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Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 310-317
Recent advances in the diagnosis of immune mediated demyelinating neuropathies

1 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

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Date of Submission14-Jan-2022
Date of Decision02-Feb-2022
Date of Acceptance06-Feb-2022
Date of Web Publication11-May-2022


Inflammatory neuropathies are a group of acquired neuropathies which could be due to autoimmune, infectious, paraneoplastic, or paraproteinemic etiology. The etiological diagnosis of inflammatory neuropathy is not simple, and often requires combination of clinical, electrophysiological, and histopathological findings to arrive at a precise diagnosis which is important for management of the disorder. Whereas there are comprehensive and sensitive panel of serological tests available for diagnosis of the infectious, paraneoplastic, paraproteinemic neuropathies, the diagnosis of immune-mediated demyelinating neuropathies remain a considerable challenge as there is both clinical and pathological overlap. Newer non-invasive methodologies such as high-resolution ultrasound, magnetic resonance imaging (MRI), and importantly, serological testing for antibodies are emerging, and it is essential for the practicing pathologist to be up-to-date with emerging modalities. In this review, we focus on the approach to diagnosis of immune-mediated demyelinating neuropathies.

Keywords: Demyelinating, diagnosis, inflammatory, nerve biopsy, neuropathies, serology

How to cite this article:
Rao S, Nagappa M, Mahadevan A. Recent advances in the diagnosis of immune mediated demyelinating neuropathies. Indian J Pathol Microbiol 2022;65, Suppl S1:310-7

How to cite this URL:
Rao S, Nagappa M, Mahadevan A. Recent advances in the diagnosis of immune mediated demyelinating neuropathies. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 24];65, Suppl S1:310-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/310/345058

   Introduction Top

Inflammatory neuropathies are a heterogeneous group of acquired disorders characterized by abnormal inflammatory cell infiltration within the peripheral nerves, nerve roots, or both, and result in demyelination or axonal degeneration, or both. The underlying etiologies include autoimmune, granulomatous, infectious, paraneoplastic, and paraproteinemic disorders.[1] The peripheral nerves are highly specialized structures and they comprise of bundles of nerve fibers bound by the endoneurium, perineurium, and epineurium. Each nerve fiber is made up of an axon surrounded by myelin sheath from the Schwann cells. The thickness of the nerve fibers varies, and fibers of different thickness serve different functions; the large myelinated fibers are involved in somato-motor and proprioceptive function, while the smaller, less myelinated and unmyelinated fibers transmit pain and temperature sensation, and are also involved in autonomic function. Overall, the caliber of the blood vessels supplying the peripheral nerves is small and ranges from the relatively large-sized vessels, namely, the arterioles, which are located within the epineurium, to the smaller-diameter vessels, namely, the capillaries and venules that are situated within the perineurium and endoneurium. Among the autoimmune conditions, an abnormal immune response may be directed either at the peripheral nerves per se, or at the vasculature supplying the peripheral nerves. When peripheral nerves are the primary target of the abnormal immune response, it frequently affects the large-diameter fibers, and results in demyelinating neuropathy. On the other hand, when the blood vessels are the primary targets of abnormal immune response, the small and large fibers are affected and vasculitic neuropathy occurs.[2]

An accurate diagnosis of inflammatory neuropathy is of paramount importance so that timely and appropriate treatment can be instituted, so as to minimize neurological deficits and hasten recovery. A number of criteria have been proposed and validated, and over the years they have been defined, refined, and re-defined in an attempt to be as accurate, and make as reliable a diagnosis as possible. All these criteria have certain common elements in that they combine clinical features with the electrophysiological and/or histopathological changes, supported by other laboratory parameters.[3] However, in routine clinical practice it is sometimes difficult to arrive at a confirmatory diagnosis with the available laboratory investigations; there are no specific blood-based or tissue biomarkers. Longitudinal follow up for the clinical course and response to treatment is useful in supporting the diagnosis. The present review focusses on the diagnostic strategies in these autoimmune neuropathies.

