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AIAN REVIEW
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1001-1008
 

Nodo-paranodopathies: Concepts, clinical implications, and management


Departments of Neurology, Bombay Hospital Institute of Medical Sciences, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India

Date of Submission27-Apr-2022
Date of Decision27-Apr-2022
Date of Acceptance28-Apr-2022
Date of Web Publication04-Aug-2022

Correspondence Address:
Satish V Khadilkar
Deanfs Office, First Floor, Bombay Hospital, 12, New Marine Lines, Mumbai - 400 020, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_382_22

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   Abstract 


Peripheral neuropathies are traditionally categorized into demyelinating or axonal. It has been proposed that dysfunction at nodal/paranodal region may be a key for better understanding of pathophysiology in patients with immune mediated neuropathies. In last few years, antibodies targeting node and paranode of myelinated nerves have been increasingly detected in patients with immune mediated neuropathies. These patients have clinical phenotype similar common inflammatory neuropathies like Guillain Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy with some additional atypical neurological and systemic features, and they respond poorly to conventional first line immunotherapies like IVIG. This review summarizes the structure of the node, concept and pathophysiology of nodopathies. We provide an overview of clinical phenotypes in patients with specific nodal/paranodal antibodies, along with electrophysiological and other diagnostic features and suggest therapeutic line of management based on current evidence.


Keywords: Conduction block, nodopathies, paranodopathies, reversible conduction failure


How to cite this article:
Khadilkar SV, Kamat S, Patel R. Nodo-paranodopathies: Concepts, clinical implications, and management. Ann Indian Acad Neurol 2022;25:1001-8

How to cite this URL:
Khadilkar SV, Kamat S, Patel R. Nodo-paranodopathies: Concepts, clinical implications, and management. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1001-8. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1001/353415





   Introduction Top


Louis Antoine Ranvier described “etranglements annulaires” of nerve fiber, the “nodes de Ranvier.”[1] Huxley and Stampfli demonstrated that the nodes in myelinated fibers are involved in saltatory conduction by generating inward membrane currents[2] and that the nodes ensure rapid and long-distance conduction of nerve impulses with the least expenditure of energy. The nodal, paranodal, and juxtanodal functions in health and diseases of the peripheral nerves have received attention in the last few years and the term nodo-paranodopathies has gained acceptance.

The term nodo-paranodopathy was originally proposed to characterize the neuropathies with anti-ganglioside antibodies having a common underlying pathogenic dysfunction at the nodal region resulting in a pathophysiological continuum from reversible nerve conduction failure to axonal degeneration.[3] This concept of nodo-paranodopathy was initially defined in cases of the axonal variant of Guillain–Barre syndrome (GBS) with anti-ganglioside antibodies. Later it was expanded to include demyelinating neuropathies like chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and neuropathies due to various etiologies like immune, inflammatory, ischemic, nutritional, and toxic.

Anatomy and molecular organization of the nodal region

Myelinated fibers are organized in four distinct domains: node, paranode, juxta-paranode, and internode [Figure 1].[4] The node of Ranvier consists of node, paranode, and juxta-paranodal regions of the nerve fiber. Cell adhesion molecules, cytoskeletal elements, and extracellular matrix proteins contribute to the formation of the node [Figure 2].
Figure 1: Figure illustrating organization of myelinated fibers

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Figure 2: Anatomy and molecular organization of the node

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Node is 1 uM in length. At the node, myelin is interrupted and axolemma is in direct contact with the extracellular fluid. It has a high density of voltage-gated sodium (Na) channels of the Nav 1.6 type and slow potassium (K) channels.[5] Na channels generate a nodal inward ionic current which depolarizes the membrane potential and generates an action potential. Slow K channels induce repolarization only in response to prolonged depolarization. Gliomedin is a cell adhesion molecule secreted by Schwann cell microvilli into the extracellular matrix which binds to neurofascin 186 (NF186) in the axolemma. Nodal Na channels are attached to gliomedin via NF186. These Na channels are also attached to the spectrin of the axonal cytoskeleton through ankyrin G[6] [Figure 1].

