosis. Their rapid recovery could not be accounted for by axonal regrowth, but is better explained by reversible conduction failure, mediated by antibody binding at the nodal/paranodal region. Such nodo-paranodopathies are strongly associated with the presence of serum anti-ganglioside antibodies [4]. 3. The Guillain-Barré syndrome The acute immune-mediated polyneuropathies are traditionally grouped under the eponym Guillain-Barré syndrome (GBS). By definition, GBS presents as an acute, monophasic, paralyzing illness, reaching its nadir within 4 weeks of onset. It is a heterogeneous disorder with multiple variants. The prototypic form most familiar to clinicians and representing roughly 85% of cases in the western world, is the acute demyelinating inflammatory polyradiculoneuropathy (AIDP) [5]. This is characterized in typical cases by progressive ascending quadriparesis and often by prominent sensory symptoms. The neurological examination reveals a hypotonic quadriparesis, often including facial diplegia in severe cases, with decreased or lost muscle stretch reflexes. An antecedent infection, within 3 weeks of onset, is noted in about two thirds of cases. Campylobacter jejuni is the most frequently identified precipitant, followed by viruses (Cytomegalovirus, Epstein–Barr virus) and other bacteria (Haemophilus influenzae, Mycoplasma pneumoniae). Nerve conduction study abnormalities in GBS are in keeping with multifocal demyelination, prominently over distal and proximal nerve segments. The cerebrospinal fluid typically reveals a normal white blood cell count with moderate elevation of the protein content

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(albumino–cytologic dissociation). This is the likely consequence of a deficient blood–nerve barrier, particularly at the level of the spinal nerve roots. Patients with AIDP affected severely enough to impair independent ambulation are treated with a course of either plasma exchange or intravenous immunoglobulins [6–9]. Multiple clinical trials have failed to show any benefit for steroids [10,11], while four small trials suggested steroids were associated with poorer recovery. Though the prognosis of GBS is generally favorable, there is still a mortality in the range of 5% in the Western world, and 20% of patients have significant persistent disability beyond 1 year [11]. Both cellular and humoral immunity have been implicated in AIDP (Fig. 1). The classic animal model of experimental allergic neuritis, induced by inoculation with myelin proteins such as MPZ, involves demyelination mainly mediated by T-cells and macrophage [12]. This model accounts well for the classical pathological findings in human GBS where T-cell and macrophage infiltration lead to segmental demyelination, often followed by variable degrees of secondary axonal degeneration [13]. In favor of an early humoral attack, immunocytochemistry has identified complement and immunoglobulin deposition, with vesicular degeneration of the outer myelin lamellae [14]. Unfortunately, for the prototypical AIDP syndrome, the search for reliable antigenic biomarkers has not yielded consistent associations with high titers and thus antibody screening is not part of accepted management strategies or diagnostic criteria, in sharp contrast with specific GBS variants [15,16] described below. (See Table 1.) 4. Guillain-Barré syndrome variants Acute motor axonal neuropathy (AMAN) is the most common GBS variant, accounting for as many as 5–10% of cases in the Western world, with much higher incidence in Asia, particularly for childhood onset GBS, where rates approach 50% [17]. As its name implies, there is selective involvement of motor axons. The clinical course and favorable prognosis are otherwise similar to classical AIDP. There is a strong association with preceding C. jejuni infection. The pathophysiology is mainly humoral, with a likely antigenic target at the level of the nodal axolemma. The pathology of AMAN, distinct from AIDP, involves selective invasion of the space between the axon and the Schwann cell, rather than a primary attack on myelin [18]. Given the rapid recovery noted in many patients with AMAN, axonal block causing reversible conduction failure may often predominate over axonal degeneration. This makes it the prototype of the newly described nodo-paranodopathies. GD1a, GM1 or GD3 gangliosides autoantibodies are found in roughly 50% of cases. Studies of AMAN post C. jejuni infection have provided strong support for the concept of molecular mimicry in the pathophysiology of immune neuropathy. The association between AMAN and preceding Campylobacter infection fulfills four criteria supporting molecular mimicry: epidemiological association between GBS and C. jejuni infection, identification of antibodies directed against host antigens (gangliosides) in affected patients, identification of microbial mimics of the target antigen (lipo-oligosaccharides extracted from C. jejuni were found to be identical to GM1 ganglioside [19]), and experimental development of neuropathy in an animal model [20]. Indeed, Yuki et al. [21] demonstrated that sensitization of rabbits with a GM1-like lipo-oligosaccharide produced a syndrome similar to AMAN, with monophasic flaccid paralysis, similar pathological findings and the production of anti-GM1 antibodies. Pathological studies of the rabbit nerves revealed disruption of nodal sodium channel clusters and detachment of paranodal myelin terminal loops, similar to paranodal demyelination. In addition, patients with C. jejuni enteritis not complicated by GBS do not produce the specific anti-ganglioside antibodies [22]. The second most common GBS variant is the Miller-Fisher syndrome (MFS), characterized by a triad of ophthalmoplegia, areflexia and ataxia [23]. MFS accounts for up to 5% of GBS cases in the Western world, with

