CONCEPT OF NODOPATHIES AND PARANODOPATHIES.pptx

emergence of autoimmune neuropathies and role of nodal and paranodal regions in their pathophysiology.
Peripheral neuropathies are traditionally categorized into demyelinating or axonal.
dysfunction at nodal/paranodal region key for better understanding of patients with immune mediated neuropathies.
antibodies targeting node and paranode of myelinated nerves have been increasingly detected in patients with immune mediated neuropathies.
have clinical phenotype similar common inflammatory neuropathies like Guillain Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy
 they respond poorly to conventional first line immunotherapies like IVIG

1. CONCEPT OF NODOPATHIES AND PARANODOPATHIES DR PRAKARSH SHARMA SR NEUROLOGY GOVT MEDICAL COLLEGE, KOTA

2. Introduction Peripheral neuropathies are traditionally categorized into demyelinating or axonal. dysfunction at nodal/ paranodal region key for better understanding of patients with immune mediated neuropathies. antibodies targeting node and paranode of myelinated nerves have been increasingly detected in patients with immune mediated neuropathies. have clinical phenotype similar common inflammatory neuropathies like Guillain Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy  they respond poorly to conventional first line immunotherapies like IVIG. 

3. Term nodo-paranodopathy was originally proposed to characterize the neuropathies with anti-ganglioside antibodies having pathogenic dysfunction at the nodal region. This concept of nodo-paranodopathy was initially defined in cases of the axonal variant of Guillain–Barre syndrome (GBS) with anti-ganglioside antibodies. Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies. Clin Neurophysiol . 2013;124:1928–34. 

4. STRUCTURE OF NEURON

5. Anatomy and molecular organization of the node Myelinated fibers are organized in four distinct domains: node, paranode, juxta-paranode, and internode. Cell adhesion molecules, cytoskeletal elements, and extracellular matrix proteins contribute to the formation of the node. Node is 1 uM in length. At the node, myelin is interrupted and axolemma is in direct contact with the extracellular fluid. has high density of voltage-gated sodium (Na) channels of the Nav 1.6 type and slow potassium (K) channels. 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. JM. Molecular dissection of the myelinated axon. Ann Neurol. 1993;33:121–36. 

6. 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

7. 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. CNTN1 and Caspr on axolemma are tightly connected to NF155 on myelin loops. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron. 2001;30:385–97.

8. 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. These K channels induce repolarization of the membrane potential. Juxtaparanodal clustering of Shaker-like K+channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol. 2003;162:1149–60. 

9.  Gangliosides are glycolipids. 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. These gangliosides interact with nodal proteins and provide stability to the axon-glial interface at the paranode. Ganglioside contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Glia. 2007;55:746–57

10. SALTATORY CONDUCTION AT THE NODE

11. S altatory conduction is normally seen in myelinated axons. 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 Pathophysiology of immune-mediated demyelinating neuropathies-part I: Neuroscience. Muscle Nerve. 2013;48:851–64. 

12. Concept of nodopathies 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.

13. 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. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration.  Mol Neurobiol .  2008;38:78.

14. 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.

15. Suspected evolution of conduction deficits in Nodo-paranodopathies (Electrophysiological characteristics and appearances in accompanying boxes)

16. In some cases of GBS having ganglioside antibody positivity, features of demyelination like CB were observed in conjunction with reduced CMAP. 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. 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. IgG anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in Guillain-Barré syndrome. Ann Neurol. 1998;44:202–8.

17. 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.

18. 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).

19. Neuropathies due to anti-ganglioside antibodies  AMAN AMAN, primarily a subtype of axonal GBS, associated with preceding Campylobacter jejuni infection (67%) and immunoglobulin G (IgG) antibodies against GM1 (64%), GM1b (66%), and GD1a (45%).  Antibodies against NF186 showed a significant correlation with AMAN, whereas antibodies reactive to gliomedin were more commonly found in patients with AIDP. Electrophysiologically , AMAN was initially characterized by reduced distal CMAP amplitudes, absent F waves, and normal sensory responses with the absence of features of demyelination. few patients with anti-ganglioside antibodies, in addition, showed prolonged distal motor latencies and CB mimicking demyelination. Guillain-Barré syndrome.  Lancet.  2005;366:1653–66.

20. 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. This indicated that AMAN is not just characterized by pure axonal degeneration, but also by RCF at the node possibly by antibody attack. TD and slow conduction velocity help distinguish demyelinating from nodal CB. nodal CB promptly reverses without TD.

21. Multifocal motor neuropathy 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.  debate on whether MMN is a primary demyelinating or axonal disorder.