Clinical features

Clinically, the diagnosis of inflammatory neuropathies is suspected based on the combination of the pattern of neurological deficits, onset and course of neuropathy, as well as the associated neurological and systemic features. The inflammatory neuropathies can broadly be divided into acute, sub-acute, and chronic neuropathies depending upon the interval between the onset of illness and the development of maximal neurological deficits.

The acute form is known by its eponym, Guillain–Barré syndrome (GBS), and it presents with rapidly progressive weakness of limbs and hypo-/a-reflexia in the affected limbs. Other clinical features include cranial nerve palsies, dysautonomia, respiratory muscle weakness, pain and fatigue. Clinical variants or atypical GBS are recognized and they include Miller Fisher syndrome, ataxic GBS, pharyngo-cervico-brachial variant, paraparetic GBS, bifacial palsy with paresthesia, and acute pandysautonomia.[4] The clinical course is monophasic, where the patients reach the nadir within four weeks of onset, plateau for a variable period, and then recover over weeks to months.

In chronic inflammatory demyelinating polyneuropathy (CIDP), the weakness progresses more insidiously to reach a peak after eight weeks. The clinical course may be progressive or relapsing–remitting in nature.[5] Similar to GBS, a number of variants or atypical forms of CIDP have been described such as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) or Lewis–Sumner syndrome, distal acquired demyelinating symmetric polyneuropathy (DADS), pure motor, pure sensory, and focal CIDP.[6]

Vasculitis of peripheral nerves may be categorized as systemic or non-systemic, and systemic vasculitis is further sub-divided into primary and secondary forms. Vasculitic neuropathy affects the peripheral nerves in a patchy and asymmetric manner, and clinically, the patients present with acute or sub-acute onset of mononeuritis, mononeuritis multiplex, asymmetric polyneuropathy or, rarely, symmetrical polyneuropathy.[7] Though any nerve can be affected, the common peroneal and tibial nerves are commonly affected. Pain is usually present. Systemic symptoms such as skin rash, arthritis or arthralgias, may be present.[8]


Nerve conduction studies confirm peripheral nerve dysfunction, can aid in sub-typing, in addition to prognostication in patients with inflammatory neuropathies. In GBS, the classical finding is one of demyelinating neuropathy as evidenced by prolonged latencies and slowed conduction velocities, with/without temporal dispersion and conduction blocks. Some patients with GBS show reduced amplitudes of evoked motor responses and are sub-typed as acute motor axonal neuropathy (AMAN) or acute motor and sensory axonal neuropathy (AMSAN) rather than as acute inflammatory demyelinating polyneuropathy (AIDP). A number of cut-off values and criteria for defining “demyelinating” and “axonal” electrophysiology have been proposed.[9] The caveat here is that the electrophysiological changes are dynamic, and patients who are initially categorized as AIDP may be re-classified as AMAN and vice-versa when serial NCS are performed.[10]

In CIDP also, the electrophysiological diagnosis is based on demonstrating features of acquired demyelination in one or more nerves. The electrophysiological criteria for demyelination have been subjected to a number of revisions in order to avoid mis-interpretation and over-diagnosis of CIDP, particularly in the presence of medical co-morbidities such as diabetes mellitus, which by themselves may lead to neuropathy.[11] At present, the European Federation of Neurological Societies/Peripheral Nerve Society's (EFNS/PNS) 2010 electrodiagnostic criteria has the best sensitivity and specificity for diagnosing CIDP.[12] In DADS, the distal nerve segments are affected, leading to disproportionately prolonged distal latencies as compared to conduction velocities. The intermediate nerve segments are more affected in MADSAM, resulting in slowed conduction velocities and conduction blocks. In the pure sensory CIDP also, abnormalities in motor conduction studies are seen in the form of slowed conduction velocities and conduction blocks. In chronic immune sensory polyradiculopathy (CISP) where the pathology is confined to sensory nerve roots, nerve conduction studies are normal, while the somatosensory evoked potential (SSEP) studies are abnormal.[13]

