JCM 13 05721

Review
Antibody-Mediated Nodo- and Paranodopathies

Valérie Quinot 1, Kevin Rostasy 2 and Romana Höftberger 1,*
1 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna,

1090 Vienna, Austria; valerie.quinot@meduniwien.ac.at
2 Department of Pediatric Neurology, Children’s Hospital Datteln, University Witten/Herdecke,
45711 Datteln, Germany; kevin.rostasy@uni-wh.de

* Correspondence: romana.hoeftberger@meduniwien.ac.at
Abstract: The recent discovery of pathogenic antibodies targeting cell adhesion molecules of the
node of Ranvier has prompted efforts to develop a new classification for a subset of antibody-medi-
ated peripheral neuropathies. These autoimmune nodo- and paranodopathies encompass epitopes
such as neurofascin 155, neurofascin 186, contactin-1, and contactin-associated protein 1, with a high
likelihood of involving additional yet unidentified proteins. So far, the investigation of this subset
of patients was primarily focused on adults, with only rare reports of pediatric cases. Low awareness
among pediatricians and insufficient availability of appropriate diagnostic methods in many labor-
atories may mask a higher pediatric incidence than currently observed. Diagnosis is made by trans-
fected cell-based assays and ELISA to characterize the specific target antigen and antibody subclass
that provides insight into the pathophysiology. Clinical features often resemble those of CIDP or
GBS in adults, whilst in pediatric patients, although rare, an atypical CIDP phenotype has predom-
inantly been reported. Yet, in contrast to classical immune-mediated neuropathies, the clinical
course is usually rapidly progressive, and response to classical first-line therapy often poor. Alt-
hough electrophysiological signs of demyelination are observed, segmental demyelination and in-
flammation are not present on pathological examination. Rather, few neuropathological reports
demonstrate features of axonal neuropathy without signs of true de- or remyelination. This review
aims to summarize recent findings on such nodo- and paranodoneuropathies, shining light on fea-
tures of these disorders in pediatric patients, a still little-explored field with only a few reports cur-
rently present.
Keywords: paranodopathy; nodopathy; neurofascin 155; neurofascin 186/140; pan-neurofascin

Citation: Quinot, V.; Rostasy, K.; contactin 1; Caspr1; CNTN1/Caspr1
Höftberger, R. Antibody-Mediated
Nodo- and Paranodopathies. J. Clin.
Med. 2024, 13, 5721.
https://doi.org/10.3390/jcm13195721 1. Introduction
Academic Editor: Stephen D. Ginsberg Peripheral neuropathies are traditionally classified into primarily axonal and demy-
elinating, with their pathophysiological characteristics delineated by electrophysiological
Received: 7 August 2024
Revised: 12 September 2024
and histopathological features [1]. In 2013, Uncini and colleagues advanced this dichot-
Accepted: 22 September 2024
omy by introducing the term “nodo- and paranodopathy”, which has since been used to
Published: 25 September 2024 describe a group of neuropathies caused by antibodies targeting gangliosides [1]. Shortly
thereafter, the concept was extended to include neuropathies in which the nodes represent
the primarily involved site of pathology, with various defining etiologies including in-
Copyright: © 2024 by the authors.
flammatory, ischemic, toxic, metabolic, and immune-mediated factors [2]. Eventually, an-
Licensee MDPI, Basel, Switzerland.
tibodies targeting peptide structures of the node and paranode including contactin1
This article is an open access article (CNTN1), contactin-associated protein 1 (Caspr1), and different neurofascin (NF)
distributed under the terms and isoforms (NF155, NF186/140) were identified in subsets of patients presenting clinical fea-
conditions of the Creative Commons tures reminiscent of Guillain–Barré syndrome (GBS) and chronic inflammatory demye-
Attribution (CC BY) license linating polyradiculoneuropathy (CIDP) [3–5]. It was, however, quickly observed that
(https://creativecommons.org/license among other features, the clinical phenotype and therapy response differed from that of
s/by/4.0/). GBS and CIDP, ultimately leading the European Academy of Neurology and Peripheral
J. Clin. Med. 2024, 13, 5721. https://doi.org/10.3390/jcm13195721 www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 5721 2 of 25
Nerve Society (EAN/PNS) guidelines to introduce a new diagnostic category in 2021 and
coining the term “autoimmune nodopathy” (AN) [6].
Highlighting the importance of this new categorization, the number of studies aimed
at further characterizing clinical and pathophysiological aspects of AN in detail has in-
creased exponentially, with a growing number of reviews emerging consequently [7–10].
Although certain features, including a tendency to gender-specific incidences, age-relat-
edness, and pathognomonic symptom constellations in specific ANs, have already been
summarized in detail, other aspects remain underinvestigated. In this review, we provide
an updated summary of clinical presentation, pathophysiology, diagnostics, and therapy,
as well as their implications for clinical practice, with a focus on pediatric features of ANs
in each section where possible, thereby drawing attention to a subgroup of patients who
strongly benefit from increased awareness among physicians.
2. Anatomy of the Node of Ranvier and Its Antibody Epitopes