At the paranode, uncompacted myelin loops tightly adhere to the axolemma. The structural integrity and function of paranodes rely on septate-like junctions which comprise NF155 on myelin loops, contactin 1 (CNTN1), and contactin-associated protein (Caspr) on the axolemma.[7] CNTN1 and Caspr on axolemma are tightly connected to NF155 on myelin loops.

Juxta-paranode has a high density of voltage-gated K (potassium) channels (VGKC). K channels are anchored by Caspr-2 and transient axonal glycoprotein (TAG-1). TAG-1 is expressed on both axolemma and Schwann cell membranes. Their interaction is crucial for the clustering of K channels in the juxta-paranodal region.[8] These K channels induce repolarization of the membrane potential.

Internode is 1–2 mm in length and is surrounded by compact myelin. They have a high absolute number of Na channels and fast/slow K channels. Fast K channels help in repolarization to resting membrane potential or hyperpolarization. Na/K ATPase pump restores transmembrane gradients of Na and K. It requires one ATP molecule with each cycle. Gangliosides are glycolipids composed of ceramide embedded in the bi-lipid membrane to which sialic acid residues are attached in the extracellular region. Gangliosides GM1 are located at nodal and paranodal axolemma, Schwann cell membrane, and microvilli. GD1a is located on the nodal axolemma and Schwann cell membrane.[9] These gangliosides interact with nodal proteins and provide stability to the axon-glial interface at the paranode[10] [Figure 2] and [Figure 3].
Figure 3: Illustration of structures involved in the axolemmal excitability, distribution of voltage-gated-ion-channels, and directions of current: Ks, slow K+ current; Kf, fast K+ current; Nat, transient Na+ current; Nap, persistent Na+ current. The Na+/K+ pump exchanges 2 K+ with 3Na+ from the axoplasma. The Na+/Ca2+ ion exchanger removes Ca2+ from the axoplasma but can reverse its action

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Saltatory conduction at the node

Saltatory conduction is normally seen in myelinated axons. At the node, the transient Na channels open, generating an inward ionic current named as action current. This leads to an outward capacitive ionic driving current at the successive node, thus accumulating positive charges inside the successive node. This causes depolarization of the membrane, which leads to the opening of Na channels inducing further depolarization and generation of an action potential at the successive node. If the myelin sheath is damaged as in segmental demyelination in patients of a classic demyelinating neuropathy, the ionic driving current leaks through the damaged myelin membrane at the node and paranode; unable to reach the successive node, thus causing impairment of depolarization. In addition, the driving current activates the exposed K channels at the juxta-paranode shifting the membrane potential to a more negative value.[11] The safety factor for impulse transmission is defined as the ratio of driving current to threshold current required to depolarize the membrane and induce action current. In normal axons, the value is 5–10. If the safety factor is less than one, impulse transmission is blocked.[11] Also, pathological studies show that paranode has a crucial role in saltatory conduction.

In nodopathies, the antibody-mediated attack results in detachment of terminal myelin loops and disruption of ion channels. Detachment of terminal myelin loops at the paranode causes current leakage, which dissipates the driving current, thus causing impairment of depolarization at the successive node. Disruption of Na channels directly impairs the generation of the action potential. There are few segments with reduced functioning of Na/K ATPase causing persistent membrane depolarization and other segments with increased functioning of Na/K/ATPase causing persistent membrane hyperpolarization, thus causing disorganized polarization of axolemma.[11]

Malfunctioning of Na/K ATPase pump as described above induces persistent depolarization with inactivation of transient Na channels and thus failure of conduction. If this process persists, then Na accumulation reverses the function of the Na/Ca exchanger, causing excess removal of Na in exchange for Ca. Also, antibodies attacking the gangliosides activate the complement pathway, and finally, membranes attack the complex causing pores in the membrane. Ca enters through the pores and accumulates in the axoplasma. This Ca accumulation activates calpain causing proteolytic cleavage of neurofilaments, mitochondrial damage, and the eventual Wallerian degeneration.[12]

Electrophysiological features: The concept of axonal conduction block (CB)

Traditionally, GBS is classified as demyelinating or axonal based on electrophysiological studies. CB, temporal dispersion (TD), and conduction velocity slowing indicate demyelination whereas reduced compound motor action potential (CMAP) amplitudes indicate axonal dysfunction.