In vasculitic neuropathy, the electrophysiological changes are patchy and non-uniform, reflecting the clinical profile. Axonal changes are noted in motor and sensory nerves. Subclinical involvement of clinically unaffected nerves may also be identified. Conduction blocks and/or slowed velocities are uncommon.[8] However, if focal nerve infarction occurs, a transient conduction block may be identified.[7]

Cerebrospinal fluid analysis

Albuminocytological dissociation, wherein raised protein levels are present in the cerebrospinal fluid (CSF) without a corresponding increase in cellularity, is a characteristic feature of GBS and CIDP, but is not seen in all patients. Mild pleocytosis, though permitted in the diagnostic criteria, also warrants a search for alternative etiologies, particularly the Human Immunodeficiency Virus (HIV) infection.[4] Age-appropriate cut-off values for defining elevated protein in the CSF (< 50 years: protein >50 mg/dl, ≥50 years: protein >60 mg/dl) have been proposed.[14] CSF analysis does not play any specific role in the diagnosis of vasculitic neuropathy, except to exclude alternative etiologies based on the clinical picture.


Many research groups have attempted to understand the pathogenesis of immune-mediated neuropathies in the recent past. Although definitive evidences are lacking, several theories are proposed. AIDP has been associated with preceding infections (bacterial or viral), raising the possibility of molecular mimicry of the antigen resulting in an immune attack of the peripheral nerves and nerve roots. The evidence for the same is found in the experimental models.

CIDP results from defects in immune tolerance with persistent activation of the immune system with resultant cell and humoral-mediated inflammation. Results from animal models suggest the role of abnormal immune response.[15],[16] Dysfunction in leucocytes (CD4+ CD25+ FoxP3+ T lymphocytes) and also abnormal B cell maturation along with aberrant activation of Th1 and Th17 cells have been implicated in CIDP. Schwann cells also play a role in potentiating the local innate and adaptive immune response with inability to abrogate the local response.[17],[18] In the biopsies of CIDP, IgG, IgM, and complement deposits have been demonstrated.

Studies have found evidence of humoral autoimmune response against various components of the nerve which result in varied clinical manifestation. Elevated C5a, C5b-9, inflammatory cytokines such as interleukin 2, interleukin 6, tumor necrosis factor alpha and others have been reported in serum and CSF of patients.[19],[20],[21],[22] These studies suggest that autoantibodies targeting different components of the nerve play a role in the pathogenesis of CIDP.

Imaging of peripheral nerves

High-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI) permit direct visualization of the peripheral nervous system along the entire length including the roots, plexuses and terminal nerves with a fairly high degree of clarity. HRUS and MRI provide information regarding the morphological alterations and complement the functional information provided by the electrophysiological studies. Besides, segments of the peripheral nerves that are not easily accessible for clinical examination and electrophysiological studies can be studied using the HRUS and MRI. HRUS and MRI reveal increased thickness or enlargement and hyperintensities of the nerves in CIDP. These changes are more prominent in the proximal portions of the peripheral nervous system that is, the cervical roots, brachial and lumbosacral plexuses and cauda equina.[5] The changes may be focal or patchy, and may guide selection of an appropriate site for biopsy and histological studies. Contrast-enhanced sequences may show abnormal enhancement of the affected segments. Specific sequences such as the short T1 inversion recovery (STIR) and diffusion tensor imaging (DTI) demonstrate not only hypertrophy of the affected nerves, but also microstructural integrity.[23] In HRUS the abnormal nerve segments are visualized as enlarged and hypoechoic nerves; the individual fascicles within the nerves also appear hypoechoic.[23] They contribute to the diagnosis of CIDP in situations when the electrophysiological studies do not fulfil the diagnostic criteria. Imaging abnormalities have been reported in 45% to 57%, and in some studies upto 90% of patients with CIDP.[24] The wide range of sensitivity is related to differences in study design, including patient selection, disease duration, and prior treatment as well as sites of measurement.[25] They are less frequent in patients with atypical CIDP as compared to those with typical CIDP. In addition, the inter-rater reliability in case of mild enlargement is rather low, and there is a lack of reliable normative data including cut-off values to define abnormal nerve enlargement. Imaging abnormalities do not correlate with the clinical severity, though they have been shown to correlate with the disease duration.[26] Differential diagnoses include hereditary neuropathies, familial amyloid polyneuropathy, paraproteinemic neuropathies, and neuro-lymphomatosis.