In the peripheral and central nervous system (PNS and CNS), myelinated nerves are
arranged into uniquely defined regions, i.e., nodes of Ranvier, and adjacent paranodal and
juxtaparanodal junctions, each characterized by different compositions of cell adhesion
molecules (CAMs), signal transduction proteins, and cytoskeletal scaffolding components
[11]. Densities of a variety of ion channels found in these domains vary respectively,
thereby ensuring the propagation of action potentials via saltatory conduction. Nodes—
the uninsulated myelin-sheath-free regions of the axolemma—comprise regions with a
high density of voltage-gated sodium channels. Recruitment and stabilization of these ion
channels are propagated by the 186-kDa isoform of neurofascin NF186 located on the ax-
olemma, which, in the PNS, clusters with the Schwann cell microvilli-secreted protein gli-
omedin extracellularly, whilst interacting with nodal scaffolding proteins such as ankyrin
G and βIV-spectrin in the axonal cytosol [11,12].
At the paranode, a further isoform of neurofascin, NF155, expressed on the terminal
myelin loops of Schwann cells in the PNS and oligodendrocytes in the CNS, interacts with
heterodimers of Caspr1 and CNTN1 [11]. Heterodimerisation occurs at the axonal endo-
plasmic reticulum, with subsequent complexes sent to the paranode directly, ultimately
forming septate-like junctions that ensure myelin insulation ibid [13,14].
Similarly, at the juxtaparanode, complexes made up of contactin-associated protein
2 on the axolemma, and contactin 2 alias transient axonal glycoprotein 1 (TAG1), anchored
on both glial and axonal membranes interact with high densities of voltage-gated potas-
sium channels involved in repolarization of the membrane potential [15,16]. Moreover,
gangliosides located in all three domains and on both glial and axonal membranes, as well
as disintegrin and metalloproteinases (ADAMs) and a plethora of further molecules, in-
cluding Nr-CAM, syndecan-3/4 and laminins, are likewise involved in structure and func-
tion of these domains [11].
Numerous studies have sought to identify specific nodal, paranodal, and jux-
taparanodal proteins involved in neuropathies, recognizing the likelihood that additional,
yet unidentified proteins contribute to these conditions. Indeed, various candidates have
been identified, such as anti-gliomedin antibodies in multifocal motor neuropathy [17]
and anti-moesin antibodies in cytomegalovirus-related Guillain–Barré Syndrome [18].
This review, however, focuses on the most common epitopes of the nodal and paranodal
regions, i.e., NF155, NF186/140, CNTN1, and Caspr1.
3. Antibody Detection
The updated EAN/PNS CIDP diagnostic guidelines from 2021 recommend testing
for nodal and paranodal antibodies in the serum of patients fulfilling the criteria of CIDP,
initially presenting with acute or subacute aggressive onset, previously diagnosed as GBS
or acute onset-CIDP, as well as in patients with a distinct set of symptoms including low-
frequency tremor, ataxia, cerebellar symptoms, and predominant distal weakness [6].
Moreover, certain antibody-specific symptoms may already hint at the respective AN
J. Clin. Med. 2024, 13, 5721 3 of 25
prior to antibody testing (see individual ANs). Respiratory failure, cranial nerve involve-
ment, nephrotic syndrome, strongly elevated CSF protein levels and resistance to the
standard intravenous immunoglobulin (IVIg), and corticosteroid therapy should also
prompt antibody diagnostics [6].
Antibodies in question should be tested in serum via cell-based assays (CBAs) using
mammalian expression vectors encoding human epitopes. However, some studies have
shown false positive antibody status on fixed cells using tagged vectors with individuals
harboring antibodies directed against specific tags, as was observed with myc-DDK-
tagged NF155 plasmids in NF155 testing [19]. Confirmation of the results with the en-
zyme-linked immunosorbent assay (ELISA) and/or teased-nerve immunohistochemistry
is also strongly recommended, and CBA or ELISA may also be used for isotype detection
[6,19]. In addition, further binding experiments conducted on myelinating neuron cul-
tures may be helpful in distinguishing distinct binding clusters [20]. Repetition of testing
may be of use if patients are initially seronegative but involvement is clinically suspected
and the sample is taken after treatment or in a remission phase [21,22]. While CSF param-
eters may be supportive of diagnosis, the value of antibody testing herein is yet to be de-
termined [6,21,23].
However, not all laboratories have equivalent resources for antibody testing. Moreo-
ver, as the initial detection of these antibodies and the assumed clinical correlations were
based on findings obtained using CBAs, in part combined with ELISA and teased nerve
fibers, it is important to consider that results yielded using diagnostic methods other than
those mentioned above may differ in comparability [21]. This issue is of particular rele-
vance regarding studies using Western blots, as conformational epitopes may not be iden-
tified, and other irrelevant domains may instead exhibit reactivity. In addition, in-house
methods may lead to inter-laboratory variability, and the range and composition of anti-
gens tested may, in part, account for differences in profiles and frequencies [20,21]. More-
over, CBAs are time- and resource-intensive and thus only available in certain specialized
laboratories. Alternative assays, including a novel immune-dot assay, have therefore been
proposed; however, larger cohorts and multicenter studies are needed to validate these
methods [24].
4. Neurofascin 155
NF antibodies were originally identified in immune-mediated axonal injury of pa-
tients with multiple sclerosis [25] and, shortly thereafter, described in a small cohort of
patients with CIDP [26]. However, since then, a growing body of evidence has suggested
a distinct clinical phenotype and disease course in patients harboring these antibodies.
Antibodies recognizing NF155, the glial isoform of NF, are associated with a subacute to
chronic onset and progressive symptoms reminiscent of distal CIDP with symmetric, pre-
dominantly distal weakness, sensory loss, and gait ataxia as well as tremor are character-
istic for anti-NF155-mediated AN [19,27–29]. Yet, in contrast to CIDP, patients affected are
predominantly males in young adulthood, with an increasing number of reports of pedi-
atric cases resembling the adult clinical phenotype (see Table 1). The youngest case cur-
rently reported in detail encompasses the history of a 2-year and 3-month-old female pa-
tient presenting with progressive lower limb weakness for a period of 6 weeks and initially
diagnosed with GBS [30].
J. Clin. Med. 2024, 13, 5721 4 of 25
Table 1. Description of clinical, paraclinical (electrophysiology and magnetic resonance imaging), and laboratory data in published studies on anti-neurofascin155-
seropositive pediatric patients.
CSF-Protein Record of
Age Antibody Subtype/ Testing Titer at Duration Initial
Reference Sex Onset Clinical Features Electrophysiology MRI Levels Therapy (Response) Prior
(years) Epitope Subclass Method Diagnosis (months) Diagnosis
(mg/dL) Infection
brain: multifocal
prolonged distal corticosteroids (CNS +,
WML, gad.
Kawamura progressive weakness of latency, CV PNS -), IVIg (+), PE (+),
acute to CCPD, enhanced; cauda
et al. (2013) 16 f NF155 N/A ELISA, CBA N/A N/A lower limbs, sensory slowing, CB, 205 Azathioprine + low- N/A
subacute CIDP equina: gad.
[23] ataxia, hyporeflexia prolonged F-wave dose corticosteroids (+,
enhanced,
latency stable)
hypertrophy
Kadoya et muscle weakness in lower
15 m NF155 IgG4 ELISA, CBA 1:800 N/A N/A DADS N/A N/A 199 N/A N/A
al. limbs
(2016) 16 m NF155 IgG4 1:800 N/A >50 CIDP gait ataxia, tremor N/A N/A 366 IVIG (-) N/A
dysesthesia in lower
[29] 18 m NF155 IgG4 1:1600 N/A 14 DADS N/A N/A 135 IVIG (-) N/A
limbs
distal predominant
prolonged distal hypertrophy of the
weakness of the lower
Fujita et al. Flow and F-wave cervical and IVIg (-), Methyl-
16 m NF155 N/A N/A subacute >28 CIDP limbs, sensory ataxia, 412 N/A
(2018) [31] cytometry latencies, decreased lumbosacral prednisolone (+)
postural tremor,
CV roots/plexus
hyporeflexia
Burnor et IgG4 > IgG1 inability to walk,
IVIg and apheresis (?),
al. (2018) 13 f NF155 and IgG2; CBA 1:200 chronic >6 CIDP multifocal numbness, N/A N/A N/A N/A
Prednisone (+)
[32] IgM areflexia
Cortese et lower > upper limb
al. (2020) 13 f NF155 IgG4 ELISA, CBA N/A subacute N/A CIDP weakness, sensory ataxia, N/A N/A N/A IVIg (+), steroid (+) N/A
[33] tremor,
ataxia (5/5), neuropathic
pain (4/5), tremor (3/5; 2 1/5
De Simoni 2 panNF, IgG4
7.9 (3– 3:2 Flow CNTN1+ and 1 panNF+) 292.4 (75– (gastro-
et al. (2020) 1 NF155, predom., N/A chronic N/A CIDP N/A N/A IVIG (-/partial)
11) (m:f) cytometry cranial nerve involvement 619) intestinal
[34] 2 CNTN1 (100–75%)
and optical neuritis in 1 infection)
CNTN1+
hypertrophy of
Ogata et al. Flow lumbo-sacral and
13 m NF155 IgG4 N/A N/A N/A DADS N/A N/A 205 N/A N/A
(2020) [35] cytometry cervical nerve
roots
J. Clin. Med. 2024, 13, 5721 5 of 25
symmetric proximal and