In some cases of GBS having ganglioside antibody positivity, features of demyelination like CB were observed in conjunction with reduced CMAP.[4] Even though classified as axonal GBS due to severe reduction of the CMAP, patients recovered rapidly. In this set of patients, the CB was considered to be secondary to antibody-mediated loss of Na channels at the node, accounting for reversible conduction failure (RCF) and rapid recovery observed in this group of patients. These cases of axonal GBS showed CB which resolved without the development of TD, hence the observation was termed as axonal CB.[13] Thus, the increased duration and fragmentation of CMAP, called TD helps to distinguish demyelinating from axonal CB. Similarly, the reduced amplitude of distal CMAP, in absence of demyelinating features is indicative of axonal degeneration, but can also be a result of CB in terminal axons. It needs to be stressed that accurate distinctions between the axonal and demyelinating CB can only be made after serial electrophysiological recordings.[4]

Nodo-paranodopathies

Currently, many phenotypic expressions having antibody associations have come under the umbrella of nodo-paranodopathies. Clinical syndromes most commonly associated with nodal-paranodal antibodies are GBS and its variants (acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN)), CIDP, and combined central and peripheral demyelination (CCPD). For this review, we have discussed them as nodal, paranodal, and juxtanodal neuropathies [Table 1], and the discussion is focused on the pathophysiology and clinic-electrophysiological insights in these nodo-paranodopathies.
Table 1: Nodo-paranodopathies[14] (modified from a review article of J. Fehmi et al.)

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Neuropathies and the node

Neuropathies due to anti-ganglioside antibodies

AMAN

AMAN, primarily a subtype of axonal GBS, is associated with preceding Campylobacter jejuni infection (67%) and immunoglobulin G (IgG) antibodies against GM1 (64%), GM1b (66%), and GD1a (45%).[15] Recently, antibodies to NF186 and gliomedin have been found in a small proportion of patients with GBS. Antibodies against NF186 showed a significant correlation with AMAN, whereas antibodies reactive to gliomedin were more commonly found in patients with AIDP.[3] Electrophysiologically, AMAN was initially characterized by reduced distal CMAP amplitudes, absent F waves, and normal sensory responses with the absence of features of demyelination. However, few patients with anti-ganglioside antibodies, in addition, showed prolonged distal motor latencies and CB mimicking demyelination. At follow-up, a subset of the above patients showed persistently low distal CMAP amplitude, while others showed normalization of distal CMAP amplitudes, distal motor latencies, and recovery of CB without the development of TD.[13],[16] This indicated that AMAN is not just characterized by pure axonal degeneration, but also by RCF at the node possibly by antibody attack. It is hypothesized that antibody-mediated attack at the node results in complement activation, formation of membrane attack complex (MAC), disruption of Na channels, myelin detachment at paranode, nodal lengthening, and disorganized polarization leading to an in-excitable axolemma, thus nerve conduction failure and muscle weakness.[17] Thus, in 2012, Uncini and Kuwaba introduced the term axonal block to describe CB without slowing of conduction velocity or TD to distinguish it from classic CB due to demyelination.[18] In 2021, Shin J Oh tried to unify the concept of CB by introducing the term nodal CB which represents a physiological CB at the node.[19] TD and slow conduction velocity help distinguish demyelinating from nodal CB. Remyelination over ongoing demyelination causes desynchronization of conduction among fibers, which induces TD. But nodal CB promptly reverses without TD.

The pathophysiological process may stop and reverse rapidly as in AMAN with CB or progress to axonal degeneration. Thus the description of patients with AMAN with CB progressing to axonal degeneration or showing reversible CB (RCB) and axonal degeneration in the same or different nerves explains the pathophysiological continuum.[20] This explains relatively complete recovery in a few patients of AMAN, while not in others. The current electrophysiological criteria for GBS do not include CB as an expression of axonal pathology. Hence, many patients of AMAN with CB are erroneously classified as acute inflammatory demyelinating neuropathy. In recent studies in the Italian and Japanese GBS populations which considered CB as an expression of axonal pathology, the percentage of axonal subtypes doubled on follow-up.[20],[21] The above findings conclude that AMAN does not fit in this traditional dichotomous classification of demyelinating and axonal neuropathy, and is the prototype of nodopathies.