These tests are non-invasive, safe, and painless. HRUS can be carried out at the point-of-care and is relatively quick and inexpensive as compared to the MRI, which is also associated with claustrophobia. Serial imaging of the peripheral nerves can be carried out during follow up. Thus, imaging studies not only provide information regarding the sites of involvement, but may also act as surrogate markers of disease activity, relapses, and recovery following treatments. Gadofluorine M-enhanced MRI and iron oxide nanoparticles are also being explored for their utility in identifying infiltration of peripheral nerves by inflammatory cells in experimental models.[27]


Nerve biopsies are not routinely indicated for diagnosis of GBS. Nerve biopsies are assessed by hematoxylin and eosin stained sections for detecting inflammation, edema, onion bulb formation and acute axonal breakdown. For studying the alterations in myelinated nerve fibres, pre fixation of tissue in Fleming' solution followed by Kulchitsky Pal stain is used. Presence of thinly myelinated fibres indicate process of demyelination followed by remyelination. Immunohistochemistry with leucocyte common antigen can be used to identify inflammation in endoneurial compartment.

Subtypes of GBS differ in the pathological processes underlying the disease. In AIDP there is extensive infiltration by mononuclear cells in the perivascular and endoneurial regions, which is more prominent in the early stages.[28] This pathology is more prominent in spinal roots and ventral roots that are more severely affected. On the other hand, sural nerve, being distal, shows only minimal changes.[29] Plaque like areas of patchy demyelination is noted along with macrophage laden myelin debris. The damage is proportionate to the extent of inflammation.[30] Macrophages enter the myelin sheath from the outer lamellae and dissect along the inter-period line leading to myelin stripping and vesicular degeneration.[29] In the AMAN variant of GBS, there is varying degree of Wallerian degeneration which is more prominent in ventral roots as compared to peripheral nerves. Fiber loss is patchy and non-uniform. Macrophages are noted in the peri-axonal space displacing the axon with the surrounding myelin sheath being intact. Axoplasm is often condensed. In severe cases the axon disappears completely leaving behind macrophages in an empty cylinder surrounded by a normal myelin sheath.[29],[31] In a proportion of patients, the pathological changes are disproportionately minimal, which is in contrast to the clinical picture of severe and complete paralysis. In these patients, changes are restricted to the paranode leading to lengthening of the node of Ranvier and occasional Wallerian degeneration.[29]

Nerve biopsy is not indicated for the diagnosis of typical CIDP. However, in atypical presentations of CIDP, nerve biopsy is performed in order to exclude other differential diagnosis such as vasculitis, hereditary neuropathy, amyloidosis, or neoplasia.[32] The histological findings in CIDP are similar to that of AIDP. However, due to chronicity of the condition, evidence of demyelination and remyelination can be seen in CIDP. This results in the formation of onion bulbs which can be identified on light microscopy [Figure 1]. These onion bulbs are mixed, that is, non-uniform and patchy demyelination results in large onion bulbs being present adjacent to fibers with normal myelination.[32] This is in contrast to inherited demyelinating neuropathies, wherein the onion bulbs are uniformly dispersed in all fascicles examined. Earlier, the AAN criteria for definite diagnosis of CIDP mandated the demonstration of unequivocal evidence of demyelination and remyelination by either electron microscopy or by teased fiber preparation.[33] Other histological features in CIDP, including subperineurial or endoneurial edema, and mononuclear cell infiltration, were considered “supportive criteria”. However, these changes are more prominent in the proximal portions of the peripheral nervous system namely, spinal roots, nerve trunks, and plexuses rather than the distally located sural nerve, which is commonly biopsied.[17],[34] Differences in histological findings in patients with variants of CIDP as compared to typical CIDP are reported. This includes variation in involvement between and within fascicles with respect to reduction in myelinated fiber density, epineural lymphocytic infiltration, and onion bulb formation.[35]
Figure 1: Sural Nerve biopsy reveals onion bulbs (a, H and E, x200) with inflammation in the endoneurium (b, LCA, x100). There is moderate loss of myelinated fibers, with presence of thinly myelinated fibers indicating demyelination and remyelination (c, Kulchitsky Pal, x100)