distal muscle weakness,
Dong et al. IgG4 > IgG2 hyporeflexia, tremor, not specified for not specified for
16 f NF155 CBA N/A chronic 21 CIDP N/A 134.19 N/A
(2022) [36] and IgG1 sensory ataxia, autonomic individual case individual case
symptoms, cranial nerve
involvement

10 m NF155 IgG4 > IgG2 N/A chronic 48 CIDP N/A 184.92 N/A
hyporeflexia, tremor,
sensory ataxia

IgG4 and
15 m NF155 N/A chronic 7 CIDP hyporeflexia, tremor, N/A 287.28 N/A
IgG2
paresthesia, sensory
ataxia
progressive muscle
PE (relapse); RTX
weakness, distal
initially signs of (modest +), AI+,
Ren et al. numbness, dysphagia,
14 f NF155 IgG4 CBA 1:10, later subacute >12 CIDP demyelination and unremarkable 182 corticosteroids (+ but cold
(2023) [37] hypoesthesia,
1:1000 axonal damage side effects),
hyporeflexia, tremor,
Telitacicept (+)
ataxia
abnormal sensory
Harris et progressive lower limb and motor 1 year after onset
IgG4 and IVIg (-), Prednisolone
al. (2023) 2 f NF155 CBA 1:800 subacute >10 GBS weakness, shoulder girdle responses, absent mild cauda equina 190 N/A
IgG1 > IgG2 (+)
[30] weakness and prolonged F- root enhancement
waves
weakness of limbs, signs of
Zhang et diffuse thickening
sensory dysfunction, demyelination and
al. (2024) 16 m NF155 N/A CBA N/A acute 5 CIDP of the lumbosacral 352 IVIg (-), PE (+), RTX (+) N/A
ataxia, cranial neve axonal damage, CV
[38] nerve roots
involvement (facial) reduction,
prolonged DML,
weakness of limbs,
CMAP amplitude
15 m NF155 N/A N/A chronic 3 CIDP sensory dysfunction, N/A 337 PE (+) N/A
reduction in both
ataxia,
patients
Abbreviations: CB = conduction block; CBA = cell-based assay; CCPD = combined central and peripheral demyelination, CIDP = chronic inflammatory demye-
linating polyneuropathy; CMAP = compound muscle action potential; CNTN1 = contactin1; CV = conduction velocity; DML = distal motor latency; DADS = distal
acquired demyelinating symmetric neuropathy; ELISA = enzyme-linked immunosorbent assay; gad. = gadolinium; GBS = Guillain–Barré syndrome; IgG = Immu-
noglobulin G; IVIg = intravenous immunoglobulin; N/A = not available; NF155 = neurofascin 155; panNF = pan-neurofascin; PE = plasma exchange; RTX = rituxi-
mab; + = positive; (+) = good response; (-) = poor response.
J. Clin. Med. 2024, 13, 5721 6 of 25
Involvement of cranial nerves has been increasingly described, and further symp-
toms including autonomic dysfunction, neuropathic pain at onset, as well as papilledema
are found in some individuals [19,36,39–41]. Furthermore, dysarthria, dysphagia, and cer-
ebellar ataxia, symptoms reminiscent of brainstem encephalitis, have also been reported
in patients with NF155-antibodies, overall hinting at potential CNS involvement [23,39].
In this context, Japanese studies have reported NF155 antibodies in patients exhibit-
ing combined central and peripheral demyelination [23], although attempts to replicate
these findings in Caucasian populations have yielded inconsistent results [42]. Moreover,
Devaux and colleagues identified central demyelination in a subset (8%) of anti-NF155-
IgG4-seropositive patients originally diagnosed with CIDP [43]. However, no clear link
between antibody isotype and CNS involvement was found. Other studies that had de-
tected anti-NF155-antibodies in the CSF, albeit at lower titers than in serum, in combina-
tion with other laboratory parameters have suggested blood–brain barrier disruption as
mechanism for the presence of the antibodies in the CSF [19]. Notwithstanding, the exist-
ence of anti-NF155 antibodies in the CSF could provide a potential explanation for cere-
bellar symptoms in NF155-AN, although further studies examining CSF are needed to
support this hypothesis [19].
4.1. Pathophysiology
Immunoglobulins targeting the glial NF isoform 155 located on myelin loops of
Schwann cells and oligodendrocytes make up a large fraction of antibodies mediating AN
[33,39]. Although the neuronal isoform 186 represents a co-target in a fraction of cases (see
pan-NF), a notable number of patients harbor antibodies specific for NF155, thereby indi-
cating the extracellular fibronectin type III (FnIII) domain 3, unique to NF155, as epitope
in this AN [44,45].
The predominant immunoglobulin subclass is IgG4 [27,46]. Because of its structural
inability to bind to C1q, the initial step in complement activation, and its low affinity for
Fcγ receptors, it is assumed that IgG4-induced-NF155-AN is likely caused by the destruc-
tion of the paranodal complex [46,47]. In line with this, Koike et al. observed the absence
of complement deposits at the paranodes, where deposits of NF155 IgG4 were identified
[48]. Moreover, unlike classical, functionally monovalent IgG4 that recognize antigen with
one Fab arm alone, a study conducted by Jentzer et al. demonstrated bivalency of anti-
NF155 IgG4 as a pathogenic trait in animal models [49].
Further IgG subclasses, as well as IgM, have also been reported in a subset of patients
[26,28,30,50]. Moreover, combinations of IgG4 and other immunoglobulins are frequently
observed, and single cases of patients harboring IgG1, IgG2, and IgG3 titers alone have
also been observed with slightly deviating disease courses and therapy responses in some
studies [28,30,36,39]. In contrast, Delmont et al. found no significant correlation between
demographic, clinical, or treatment data and antibody isotypes, with the exception of an
older age at onset in patients with IgG4 in combination with other IgG isotypes versus
IgG4 alone in younger patients (44a (42–47) versus 60a (54–67), p = 0.006) [50]. Differences
in CSF protein concentration and outcome between IgG4 and IgG4-negative/IgM-NF155
patients have also been reported [41]. Yet, to date, the underlying mechanism and clinical
significance of this observation remain uncertain. Although a potential immunoglobulin
class and subclass switch has been proposed, in a longitudinal assessment of AN (up to
>20a) serum, IgG switch was not observed [39]. Interestingly, a number of pediatric cases
harboring IgG2 have been reported, albeit the exact relevance is currently unclear [30,36].
In general, further studies are needed to elucidate phenotypic correlations of immuno-
globulin class and subclass, potentially shedding light on pathophysiology, and thereby
providing treatment guidance and prognostic value.
J. Clin. Med. 2024, 13, 5721 7 of 25
4.2. Etiology
Although specific etiological factors of NF155-AN remain to be elucidated, an asso-
ciation between specific human leukocyte antigen (HLA) allele DRB1*15 (15:01 or 15:02)
and patients with NF155-IgG4-AN compared with CIDP and controls has recently been
identified, hinting at an HLA class II-restricted T-cell involved pathomechanism
[19,51,52]. Higher incidences in East Asian [38,46] versus Western cohorts [50] point to this
HLA association [51]. Moreover, only subtle clinical differences between HLA-
DRB1*15:01 and HLA-DRB1*15:02 carriers have been identified, including a tendency of
younger age in patients with DRB1*15:02 (45.2 ± 20.5 vs. 30.6 ± 14.6, p = 0.14) and more
frequent CNS involvement in HLA-DRB1*15:02-DQB1*06:01 compared with HLA-
DRB1*15:01-DQB1*06:02 carriers [19,51].
Prior infections have been reported in single patients, posing the question of a mo-
lecular mimicry-induced mechanism similar to that of GBS [30,33,50].
4.3. Pathology
Ultrastructural studies on NF155-IgG4-AN have so far identified significant widen-
ing of the nodes and periaxonal spaces, along with loss of transverse bands, thereby re-
sulting in detachment of myelin loops and, ultimately, in disruption of the paranodal bar-
rier [48,53]. Multifocal fiber loss, characterized by diminished large, myelinated nerve fi-
bers, and varying overall reduction in myelinated fibers as well as subperineurial edema
were also found in a subset of patients [41,46,48,53,54]. Onion bulbs are generally not ob-
served. One study showed increased rates of segmental demyelination in biopsies of pa-
tients with NF155-IgG4, most often found in fascicular sciatic biopsy [41], while another
group observed paranodal demyelination in <10% of teased myelinated nerve fibers in 2
biopsied patients [46]. While macrophage or inflammatory cells are usually scarce, high-
lighting a macrophage-independently mediated mechanism contrary to CIDP [48,54],
Shelly et al. describe single endoneurial and epineurial inflammatory infiltrates identifia-
ble in 81% (9/11), and one more severely affected patient showing a more widespread
infiltration of epineurial mononuclear cells proximally than distally [41]. Myelin ovoids,
providing evidence for axonal destruction, have also been identified, along with myelin
thickening and variable degrees of paranodal separation in teased fiber preparations
[41,48].
4.4. Paraclinical and Laboratory Findings