Multifocal Motor Neuropathy (MMN)

MMN is characterized by slowly progressive asymmetric pure motor predominantly distal limb weakness with cramps and fasciculations in the affected nerve distribution. Electrodiagnostic examinations show persistent motor CB without TD in various nerves in half of the patients. IgM antibodies to GM1 are found in about 50% of the cases and a favorable response to intravenous immunoglobulins (IVIGs) is seen in up to 90% of cases.[22] There has been a debate on whether MMN is a primary demyelinating or axonal disorder. Pathology studies show evidence of both mild demyelinations with axonal degeneration as well.[23],[24] It is hypothesized that IgM GM1 antibodies bind at the nodes and activate complement which leads to the formation of MAC, disrupts the ion channels and paranodal structures leading to CB, and finally causes axonal degeneration.[21] Recently antibodies to NF186 and gliomedin have been detected in 62% of patients with MMN, of which 10% were anti-GM1 negative.[4] This suggests an additional role of the nodal region in the pathogenesis of MMN. MMN is now categorized as chronic dysimmune nodopathy.

Neuropathies and paranode

CIDP

CIDP is considered to be macrophage-mediated demyelination. Recent studies have shown that around 10% of cases of CIDP have antibodies directed against paranodal proteins, namely, CNTN1 or NF155.[25],[26] These antibodies are rarely found in patients with GBS. The presence of these antibodies in patients with GBS-like clinical presentation favors acute CIDP as the diagnosis.

Anti-NF155 antibodies

IgG4 antibodies against NF155 were initially detected in patients with inflammatory neuropathies. Ng and colleagues detected these antibodies in 5 of 119 patients with CIDP.[27] A similar proportion of IgG4 antibodies were found in a Spanish CIDP cohort.[28] The clinical phenotype associated with anti-NF155 antibody comprises of young age at onset with aggressive distal motor predominant syndrome associated with ataxia, tremor, and robust response to rituximab as compared to IVIG.[26],[27],[28],[29],[30],[31]xxv It is also associated with higher cerebrospinal fluid (CSF) proteins and prominent radicular involvement.[31]xxxi MRI findings include marked symmetric hypertrophy of cervical and lumbosacral roots.[28],[32] Pathologically, there is the absence of a macrophage-mediated demyelinating process in this cohort of patients thus indicating an alternate pathogenic mechanism. Pathological studies suggest that there is the destabilization of septate-like junctions at the paranode leading to nodal widening and paranodal demyelination causing conduction slowing.[33] It is hypothesized that IgG4 antibodies act without fixing complement by blocking the interaction of NF155 with the Caspr/CNTN1 complex.[27] In NF155 associated CIDP, electrophysiology shows marked prolongation of distal motor latencies and minimal F wave latencies as compared to antibody-negative CIDP.[28] In large study of 22 patients who fulfilled Electrodiagnostic criteria of CIDP (based on 11. European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) criteria) were detected positive for NF 155 and CNTN1 antibodies.[34]

Anti-CNTN1 antibodies

Anti-CNTN1 antibodies are detected in a small proportion of patients with CIDP. In one study, antibodies to CNTN1 were present in 3 of 46 patients with CIDP.[35] The clinical phenotype is older age at onset with the aggressive course, motor predominance with early axonal loss, and poor response to IVIG.[36] Electrophysiological studies have reported decreased motor amplitudes at the onset.[35]xxxv Pathological studies suggest that there are structural alterations at paranode. Antibodies act by blocking axoglial interactions mediated by the Caspr-CNTN1-NF155 complex, without fixing complement. This may be the reason for resistance to IVIG. Nephrotic syndrome is being increasingly identified in patients with antibodies to CNTN1.[37],[38]