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rates as high as 25% in Japan and other Asian countries. This syndrome has been strongly linked to serum anti-GQ1b antibodies in up to 85% of cases [24–26], and less frequently to the closely related ganglioside GT1a, though there is strong cross-reactivity between these two antibodies [27,28]. There is even greater specificity for the presence of anti-GQ1b antibodies in CSF [29]. This antibody reacts with paranodal myelin epitopes strongly expressed in oculomotor nerves, dorsal root ganglia and muscle spindles, and cerebellar molecular layer, a distribution that fits well with cardinal clinical manifestations [24,30]. Incomplete forms with acute ophthalmoparesis without ataxia or acute ataxic neuropathy without ophthalmoplegia have also been described. While the former shows strong association with anti-GQ1b antibodies [31], acute ataxic neuropathy frequently displays anti-GD1b reactivity [32]. Bickerstaff brainstem encephalitis presents similarly to MFS with ataxia, ophthalmoplegia and areflexia but shows prominent central nervous system involvement, manifested in disturbances of consciousness and upper motor neuron signs. Bickerstaff encephalitis shares many other features of MFS, including anti-GQ1b antibodies, antecedent C. jejuni infection and albumino-cytologic dissociation [33]. Much less common variants of GBS include the devastating acute motor and sensory axonal syndrome (AMSAN), which shows some association with anti-GD1a, and often carries a much worse prognosis. The acute pure sensory variant has been linked to anti-GD1b antibodies and overlaps with the acute ataxic neuropathy without ophthalmoplegia variant of MFS. A form of GBS dominated by autonomic failure has also been described, showing a strong association with ganglionic (nicotinic) acetylcholine receptor antibodies [34]. Finally, a variant with pharyngeal–cervical–brachial weakness has been described, falling within the continuum between MFS and AIDP, and associated with antibodies against GT1a and GQ1b gangliosides. The IgG antibody isotype noted in post-infectious GBS may also be an important determinant of the clinical syndrome. For example, IgG1 antibodies cross-reacting with gangliosides and Campylobacter lipo-oligosaccharides correlate with poor outcome and diarrhea, whereas the combination of IgG1 and IgG3 cross-reacting with Haemophilus influenzae lipo-oligosaccharides is associated with a better outcome [35]. 5. Chronic inflammatory demyelinating polyradiculoneuropathy CIDP is an immune-mediated chronic neuropathic disorder characterized by progressive weakness in association with impaired sensation and diminished or absent muscle stretch reflexes. In its classical form, it is a motor-predominant polyradiculoneuropathy leading to relatively symmetrical, proximal and distal weakness. The course is more often slowly progressive than spontaneously relapsing or recurrent, and by definition, CIDP should progress for a period greater than 8 weeks. The mean age of onset is around 50 years, with a prevalence in the range of 1–2/100,000, with a slightly lower prevalence in children and women [36]. There is significant morbidity associated with CIDP. In a series of 83 patients described at an average time point of 6 years after symptomatic onset, Bouchard et al. [37] reported a favorable outcome in 56%, and mortality in 17%. The 69 surviving patients were described to have the following outcomes: 5 were bedridden, 6 had severe deficits, 34 had mild to moderate handicaps, and 24 were fully independent for activities of daily living. In more recent observations, roughly two-thirds of patients respond significantly to a first line therapy, typically steroids or intravenous immunoglobulins. The diagnosis of CIDP is mostly based on clinical and electrophysiological criteria, often supported by the finding of a raised CSF protein without significant pleocytosis, whereas nerve biopsies are much less frequently performed. Recent consensus criteria characterize sural nerve pathology as a supportive feature only [38] whereas some earlier diagnostic algorithms considered sural nerve biopsy to be mandatory [39]. Because of the importance of recognizing this potentially treatable neuropathy, the complexity of the electrodiagnostic criteria for