Paraclinical tests and laboratory parameters usually precede antibody testing and
may aid the diagnosis of AN [6]. Electrophysiological results of NF155-AN show features
consistent with demyelinating changes, commonly showing slowing of motor conduction
velocities, prolonged distal motor latency, prolonged or absent F-waves, temporal disper-
sion, prolonged distal compound action muscle potential (CMAP) duration, and conduc-
tion block, with most patients meeting the EAS/PNS demyelinating electrophysiologic di-
agnostic criteria for CIDP [41,46,55].
Magnetic resonance imaging findings often show marked symmetric hypertrophy of
cervical and lumbosacral roots/plexuses, with root diameters hinting at a positive corre-
lation of disease duration, but this may be unremarkable [27,38,46]. A similar trend was
observed in cranial nerve involvement, specifically the trigeminal nerves, although the
clinically suspected involvement of optic nerves was not mirrored on MRI in one study
investigating cranial nerve involvement [35].
CSF findings may also deviate from those found in CIDP. Patients with NF155-AN
show significantly elevated CSF protein levels compared with seronegative CIDP patients
[27,29,38]. In addition, Ogata et al. recently identified a distinct intrathecal chemokine pro-
file in NF155-positive AN with a CIDP-like phenotype compared with classical CIDP, i.e.,
interleukin (IL)-13, CC motif chemokine ligand/eotaxin, and CXC motif chemokine ligand
8/IL8, with marked elevations of Th2-type cytokines [56]. The authors suggested that this
J. Clin. Med. 2024, 13, 5721 8 of 25
increase in proinflammatory cytokines in the CSF may lead to disruption of the blood–
nerve barrier at nerve roots, resulting in nerve edema and hypertrophy observed upon
histology and MRI findings, respectively [35,56]. Furthermore, as mentioned above, some
studies have found positive antibodies in CSF, with the significance of this observation
not yet clear [19]. However, antibody titers are lower than in the periphery, and combined
with the absence of oligoclonal bands, intrathecal antibody synthesis seems unlikely [19].
Moreover, lymphocytic pleocytosis is rare and, in most cases, instead, normal to discretely
elevated cell count is mostly observed [19,27].
Discrepant data exist on the clinical correlation of antibody titers, with a recent study
including a large cohort of NF155 AN showing a correlation of anti-NF155 antibody titers
with modified Rankin scale results (r = 0.41, p = 0.004) and serum neurofilament when
follow-up anti-NF155 antibody titers were evaluated using baseline titers as a reference,
thereby illustrating potential biomarkers for monitoring disease activity [19,49].
4.5. Therapy
In contrast to CIDP, the response to IVIg in NF155 IgG4-mediated AN is usually poor,
while treatment with B-cell depleting rituximab has a higher response rate in many pa-
tients, a phenomenon not uncommon in IgG4-mediated diseases [19,38,57]. In addition, a
growing number of studies and case reports describe relapses after the initial response to
therapy [27,39,57–59]. In this context, antibody subclass characterization may also play an
important role in therapy guidance, as IgG3 > IgG1 > IgG2 antibodies activate complement
and have been identified in a fraction of NF155-AN that might provide a rationale for a
complement-targeting therapy in individual cases [21].
5. Neurofascin 186
The first observations of NF186 antibodies were reported by Devaux and colleagues
in 2012 in patients diagnosed with GBS and CIDP, although not screened for cooccurrence
with NF155 [5]. Since then, single descriptions of the presence of NF186 antibodies alone
in patients with different clinical phenotypes have been reported [17,30,44], with larger
cohorts only recently described, mainly in Chinese cohorts [32,60,61]. Age of onset is usu-
ally older than in NF155-AN, and, so far, cases of patients under the age of 20 are rare
[30,32,61]. Two such cases entail 2-year-old male patients presenting with acute to sub-
acute ascending weakness of the lower limbs and evidence of bulbar palsy in one (see
Table 2).
J. Clin. Med. 2024, 13, 5721 9 of 25
Table 2. Description of clinical, paraclinical (electrophysiology and magnetic resonance imaging), and laboratory data in published studies on anti-neurofas-
cin186/140-seropositive pediatric patients.
Age Antibody Subtype/ Testing Titer at Duration Initial Therapy
Reference Sex Onset Clinical Features Electrophysiology MRI Levels Prior
(years) Epitope Subclass Method Diagnosis (months) Diagnosis (Response)
(mg/dL) Infection
conduction diarrhea
slowing, CMAP reported 3
Carrera- IVIg (mild +,
1, relapse 1 weakness and areflexia of amplitude days prior
Garcia et al. 2 m NF186/140 N/A CBA N/A acute CIDP N/A 125 relapse), methyl-
year later lower limbs decrease, to
(2019) [62] prednisolone (+)
prolonged distal symptom
latencies onset
abnormal sensory
enhancement in
progressive weakness of and motor
Harris et al. the cauda
2 m NF186/140 IgG2 CBA N/A chronic >4 N/A lower and upper limbs, responses, 105 IVIg (+) N/A
(2023) [30] equina nerve
evidence of bulbar palsy demyelinating
roots
changes
Abbreviations: CBA = cell-based assay; CIDP = chronic inflammatory demyelinating polyneuropathy; CMAP = compound muscle action potential; IgG = Immu-
noglobulin G; IVIg = intravenous immunoglobulin; N/A = not available; NF186 = neurofascin 186/140; (+) = good response.
J. Clin. Med. 2024, 13, 5721 10 of 25
Similar to NF155-AN, reports on clinical data of NF186-AN describe sensory motor

polyneuropathy similar to GBS and CIDP. However, it must be noted that in earlier stud-
ies describing the presence of NF186, epitope distinction between NF186 and NF155 was
not performed or was not explicitly described, rendering cross-study comparisons chal-
lenging [5,17,30].
Unlike NF155 AN, however, tremor is usually not observed, and onset is more often
acute to subacute [44,61]. Although an NF186-AN-specific phenotype has not yet been
elucidated, as with pan-AN, rare cases of glomerulosclerosis have been identified [44,63].
Furthermore, in a larger cohort, CNS involvement was described in approximately half of
the patients, characterized by dizziness, impairment of vision, cranial nerve involvement
and headache, as reported by Xie et al. [60], while in another study, signs of central demy-
elination on imaging were only present in one patient with concomitant CV2 antibodies
[64].
Antibodies targeting the transmembrane protein NF186 bind to the extracellular Ig
domains common to all NF as well as the isoform NF140 predominantly expressed in early
development [32,44,65]. Older animal studies have indicated direct antibody pathogeneity
in experimental autoimmune encephalitis models primed with human NF186, showing
exacerbation of axonal injury and disease severity. Moreover, in NF186-knock-out mice,
nodal disorganization was observed with loss of nodal Nav channels and AnkG enrich-
ment, resulting in significantly reduced nerve conduction velocity [12]. In another animal
study using spatiotemporal ablation, post-natal loss of NF186 resulted in gradual, pro-
gressive nodal destabilization and axonal degeneration in transgenic mice, alluding to a
temporal component [66]. Indeed, ultrastructural observations of a patient with a CIDP-
like phenotype also showed severe disorganization at an advanced stage, yet the exact
mechanism and relevance are currently unknown [61].
Although IgG4 has been identified as a predominant subclass in many studies, find-
ings from more recent cases show otherwise [30,36,61]. While Burnor et al. identified the
presence of NF186-IgM in five patients with a CIDP-like phenotype, with a single patient
showing additional low titers of IgG4 antibodies [32], Xie et al. found all three antibody
classes in the majority of the cases [60]. It must be noted, however, that antibody isotype
characterization has only been performed in single studies, and findings vary substan-
tially, possibly because of in-house laboratory parameters [30,36,61,67].
5.2. Pathology
To date, only single reports describing the histopathological changes in NF186 exist
[61,68]. A biopsy of a patient with NF186 antibodies reported by Liu et al. revealed a se-
vere reduction in large and small myelinated fiber density in the absence of onion bulb
formation [61]. T-cell, B-cell, and macrophage infiltrates were not observed. On ultrastruc-
tural examination, the extension of paranode length and fusing of paranode loops was
noted. Vallat et al. described ultrastructural changes in detail in a patient with NF186;
however, reactivity to NF155 was also noted and is therefore discussed in further detail in
the section below [68].