Anti-Caspr antibodies

Caspr is recently highlighted as a target antigen in a cohort of 57 patients with GBS or CIDP, one from each group detected positive.[39] Neuropathic pain was the most prominent feature in those two patients. There was the resolution of pain following therapy with rituximab in one patient with a CIDP phenotype. Pathology revealed disruption of paranode in myelinated fibers, which is implicated in the development of neuropathic pain. Electrophysiology in patients of CIDP showed evidence of temporal disruption, yet biopsy revealed axonal degeneration with IgG deposition at paranodes.[39]xxxix

Pan-NF antibodies

Aggressive onset neuropathy with involvement of cranial nerves, autonomic dysfunction, and respiratory paralysis occur in patients who have antibodies that cross-react with both neurofascin isoforms (NF155 and NF186).[40],[41] Nephrotic syndrome is also frequently associated with pan-NF antibody-associated neuropathy. Additionally, hematological disorders like Hodgkin's lymphoma, chronic lymphocytic leukemia, and myeloma are also closely associated with pan-NF neuropathies.[40] These patients have an incomplete response to first-line therapies like IVIG and plasma exchange (PLEX), but a more sustained response to rituximab.

Neuropathies and Juxta-paranode

Normal functionality of juxta-paranode depends on the stability of the VGKC complex, in which VGKC co-localizes with CNTN2 and Caspr 2 in myelinated nerve fibers. Pathogenic antibodies bind to proteins such as LGI1 and Caspr 2 instead of ion channels themselves, thus causing a reduction in VGKC density leading to impairment of repolarization and neuronal hyperexcitability.[42]

Anti-Caspr 2 antibodies

Caspr 2 antibodies have been detected in large cohorts of patients with peripheral nerve hyperexcitability in isolation or as a part of a disorder of acquired neuromyotonia also known as Issac's syndrome. In addition to classic muscle symptoms of Isaac's syndrome, there is a spectrum of autonomic and central nervous system involvement like insomnia, limbic encephalitis, seizures, and dysautonomia that link Isaacs's syndrome to other autoimmune disorders.[43] More recently, Caspr 2 antibody has been linked to neuropathic pain. 17% of Caspr seropositive patients have evidence of sensorimotor neuropathy.[44] Two pediatric cases of GBS with Caspr 2 antibodies are documented.[45] A single patient who presented with aggressive axonal GBS which was treatment unresponsive in association with lung adenocarcinoma was shown to have Caspr 2 antibodies.[46]

Significance of IgG subtype

IgG is the most abundant of the five antibody subtypes. They are further divided into IgG1 to 4. IgG1 and IgG3 are potent activators of complement whereas IgG2 and IgG4 are not. IgG4 antibodies are most frequently detected in patients with nodo-paranodopathies. IgG1 and 3 subtypes are detected in low titers. Patients with a non-IgG4 subclass of antibodies have a more favorable response to IVIG. The proposed explanation is that IVIG acts by suppressing the complement, whereas IgG4 subclass antibodies do not fix the complement. This also explains transient relief in patients where IgG1–3 antibodies predominate.[40] In a study by Davies and colleagues, it was shown that repeated PLEX may be required to induce sustained suppression of antibody levels and thus clinical improvement.[47] Prolonged suppression of antibody titers is known to correlate with long-term clinical remission. Hence, it is seen that rituximab is more effective if given early in the course since it targets immature cluster of differentiation (CD) 20 positive B cells which generate antibody-secreting cells which may be responsible for nodal/paranodal antibody production. In 77% of antibody-positive patients refractory to standard immune therapies, rituximab has shown a favorable and enduring effect.[40] Few patients have shown good response even after starting rituximab many years after disease onset.[48]

Treatment

The treatment for immune nodopathies is based on research and experience with the management of typical antibody-negative CIDP. Most of the data come from case series and retrospective reviews. The most commonly used first-line therapies for CIDP are IVIG, corticosteroids, and PLEX.[49] Nodopathies are likely to be refractory to first-line therapies for CIDP. Hence, it is important to identify them and treat them early.