demyelination and the lack of a specific disease marker, CIDP may currently be over diagnosed. Both AIDP and CIDP may respond to intravenous immunoglobulin or plasma exchange treatment, but a favorable response to steroids or other forms of chronic immunotherapy has only been documented in CIDP. Autoantibodies have not yet proven to be useful biomarkers for the core CIDP syndrome, whereas potential antiganglioside antibody associations have been more closely linked to some specific CIDP subtypes. 6. CIDP variants Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also referred to as Lewis-Sumner syndrome, is the most commonly diagnosed variant of CIDP. Its hallmark is an asymmetric pattern of involvement, with weakness often circumscribed to multiple individual nerve territories. Similar to classic CIDP, MASAM has not been yet been associated with specific serum autoantibodies. Distal acquired demyelinating symmetrical polyneuropathy (DADS) describes a predominantly sensory subtype of CIDP, affecting most commonly men over the age of 60 years, where both clinical deficits and electrophysiologic abnormalities are symmetric and distally accentuated [40,41]. There is a strong association with the presence of serum IgM monoclonal gammopathy, in which case roughly 50% of patients have demonstrable serum autoantibodies directed against MAG [42,43]. In turn, most patients with anti-MAG IgM have either an IgM monoclonal gammopathy of uncertain significance (80%) or an indolent form of Waldenstrom's macroglobulinemia, although it has also been described in cases of light-chain amyloidosis. Ultrastructural studies of sural nerve biopsies in these patients frequently show a hallmark of widely spaced peripheral myelin lamellae. There are several lines of evidence linking anti-MAG antibodies and neuropathy: characteristic clinical syndrome (DADS), demonstration of deposition of M-protein on affected myelin sheaths, induction of neuropathy with passive transfer of antibodies in experimental animals, and clinical improvement with reduction of serum antibody titer [44]. Unfortunately, patients with anti-MAG antibodies tend to have only marginal and transient responses to conventional immunotherapies and some are severely disabled by sensory ataxia. Although there were promising results from case reports and small series, more systematic recent controlled trials of rituximab in the treatment of anti-MAG neuropathy have not met their primary outcome measures, despite some absolute improvements compared to placebo [45,46]. In contradistinction, the presence of IgG or IgA monoclonal gammopathy may not significantly alter the prognosis or management of CIDP, with the exception of cases where such gammopathy signals the presence of myeloproliferative disorders such as osteosclerotic or multiple myeloma, and systemic amyloidoisis. It must be emphasized that monoclonal gammopathy of uncertain significance is a common finding in the general population, with a prevalence of 1% below the age of 60 years and 3% in subsequent decades [47]. The polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome is a rare neuropathic syndrome resulting from an underlying plasma cell disorder, most often an osteosclerotic myeloma, or Castleman syndrome (angiofollicular hyperplasia). Oversecretion of vascular endothelial growth factor (VEGF) is both a diagnostic criterion and a marker of disease progression. A small monoclonal protein is usually detected on immunofixation (85% of cases), most often comprising of a lambda light chain (95% of cases). Treatment includes eliminating clonal plasma cells, either with local radiotherapy when the disease is circumscribed, or with systemic chemotherapy and stem cell transplantation for more diffuse disease [48]. Multifocal motor neuropathy (MMN) is a distinct chronic immune neuropathy characterized by indolent progressive patchy pure motor deficits. MMN typically selectively affects branches of the brachial plexus and manifests in focal muscle weakness and atrophy. The