Electrophysiological studies of patients with NF186-AN have revealed signs of de-
myelination characterized by reduced conduction velocity and axonal loss, which may
occur both coincidingly or independently [30,60,61]. Conduction blocks have also been
reported [60]. F-wave and distal motor latency that are prolonged but shorter than in
NF155-AN have been noted [61].
Abnormalities in brachial plexus MRI were rare in one study [61], whilst the pediatric
patient described by Harris et al. revealed enhancement in the nerve roots of the cauda
J. Clin. Med. 2024, 13, 5721 11 of 25
equina [30]. Increased T2-weighted signals in the cerebellum, cerebral white matter, and
brain stem, as well as in the meninges and spinal cord, have been described in single cases
with CNS involvement [60].
CSF testing has so far revealed elevated protein levels in a large proportion of patients
(75%) [61] in addition to WBC count in patients with CNS involvement versus PNS man-
ifestation alone in a study by Xie et al. [60].
5.4. Therapy
Varying response rates to IVIg treatment possibly attributable to the immunoglobulin
subclass, in combination with corticosteroids, have so far been reported, although leading
to improvement in some cases and, again, potentially mirroring the relevance of the anti-
body subclass [30,32,61,63]. The pediatric patient described by Harris et al. responded well
to IVIg therapy but relapsed at 3 months, following subsequent treatment with cortico-
steroids with initial improvement, and experienced yet another relapse at around 8
months and only slow improvement thereafter [30]. Therapy with rituximab has so far
shown a good response [61].
6. Pan-Neurofascin
Pan-NF-AN represents a rare type of AN presenting with the following distinct clin-
ical phenotype: patients are predominantly male, >60a with an acute onset, rapidly as-
cending symmetric sensorimotor weakness, reminiscent of GBS, and not uncommonly re-
sulting in tetraplegia [69,70]. In contrast to NF155-AN, often characterized by a milder
disease phenotype and younger age of onset, tremors and ataxia manifest less frequently
[70]. Furthermore, pan-NF has a higher morbidity and mortality rate than NF155-AN [67].
In addition, cranial nerve involvement and autonomic instability with respiratory failure,
as well as neuropathic pain, are also often observed [70]. Moreover, nephrotic syndrome,
as mentioned above, is thought to be caused by the expression of NF186 in the renal glo-
meruli and represents a frequently cooccurring symptom of pan-NF-AN [69,71]. Pediatric
reports are rare and clinically grossly resemble the adult phenotype (see Table 3).
J. Clin. Med. 2024, 13, 5721 12 of 25
Table 3. Description of clinical, paraclinical (electrophysiology and magnetic resonance imaging), and laboratory data in published studies on anti-pan-neurofas-
cin-seropositive pediatric patients.
Age Antibody Subtype/ Testing Titer at Duration Initial
Reference Sex Onset Clinical Features Electrophysiology MRI Levels Therapy (Response) Prior
(years) Epitope Subclass Method Diagnosis (months) Diagnosis
(mg/dL) Infection
Delmont et ELISA, NF186 1:1000,
weakness of lower demyelinating
al. (2017) 2 m panNF IgG4 > IgG2 Western NF140 1:2000, subacute >5 CIDP N/A N/A IVIg (+), steroids (-) 0
limbs, hyporeflexia changes, CV
[44] blot, CBA NF155 1:2000
Cortese et lower limb
al. (2020) 2 m panNF IgG3 ELISA, CBA N/A subacute N/A CIDP weakness, gait N/A N/A N/A IVIg (+) N/A
[33] instability
ataxia (5/5),
neuropathic pain
De Simoni 2 panNF, 1 IgG4 (4/5), tremor (3/5; 2 1/5 (gastro-
7.9 (3– 3:2 Flow 292.4 (75–
et al. NF155, 2 predom., N/A chronic N/A CIDP CNTN1+, 1 panNF+) N/A N/A IVIg (-/partial) intestinal
11) (m:f) cytometry 619)
(2020) [34] CNTN (100–75%) CN involvement and infection)
optical neuritis in 1
CNTN1+
enhancement in
progressive ataxia, 230 tick bite 10
Harris et bilateral CN III, IVIg (initial +,
weakness of lower demyelinating (initially); days prior
al. (2023) 5 m panNF IgG2 CBA N/A acute >7 CIDP cervical root and response reduced
limbs, changes 470 (follow to symptom
[30] cauda equina nerve during relapses)
areflexia up 5 weeks) onset
root
initially
GBS
progressive lower unremarkable
(initally),
5 m panNF IgG2 N/A subacute >48 limb weakness and except from unremarkable 52 IVIg (+), RTX (+) N/A
CIDP
areflexia absent F-wave
(reclassified)
responses
IVIg and methyl-
prednisolone (-), RTX
Broers et severe muscle and steroids (initial +
IgG3 > IgG1
al. (2024) 3 m panNF CBA IgG 1:1600 acute N/A GBS weakness, ataxia, N/A N/A elevated with relapse after 2 N/A
and IgG2
[39] pain months); long-term
RTX, PE and
cyclophosphamid (+)
Abbreviations: CBA = cell-based assay; CIDP = chronic inflammatory demyelinating polyneuropathy; CN = cranial nerve; CNTN1 = contactin 1; CV = conduction