22.  Pathology studies show evidence of both mild demyelination with axonal degeneration as well. hypothesized that IgM GM1 antibodies bind at the nodes and activate complement which leads to the formation of MAC, CB, and finally causes axonal degeneration. NF186 and gliomedin have been detected in 62% of patients with MMN, of which 10% were anti-GM1 negative. suggests an additional role of the nodal region in the pathogenesis of MMN. Multifocal motor neuropathy: Diagnosis, pathogenesis and treatment strategies.  Nat Rev Neurol.  2011;8:48–58. 

23. Neuropathies and paranode CIDP is considered to be macrophage-mediated demyelination. Recent studies have shown that around 10% of cases of CIDP have antibodies directed against para-nodal proteins, namely, CNTN1 or NF155. 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. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia.  Brain.  2015;138:1484–91. 

24. Anti-NF155 antibodies 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. IgG4 antibodies against NF155 higher cerebrospinal fluid (CSF) proteins and prominent radicular involvement. MRI findings include marked symmetric hypertrophy of cervical and lumbosacral roots. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.  Neurol Neuroimmunol Neuroinflammation. 2015;2:e149. 

25.  Pathologically, there is the absence of a macrophage-mediated demyelinating process. studies suggest that there is the destabilization of septate-like junctions at the paranode, leading to nodal widening and paranodal demyelination causing conduction slowing.  IgG4 antibodies act without fixing complement by blocking the interaction of NF155 with the Caspr /CNTN1 complex.

26. electrophysiology shows marked prolongation of distal motor latencies and minimal F wave latencies as compared to antibody-negative CIDP

27. Anti-CNTN1 antibodies Anti-CNTN1 antibodies are detected in a small proportion of patients with CIDP. The clinical phenotype is older age at onset with the aggressive course, motor predominance with early axonal loss, and poor response to IVIG. Electrophysiological studies have reported decreased motor amplitudes at the onset. 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 “Neuro-renal syndrome” related to anti-contactin-1 antibodies.  Muscle Nerve.  2019;59:E19–21.

28. Anti- Caspr antibodies Neuropathic pain was the most prominent feature. resolution of pain following therapy with rituximab 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    Contactin -Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region. J Neuropathol Exp Neurol. 2016;75:1155–9.

29. 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). Nephrotic syndrome, hematological disorders like Hodgkin's lymphoma, chronic lymphocytic leukemia , and myeloma are also closely associated with pan-NF neuropathies. These patients have an incomplete response to first-line therapies like IVIG and plasma exchange (PLEX), but a more sustained response to rituximab. IgG 1 pan- neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality.  J Neurol Neurosurg Psychiatry.  2021;92:1089–95.

30. 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.

31. Anti- Caspr 2 antibodies Caspr 2 antibodies ,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. Caspr 2 antibody has been linked to neuropathic pain.

32. SIGNIFICANCE OF IgG SUBCLASS 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 . 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. 

33. Treatment The most commonly used first-line therapies for CIDP are IVIG, corticosteroids, and PLEX. Nodopathies are likely to be refractory to first-line therapies for CIDP. Hence, it is important to identify them and treat them early. Querol  et al . 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. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology. 2014;82:879

34. Key points and take home message The final common pathway is the dysfunction/disruption of the excitable axolemma at the nodal region. display a pathophysiological continuum from reversible conduction failure/CB to axonal degeneration. CB is the result of paranodal myelin detachment, nodal lengthening, disruption of nodal Na channels, and disorganized polarization at the axolemma. CB may be reversible without the development of TD (axonal CB) or may progress to axonal degeneration.

35. I n clinical practice, serial electrophysiological studies should be done to document reversible CB without TD or progression of CB to axonal degeneration. Patients with atypical presentations of GBS or CIDP should undergo early testing for nodo-paranodal antibodies. Nodo-paranodopathies are less responsive to first-line therapies like IVIG. But they show a good response to steroids, PLEX, and rituximab. 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. Further data is required to establish the prognostic implications and clinical utility of antibody measurement. With an increasing understanding of the pathophysiological mechanism of antibody production and nodal injury, newer therapies may emerge.

36. REFERENCES Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies. Clin Neurophysiol . 2013;124:1928–34.  JM. Molecular dissection of the myelinated axon. Ann Neurol. 1993;33:121–36.  Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron. 2001;30:385–97. Juxtaparanodal clustering of Shaker-like K+channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol. 2003;162:1149–60.  Ganglioside contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Glia. 2007;55:746–57 IgG anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in Guillain-Barré syndrome. Ann Neurol. 1998;44:202–8. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.  Neurol Neuroimmunol Neuroinflammation. 2015;2:e149.  “Neuro-renal syndrome” related to anti-contactin-1 antibodies.  Muscle Nerve.  2019;59:E19–21.

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