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The presence of infiltration by inflammatory cells, destruction of the vessel wall, fibrinoid necrosis, hemosiderin deposition and non-uniform multifocal nerve fibre loss aid in the histological diagnosis of vasculitic neuropathy.[36] Necrotizing arteritis is a feature of primary systemic vasculitis, including polyarteritis nodosa, microscopic polyangiitis, and Churg–Strauss syndrome. In addition, eosinophilic infiltrates are noted in Churg–Strauss syndrome.[7] Combined muscle and nerve biopsy has a higher diagnostic yield as compared to nerve biopsy alone in the diagnosis of vasculitic neuropathy.[37]


The search for autoantibodies has been the object of research for several decades. Passive transfer and response to plasmapheresis support the role of autoantibodies in the pathogenesis of inflammatory neuropathies. These autoimmune-mediated neuropathies in general are associated with poor response to conventional therapies. Gangliosides, which are composed of a ceramide attached to one or more sugars (hexoses) and contain sialic acid (N-acetylneuraminic acid) linked to an oligosaccharide core, are important components of the peripheral nerves. Four gangliosides, namely, GM1, GD1a, GT1a, and GQ1b differ with regard to the number and position of their sialic acids, where M, D, T, and Q represent mono-, di-, tri-, and quadri-sialosyl groups. Gangliosides are considered to be the antigenic targets in GBS. Yuki et al.[38] reported two patients, who developed AMAN following C. jejuni enteritis, and were found to have IgG antibodies against GM1 ganglioside. Following this report, antibodies against several gangliosides were identified, some associated with specific infection. Clinical profile may be determined by ganglioside antibody profile rather than by electrophysiological categorization. Ganglioside antibodies were associated with axonal subtypes of GBS rather than AIDP.[39–41] Patients with anti-GM1 associated neuropathy frequently have preceding history of gastrointestinal infection. Facial nerve involvement was common in anti-GD1a associated neuropathy, with a predilection for young males. Bulbar weakness was unique to anti-GT1a associated neuropathies. In cases with co-existing anti-GQ1b antibody, there was increased association with ophthalmoplegia. Patients with GalNAc-GD1a antibodies have features identical to pure motor variant of GBS, distal-dominant weakness, infrequent cranial nerve palsies and AMAN pattern on NCS. An immunohistochemical study using human peripheral nerves showed that GalNAc-GD1a is localized to the nodes of Ranvier in motor nerves, inner part of compact myelin, and peri-axonal region in the ventral roots and intramuscular nerves.[43] Antibodies to GQ1b which is localized to the para-nodal regions of the extramedullary portion of the human oculomotor, trochlear, and abducens nerves have been associated with MFS and GBS with ophthalmoplegia.[44] Likewise, the pharyngo-cervico-brachial variant of GBS has been associated with antibodies against GT1a and GD1a, while the GD1b antibodies have been associated with ataxia in patients with GBS.[45–47]

