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

6. 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.

8. • 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

9. • 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.

10. • 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.

12. • 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

13. SALTATORY CONDUCTION AT THE NODE

14. • Saltatory 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.

15. 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.

17. • 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.

18. 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.

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

20. • 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.

21. • 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.

24. 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).

25. 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.

26. • 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.

27. 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.

28. • 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.

29. 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.

30. 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.

31. • 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.

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

33. 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.

34. 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.

35. 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.

36. 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.

37. 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.

39. 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.

40. 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

43. 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.

44. • In 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.

45. 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.