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Fig. 3. Multifocal motor neuropathy. Selective weakness of right finger extensor muscles (extensor digitorum, extensor pollicis longus) due to selective partial motor conduction block of the right radial nerve, in a patient with multifocal motor neuropathy. There is normal extension of fingers on the left side. This patient rapidly achieved clinical remission with monthly intravenous immunoglobulin infusions.

additional feature of cramps and fasciculations occurs in 50% of patients [49] (Fig. 3). This treatable neuropathy is an important diagnostic consideration in patients with suspected early motor neuron disease. The presence of multifocal partial motor conduction block with sparing of sensory conduction is the hallmark on nerve conduction studies. Patients with MMN often show an excellent response to intermittent intravenous immunoglobulin infusions, whereas most other immunotherapies are either ineffective or pose unacceptable risk, with the exception of cyclophosphamide in cases of severe and widespread involvement. The prevalence of IgM anti-GM1 antibodies in MMN has been reported to vary widely in the literature, ranging from 25% to 85% [50]. This wide range in part reflects a lack of consensus on ELISA methodology. For example, different results are obtained with assays that use GM1 ganglioside molecules covalently linked to ELISA wells, compared to linking them to plastic wells, or using an anti-GM1:GalC glycolipid assay [51]. In addition, a direct pathogenic role for these antibodies, whether by inducing focal demyelination or by blocking sodium channels, has not yet been conclusively established [52], although mounting evidence suggests that it can probably be classified as a chronic nodo-paranodopathy. The presence of autoantibodies is neither mandatory for the diagnosis nor reliably predictive of a different clinical course or response to treatment. Other antibodies much less frequently found in MMN include anti-GM2, GD1a, NS6S and Asialo GM1 antibodies. Finally, some patients present with a similar syndrome of pure multifocal motor dysfunction without demonstrable conduction block on electrophysiological testing, a syndrome which has been coined multifocal acquired motor axonopathy (MAMA). The chronic predominantly sensory subtype of CIDP has mostly been referred as chronic ataxic sensory neuropathy. Some patients who also display ophthalmoplegia and have an associated M-protein have been described under the acronym CANOMAD for chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosylantibodies [53]. Indeed, there is an association with IgM autoantibodies directed against the disialylated gangliosides family, notably anti-GD1b [54], less frequently GT1b, GD3 or GQ1b. This finding may be of clinical importance, as about 70% of such patients respond at least partially to IvIg infusions. 7. Additional controversial antibody-mediated chronic neuropathies Antibodies to sulfated glucuronyl paragloboside (SGPG) are often found in association with MAG antibodies however, their significance in the absence of MAG antibodies remains unclear. Isolated case reports