It has been noted in some studies that patients with GBS express autoantibodies that react with ganglioside complexes (GSC), but not the individual ganglioside in the complex. This reflects the capacity of gangliosides to form hetero-dimeric complexes. Glycosphingolipids penetrate the outer leaflet of plasma membrane via ceramide and are preferentially packaged with cholesterol, forming lipid rafts. Within the plasma membrane microdomains, glyco-sphingolipids, particularly gangliosides, interact with transmembrane receptors and signal transducers involved in cell adhesion and signaling. Because proteins in the micro domains are not free to spread over the plasma membrane, specific ones tend to be concentrated within micro domains that often are essential for protein function. Antibodies to a GSC therefore may alter the function of the axon or Schwann cell through their binding to clustered epitopes of glycosphingolipids in the plasma membrane microdomains.[48],[49] Rinaldi et al.[50] reported that while antibodies to single gangliosides are predominant in axonal GBS, antibodies to GSCs are frequent in AIDP. Antecedent gastrointestinal infection, ophthalmoplegia and lower cranial nerve palsies were more frequent in those with GSC antibodies. GD1a/GD1b and/or GD1b/GT1b antibodies associated IDP are known to have severe disability and ventilator dependence. Hence, they may be useful predictors of severe disease course.[51] In another study, patients with GSC-antibodies were characterized by preserved sensory system and infrequent cranial nerve deficits.[52] Further, GSCs containing GQ1b or GT1a have been considered to be the key target antigens in MFS and ophthalmoplegia in GBS.[53]

Testing methods available for detection of gangliosides in serum include immunoblot, enzyme-linked immunosorbent assay (ELISA) and immunochromatography. Anti-ganglioside antibodies tend to bind with low avidity which may result in false negative results. Longer incubation period and avoiding the use of detergents in washing buffer can overcome this issue and thus increase the sensitivity of ELISA.

Since demyelination is the prominent feature in electrophysiological and histological studies, proteins in the compact myelin such as P0, P2, PMP22, and connexin were explored as potential antigenic targets, but the pathogenicity of antibodies against these proteins has not been conclusively demonstrated.[17] Knowledge of the molecular architecture of nerve fibers has improved, and antibodies against the non-compact myelin, that is, the node-paranode-juxtraparanode complex are gaining importance.

The myelinated nerve fibers are organized into distinct domains such as node, paranode, juxta-paranode, and inter-node. Node is the region of the nerve fibre where axolemma is not covered by myelin and is in proximity to extracellular fluid, which is not seen in paranode and internodes. Uncompacted myelin are attached to axolemma in the paranodal region and compacted myelin in the internodal region. The axolemma of mammalian myelinated axons is a highly ordered molecular structure with a non-uniform distribution of ion channels. There are a number of proteins which can act as antigenic targets. These include the neurofascin 186 (NF186), neurofascin 140 (NF140), and gliomedin at the node, complexes of contactin1 (CNTN1) and contactin-associated protein 1 (Caspr1) on the axonal side, and neurofascin 155 (NF155) on the glial side of the paranode, and the CNTN2 and Caspr2 in the juxtaparanode. At internodes, which are 1 to 2 mm long, the axons are surrounded by compact myelin.[54] These autoantibodies have been detected by tissue-based fluorescence assays using serum from patients with immune-mediated neuropathies on rat sciatic nerve sections.[55]

Amongst the nodal targets, the most commonly investigated antigenic targets are neurofascin, meosin and gliomedin. Neurofascin 186 have been found to be associated with CIDP. Gliomedin and neurofascin interact with other molecules and play a role in axonal conduction, thereby the antibodies against these antigenic targets interfere with the conduction and cause symptoms.[56–58]

The NF155 is a member of the L1 family of adhesion molecules expressed in the terminal loops of myelin. It binds with the axonal cell adhesion molecules CNTN1 and Caspr1 at the paranodes to form a septal barrier.[59] Pathological studies suggest that NF155 autoantibodies cause destabilization of the transverse bands or the septate-like junctions, which link the paranodal myelin loops to the axon, with subsequent conduction slowing, likely secondary to nodal widening and paranodal demyelination.[60] The electrophysiological correlate of antibody-mediated attack at the node or paranode is 'reversible conduction failure' (RCF). RCF is characterized by reversible conduction slowing or block, mimicking demyelination, but without temporal dispersion. This explains why patients with 'axonal' GBS make good recovery.[9]