velocity; ELISA = enzyme-linked immunosorbent assay; GBS = Guillai–Barré syndrome; IgG = Immunoglobulin G; IVIg = intravenous immunoglobulin; N/A = not
available; NF155 = neurofascin 155; panNF = pan-neurofascin; PE = plasma exchange; RTX = rituximab; + = positive; (+) = good response; (-) = poor response.
J. Clin. Med. 2024, 13, 5721 13 of 25
Pan-NF antibodies co-target the glial NF isotype NF155 and the neuronal isotype
NF186, both expressed in adult nodes, with prevalent reactivity to NF186 [44]. Six immu-
noglobulin-like domains, common to all NF-isoforms, represent the main epitopes of pan-
NF antibodies, thereby permitting direct access to the node of Ranvier, as well as the FnIII
domains 3 and 4, thought to be unique to NF155 [32,44,67]. As briefly mentioned above,
pan-NF antibodies were first described in a small cohort of patients with MS by Mathey
et al. in 2007, and their direct pathogeneity, i.e., inducible axonal damage, impairment of
neuronal conduction, and clinical exacerbation, thereby assumed [25]. Direct access to the
node, likely due to the nodal NF186 epitope, has been demonstrated and thought to be of
pathophysiological relevance [67]. Moreover, a recent animal study investigating the in-
traneural passive transfer of pan-NF-IgG3 demonstrated an increased nodal length at the
nerve roots of rats [72].
As immunoglobulin subclasses are found in various constellations, it is yet unclear
which subclass plays the predominant pathogenic role. Initially, IgG3 and IgG4 were
thought to represent the predominant subclass as these immunoglobulins were described
in different reports [44,70]. Since then, however, IgG1 in patients with a severe disease
course has been reported [69], as well as the cooccurrence of IgG2 in various cohorts [32].
Furthermore, the presence of IgG1 and IgG3—immunoglobulin subclasses that activate
complement more strongly than IgG2 and IgG4, which have only limited complement
activation potential—has been reported to lead to a more severe course and a relatively
better response to IVIg therapy [69,70]. Although complement binding assays using pa-
tients’ derived pan-NF IgG3 have revealed complement deposition, a complement-medi-
ated aggravation of the disease, rather than a complement-dependent cause, has been pro-
posed as in vitro preincubation experiments have demonstrated a directly pathogenic role
of pan-NF-antibodies, in the absence of humoral complement factors, and data on subclass
and course deviate among studies [35,62,68,70]. Therefore, it has also been argued that the
major phenotype determinant is the epitope itself, rather than the IgG subclass [70]. Nat-
urally, further studies looking at long-term profiles are needed for elucidation.
Interestingly, a recent case study identified pan-NF antibodies predominantly of the
IgG2 subclass in two five-year-old male patients presenting with GBS- and CIDP-like
symptoms with partial response to IVIg and steroids and prolonged recovery of up to 4
years [30]. Class switching, as observed in CNTN1-AN, and general subclass differences
in adults and children may offer an explanation [30,67]. Indeed, Stengel et al. observed
transiently detectable minor titers of IgG4 during the peak of IgG3 throughout the disease
course of a severely affected patient with tetraplegia and near to locked-in syndrome [70].
In contrast, in a longitudinal assessment, Broers et al. reported the presence of IgG1, 2,
and 3, with predominance of the latter in a 3-year-old toddler with a severe and prolonged
disease course without observing a subclass switch [39].
6.2. Pathology
Only a few histopathological and ultrastructural reports of patients with pan-NF an-
tibodies exist. Varying degrees of axonal loss have been reported, in the absence of cellular
infiltration, inflammation, and onion-bulb formations [68,69,73]. In contrast, a biopsy
specimen of a patient with a fulminant disease course showed single inflammatory T-cell
infiltrates and increased floridity [74]. While segmental demyelination and signs of par-
anodal retraction or detachment were absent in two patients reported with IgG1 pan-NF
antibodies [69], discrete demyelinating changes and single clusters of regeneration in a
patient with pan-NF antibodies predominantly of the IgG3 subclass have also been de-
scribed [68,74]. Ultrastructural analysis of a patient presenting with the latter and catego-
rized as NF186-positive, although NF155 antibodies were also identified, demonstrated a
varying degree of loss of Schwann cell microvilli as well as damage to the node of Ranvier,
J. Clin. Med. 2024, 13, 5721 14 of 25
providing indirect evidence of pathogenicity, contrary to the normally appearing par-