Most of the data on the management of nodopathies is based on patients with NF155 antibody-positive subtype. Querol et al.[27] reported four cases of IgG4 predominant NF155 positive cases who were refractory to IVIG, but with partial response to steroids in one patient and good response to PLEX in two of them. This same group later described three patients (two NF155 and one with CNTN1 antibodies) all with good responses to rituximab. Devaux et al.[26] described 38 IgG4 NF155 antibody-positive patients. Five of 25 patients responded to IVIG and 15 out of 29 responded to steroids. Ng et al. described three NF155 positive patients with good responses to PLEX. In a study by Davies and colleagues, it was shown that repeated PLEX may be required to induce sustained suppression of antibody levels and thus clinical improvement.[47] Thus, after reviewing all the literature described, it is seen that the highest response rates for IgG NF155 associated nodopathy are seen with PLEX (78%) followed by rituximab (75%), steroids (56%), and IVIG (32%).[50] Patients with IgG CNTN1 antibodies are refractory to treatment with IVIG but good response to steroids, rituximab, and PLEX.

Thus, in clinical practice, it is recommended to test for nodal and paranodal antibodies if the patient has acute to subacute onset, aggressive, distal and motor predominant neuropathy and associated cranial neuropathy, and respiratory involvement or is initially diagnosed as AIDP [Table 2] and [Figure 4]. Patients should be started on first-line therapies like corticosteroids with or without IVIG depending on severity. If a patient is refractory to IVIG/steroids or nodal/paranodal antibody is detected, then treatment should be rapidly escalated to PLEX. If a patient does not respond to first-line therapies during the first 8 weeks of illness or the clinical phenotype is aggressive at the onset with evidence of early axon loss, then rituximab should be considered. If there is a response to first-line therapies or the clinical phenotype is that of mild typical CIDP, then one should have a low threshold to escalate the therapy.
Table 2: When to suspect nodo-paranodopathy?

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Figure 4: Approach to management of nodo-paranodopathies

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Emerging therapies include complement and Fc receptor inhibitors and hypersialylated IVIG.[51] Eculizumab, a humanized antibody against C5 has shown promising results as an add-on therapy to IVIG.[52] With further understanding of pathophysiological mechanisms, newer therapies will emerge.


   Conclusions Top


Nodopathies and paranodopathies are a subtype of acquired chronic immune neuropathies with clinical phenotype of GBS and CIDP with atypical features. They have characteristic electrodiagnostic features of nodal CB without TD as recorded in serial studies. Early diagnosis of nodopathy can be made by early clinical suspicion and testing of known antibodies. The selection of immune therapies should be made on a case-to-case basis depending on the clinical phenotype and severity. Larger multicentric trials are needed to establish the prognostic implications and clinical utility of antibody measurement and to define an optimal line of management.

Key points

Nodopathies of peripheral nerve have the following key characteristics:

  1. The final common pathway is the dysfunction/disruption of the excitable axolemma at the nodal region.
  2. They display a pathophysiological continuum from reversible conduction failure/CB to axonal degeneration.
  3. CB is the result of paranodal myelin detachment, nodal lengthening, disruption of nodal Na channels, and disorganized polarization at the axolemma.
  4. CB may be reversible without the development of TD (axonal CB) or may progress to axonal degeneration.
  5. In clinical practice, serial electrophysiological studies should be done to document reversible CB without TD or progression of CB to axonal degeneration. In chronic disorders like CIDP or MMN, both may co-exist.
  6. Patients with atypical presentations of GBS or CIDP should undergo early testing for nodo-paranodal antibodies.
  7. Nodo-paranodopathies are less responsive to first-line therapies like IVIG. But they show a good response to steroids, PLEX, and rituximab. In patients with IgG4 subclass paranodal antibody, IVIG is often ineffective and rituximab or newer therapies should be considered early in the disease course for meaningful recovery.
  8. Patients with antibodies have a severe disability at nadir, but they have the potential to achieve long-lasting remission with the early use of rituximab.
  9. Further data is required to establish the prognostic implications and clinical utility of antibody measurement.
  10. With an increasing understanding of the pathophysiological mechanism of antibody production and nodal injury, newer therapies may emerge.


Acknowledgements

The authors thank Rakesh K. Singh, Rajesh Benny, Hiral Halani, and Harsh Oza for helping in the preparation of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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