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of SGPG-positive/MAG-negative polyneuropathy patients showing a good response to immune treatments have been published [55] and an ataxic sensory neuronopathy was induced in cats after injection of purified SGPG [56]. However, the demonstration of SGPG antibodies in patients with non-immune axonal neuropathies has raised doubts about their pathogenic significance. Anti-sulfatide antibodies are also often found in association with MAG antibodies and occasionally with SGPG antibodies. While low-titers are non-specific, titers greater than 1:8000 are usually associated with a chronic immune sensorypredominant distal neuropathy. This entity resembles anti-MAG DADS neuropathy, but demonstrates more frequent axonal features on electrophysiology and may have a worse long-term prognosis despite immunosuppressive treatment [57,58]. GALOP syndrome (gait disorder, autoantibody, late-onset polyneuropathy) is a rare disorder described with IgM antibodies binding to sulfatide, only when present in a lipid membrane environment. Clinical reports of this syndrome are scarce but suggest instances of clear response to IvIg or cyclophosphamide [59,60]. Antibodies to heparan sulfate, while described in GBS, appear to be non-specific as they are present in 3% of neurological disorders (not only neuropathies), that share a presumed inflammatory etiology [42]. Finally, similar to MAG and other sulfated glycolipids, MPZ and PMP22 all display a glucoronic acid-containing carbohydrate (the HNK-1 epitope) that may confer binding specificity. Antibodies have been described to these proteins in different neuropathic syndromes but seem to have little specificity or clinical relevance [61]. 8. Benefits and controversies of autoantibody testing for suspected immune neuropathy The search for reliable biomarkers has vastly expanded our understanding of the pathophysiology underlying immune neuropathies [62]. For example, there is a suggestion that GD1a gangliosides are enriched in motor axons [63], whereas GD1b may be more strongly represented in sensory neurons. The anatomical distribution of GQ1b in different neuron populations (very high concentration in the three ocular motor nerves, in the vagus and glossopharyngeal nerves, and in muscle spindles) parallels the clinical pattern of MFS. Patterns of cross-reactivity between bacterial lipo-oligosaccharides, more specifically Campylobacter jejuni, and human gangliosides have provided insights into potential immunologic mimicry as discussed above. The strongest potential biomarker associations proposed occur between anti-MAG antibodies and DADS, anti-GQ1b antibodies and MFS, and IgM anti-GM1 antibodies and MMN. Nonetheless, a direct pathogenic role remains to be proven for most anti-ganglioside antibodies, in spite of decades of study. Some authors have favored systematic multiparametric detection of large panels of antiganglioside antibodies, in the assessment of patients with idiopathic neuropathy where an immune pathogenesis seems likely [64]. However, there remains a lack of consensus on many technical aspects of such testing, including the number and choice of specific purified gangliosides, ELISA methodology, titer cutoff level required, distinction between IgG or IgM reactivity, significance of polyclonal versus monoclonal increase and the selection of control antigens. Many commercially available antibody test panels purport improving the diagnostic sensitivity of motor, sensory or sensorimotor patterns of immune neuropathy, yet the diagnostic gain remains limited and controversial [65], with the potential exception of anti-MAG antibodies. 9. Conclusion The last two decades of research have led to remarkable advances in the clinical and electrophysiologic categorization of acute and chronic immune-mediated neuropathic syndromes, in parallel with the identification of multiple novel antibodies and antigenic targets. The value of autoantibody testing has been well established for only a minority of

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chronic immune neuropathies, where it helps confirm the diagnosis and provides a framework for prognosis and may guide specific therapy. This is particularly true for antibodies against GM1 in MMN and against MAG in DADS. In most immune-mediated neuropathies, autoantibodies lack sensitivity and specificity. Their presence may help suggest the possibility of a treatable immune-mediated disorder but a direct pathogenic role remains to be established. As new targeted treatments for specific components of the immune system become available, such as monoclonal antibodies against B-cells or against complement cascade, a reliable categorization of these serological biomarkers is likely to play an increasing role. References [1] Gardner ED, Bunge RP. Gross anatomy of the peripheral nervous system. In: P.J. D, Thomas PK, editors. Peripheral neuropathy. Philadelphia: Saunders; 2005. p. 9. [2] Yuki N. Ganglioside mimicry and peripheral nerve disease. Muscle Nerve 2007;35: 691–711. 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Please cite this article as: Bourque PR, et al, Autoimmune peripheral neuropathies, Clin Chim Acta (2015), http://dx.doi.org/10.1016/ j.cca.2015.02.039

Autoimmune peripheral neuropathies.

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence o...
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