anodal regions [68].

Electrophysiological findings demonstrate slowing of conduction velocity and con-
duction block without temporal dispersion, suggestive of nodal pathology [69,73]. Addi-
tionally, nerve inexcitability was reported in one patient two weeks after onset [69].
Throughout the disease course, signs of severe axonal degeneration with unrecordable
sensory nerve action potentials (SNAPs) and CMAP have been described [69,73,75]. More-
over, electromyography may show abnormal spontaneous activity with fibrillation and
positive sharp waves [74].
So far, reports on imaging in patients with pan-NF AN are scarce, with current de-
scriptions including no apparent alterations on MRI in approximately 50% of patients and
plexus and/or root abnormalities as well as in the cauda equina in the other half [30,69,74].
CSF protein levels may vary, with reports of mild elevation at onset and more severe
albuminocytologic dissociation in other cases, while cell count is within the normal range
[30,69,73,74]. Antibody titers may be found in the CSF, though lower than in serum, and
oligoclonal bands have not been observed, again, suggesting a blood–brain barrier leakage
rather than intrathecal synthesis [70,73,74]. Further serological findings include elevated
levels of serum neurofilaments, which are thought to correlate with severity and outcome
intra-individually [67].
6.4. Therapy
The administration of IVIgs may at first lead to improvement in some patients, in
both adults and children; however, fulminant relapse has been observed within a few days
or weeks [30,67,68]. Moreover, Harris and colleagues reported gradual and slow recovery
upon treatment with IVIg in two pediatric cases with IgG2 antibodies, with relapse of
symptoms in therapy absence in one of the patients [30]. Similarly, response to plasma-
pheresis is poor, while patients treated with rituximab have shown significant improve-
ment [67]. Moreover, Fels et al. report improvement in clinical symptoms in a patient with
predominant IgG4 pan-NF antibodies upon therapy escalation with the proteasome in-
hibitor bortezomib, thereby aiming at the entire B-cell axis, as well as T-cells and mono-
nuclear phagocytes [74].
7. Contactin-1
Antibodies targeting CNTN1 were first described in 2012 by Devaux et al. in sera of
a small subset of patients presenting with GBS-like and CIDP-like symptoms using com-
bined cell-binding and nerve-binding assays [5]. They were further validated by Querol
in 2013 using immunoprecipitation and CBAs in two patients with an acute, aggressive
symptom onset mimicking CIDP with predominant motor involvement and poor re-
sponse to IVIg [3]. Since then, several studies have shown a similar clinical phenotype in
patients with CNTN1-AN, often presenting with acute to subacute disease onset with dis-
tal motor weakness and sensory ataxia, which is more prominent in males than females
[50]. Although less frequent than in NF155-AN, tremor is more commonly found than in
CIDP, and cranial nerve involvement with facial paralysis has also been reported in a sub-
stantial number of patients hinting at potential CNS involvement [33,50]. Nephrotic syn-
drome with proteinuria and hypoalbuminemia, as well as changes in the glomerular fil-
tration rate, has additionally been reported in approximately 50% of patients, with im-
mune complex deposits in renal biopsies [55,76,77].
While the age of disease of onset is usually towards the fifth or sixth decade, single
cases of affected children have been described, clinically resembling the adult phenotype
with ataxia and neuropathic pain (see Table 4) [3,34,39,62].
J. Clin. Med. 2024, 13, 5721 15 of 25
Table 4. Description of clinical, paraclinical (electrophysiology and magnetic resonance imaging), and laboratory data in published studies on anti-contactin1-
seropositive and anti-Caspr1-seropositive pediatric patients.
Age Antibody Subtype/ Testing Titer at Duration Initial Therapy
Reference Sex Onset Clinical Features Electrophysiology MRI Levels Prior
(years) Epitope Subclass Method Diagnosis (months) Diagnosis (Response)
(mg/dL) Infection
ataxia (5/5), neuropathic
pain (4/5), tremor (3/5; 2
De Simoni 2 panNF, 1 IgG4 1/5 (gastro-
7.9 (3– 3:2 Flow- CNTN1+ and 1 panNF+)
et al. (2020) NF155, 2 predom., N/A chronic N/A CIDP N/A N/A 292.4 (75–619) IVIg (-/partial) intestinal
11) (m:f) cytometry cranial nerve involvement
[34] CNTN (100–75%) infection)
and optical neuritis in 1
CNTN1+
relatively
unremarkable
weakness and numbness
sensory CV and
Tang et al. IgG1 and CIDP and of lower limbs, ataxia, Steroids (+,
14 m CNTN1 CBA 1:10 acute N/A amplitudes of unremarkable 284 1
(2023) [78] IgG4 nephropathy pain, autonomic relapse)
SNAPs in both
symptoms, nephropathy
lower and upper
limbs
IVIgs (-), RTX
Broers et al. IgG4 > IgG1 weakness of lower
5 f CNTN1 CBA IgG 1:6400 acute N/A CIDP N/A N/A elevated and prednisolone N/A