In a cohort of 50 patients with CIDP, NF155 autoantibodies were identified in 18%, predominantly of the IgG4 subclass. NF155 autoantibody-positive CIDP patients are significantly younger at onset, with higher frequency of foot drop, gait disturbance, tremor, DADS phenotype, and higher cerebrospinal fluid (CSF) protein levels as compared to NF155 autoantibody negative patients.[61] Likewise, CNTN1 antibodies are associated with aggressive disease onset, ataxia, and prominent motor involvement with evidence of “axonal” damage at onset and poor response to intravenous immunoglobulin. These patients may respond to B cell depletion. CASPR1 antibodies are associated with neuropathic pain, while CASPR2 antibodies are classically associated with the clinical phenotype of motor neuropathy and positive symptoms in the form of myokymias, fasciculations and neuromyotonia. More recently, FGFR3 antibodies have been implicated in sensory neuropathy or neuronopathy.[54]

Other studies have analyzed the role of autoantibodies to myelin proteins and gangliosides in immune-mediated neuropathies. There is evidence of autoantibodies to myelin associated glycoprotein in patients with DADS.[62] However, no such evidence exists for antibodies to other myelin proteins such as myelin protein zero, peripheral myelin protein 2 or 22, and connexin 1.[16],[63],[64]

Although earlier studies found low incidence of autoantibodies to sulfatide component and its association with axonal neuropathies, recent studies have been able to demonstrate sulfatide autoantibodies in a substantial proportion of demyelinating neuropathies.[65] These patients are younger and show manifestations of CIDP.[66],[67] Many authors have observed that for the detection of these autoantibodies, the choice of the technique is important. Line immunoassay or combinatorial glycoarray have shown to yield better results due to optimal antigenic epitope-preserving binding on the hydrophobic membranes.[65],[67],[68],[69] Klehmet et al.[65] observed that, patients with autoantibodies to sulfatide showed a higher rate of conduction blocks. These results suggest that complement mediated pathology causes conduction abnormalities through antibodies against GM1 ganglioside. The GM1 ganglioside is highly expressed on membranes of motor nerves and on the surface of Schwann cells.[70]

This understanding has led to the emergence of a new concept of pathophysiology of autoimmune neuropathies, that is, nodo-paranodopathies, and this is expected to replace the current classification of inflammatory neuropathies. [Table 1] summarizes the clinical and serological findings in various immune-mediated neuropathies.
Table 1: Clinical features, antibody profile and nerve biopsy features of demyelinating neuropathies

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Treatment of CIDP

Plasmapheresis and intravenous immunoglobulins (IVIg) have been shown to hasten the speed of recovery, and improve the completeness of recovery in GBS, as well as reduce the need for mechanical ventilation.[71] In case of subjects with protracted and severe course, a second course of IVIg and eculizumab have been used.[72] Steroids, plasmapheresis and intravenous immunoglobulins are the mainstay of treatment in CIDP and are equally efficacious.[18] The average time for improvement in CIDP is approximately two months. Pulsed oral and intravenous steroids may offset the adverse effects of daily oral steroids.[73] The treatment is broadly classified into induction and maintenance phases.[5] The short-term efficacy and long-term maintenance therapy with IVIg have been demonstrated. Low-dose steroids are generally continued in order to maintain remission. Other immunosuppressants such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine are routinely administered as steroid-sparing agents. In subjects who are refractory to the conventional therapies, monoclonal antibodies such as rituximab and alemtuzumab, and complement inhibitors play a role in inducing remission.[5] There are no fixed treatment regimens and “response-based dosing” is used for taking therapeutic decisions. Besides pharmacotherapy, strength training and physiotherapy have been shown to be beneficial in promoting recovery.[23]

   Conclusion Top

Recent studies have identified an expanding panel of autoantibodies associated with immune-mediated inflammatory neuropathies, which is expected to result in a shift from the existing clinicopathological-based classification to serology-based diagnosis, which could be more accurate and aid in specific treatment of these disorders. The discovery of a wide panel of pathogenic autoantibodies in CIDP, and its role in disease causation has led to a new concept in pathophysiology of autoimmune neuropathies, namely, the nodo-paranodopathies, which is expected to replace the current classification of inflammatory neuropathies.

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Correspondence Address:
Madhu Nagappa
Additional Professor, Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_50_22

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