(2024) [39] and IgG2 extremities, pain, tremor
(+)
proximal and distal
Cortese et
weakness of lower limbs, IVIg (+),
al. (2020) 7 f Caspr1 IgG1 CBA N/A subacute N/A CIDP N/A N/A N/A N/A
postural and intentional steroids (-)
[59]
tremor, sensory ataxia
not lower limb weakness, gait
10 f Caspr1 CBA N/A chronic N/A CIDP N/A N/A N/A IVIg (+) N/A
detectable disturbances
Abbreviations: Caspr1 = contactin-associated protein 1; CBA = cell-based assay; CIDP = chronic inflammatory demyelinating polyneuropathy; CNTN1 = contactin
1; CV = conduction velocity; IgG = Immunoglobulin G; IVIg = intravenous immunoglobulin; N/A = not available; NF155 = neurofascin 155; panNF = pan-neuro-
fascin; RTX = rituximab; SNAP = sensory nerve action potential; + = positive; (+) = good response; (-) = poor response.
J. Clin. Med. 2024, 13, 5721 16 of 25
The glycosylphosphatidylinositol-anchored protein CNTN1 shares properties with
NF as both have six Ig domains and four Fn domains. It interacts with Caspr1 at the en-
doplasmatic reticulum, thereby forming a complex important for the function and stabil-
ity of the paranode [13,79]. Moreover, trafficking of CNTN1 to the paranode is Caspr1-
dependent [79,80].
Binding of antibodies to the Ig domain of CNTN1 is thought to induce damage to the
paranodal architecture, with controversial evidence of N-glycans within the IgG5-6 do-
main representing the main epitope [81,82]. In myelinating cultures of dorsal root ganglia
neurons, CNTN1 antibodies lead to disruption between CNTN1/Caspr1 and NF155, re-
sulting in paranodal alterations in myelinated fibers [81]. These changes are thought to be
complement-independent and happen in the absence of inflammatory cells [81]. Moreo-
ver, a rodent study using the intraneural injection of patient-derived CNTN1-IgG4
showed induced paranodal destruction with lengthening of the node, resulting in conduc-
tion failure [83]. Further evidence for a direct pathogenic role was provided by Grüner et
al., who showed a decrease in surface expression of CNTN1 and Nav current densities on
neurons upon chronic exposure to patient sera [84]. These studies also support the notion
of a further site of attack, i.e., the dorsal root ganglia, potentially providing an explanation
for certain symptoms like sensory ataxia [82,84].
Similar to NF155-AN, IgG4 has been identified as a prevailing subclass, although fur-
ther classes and subclasses with currently unknown detailed significance have also been
reported [50,82]. Indeed, IgG3 may be particularly present at disease onset, with comple-
ment deposition identified in CNTN1-IgG3-positive patients, which were bound by IVIg
[85]. Similarly, in the above-mentioned study by Grüner and colleagues, more pro-
nounced effects were observed in IgG3-predominant sera than in IgG4 [84]. Moreover,
Doppler et al. compared the effects of IgG3 derived serum from a patient tested during
acute onset versus IgG4 from a patient obtained several years into the disease in a rodent
model, thereby concluding that acute disease onset may be IgG3-mediated, while IgG4
antibodies may lead to a more chronic course [86]. Further evidence for a pathological role
of these antibodies is demonstrated upon histopathological examinations (see pathology).
Similar to NF186-AN, associated nephropathy is attributed to the presence of CNTN1
expressed by podocytes of the kidney [87]. IgG4 deposits have been identified along the
glomerular basement membrane in kidney biopsies of patients with CNTN1-AN [87]. In
these patients, similar to the underlying neuropathy, the glomerulopathy responds poorly
to IVIgs, while therapy response to rituximab is usually good.
7.2. Pathology
To date, histopathological findings of affected nerves in CNTN1-AN have revealed
axonal loss and fiber degeneration in the absence of onion bulbs, as well as scant thinly
myelinated fibers and prominent sub-perineurial edema, in contrast to biopsies of patients
with CIDP [48,88,89]. Endoneurial presence of macrophages without T-cell infiltration
was identified in some cases [88], whereas another study found no evidence for macro-
phage-induced demyelination, characteristic of CIDP [48]. Further ultrastructural find-
ings include paranodal axo-glial detachment and widening of periaxonal space and,
thereby, the impairment of saltatory conduction [48]. Moreover, skin biopsies examining
myelinated fibers have shown elongated nodes and altered immunoreactivity signaling
loss or destruction of paranodal Caspr1 and/or NF, which were less present in GBS or
CIDP [88].

Patients with anti-CNTN1 antibodies display severely abnormal nerve conduction,
with slowed conduction velocities and prolonged distal latencies, consistent with signs of
J. Clin. Med. 2024, 13, 5721 17 of 25
demyelination and often more pronounced than in CIDP, as well as early axonal involve-
ment with varying reports of conduction block, similar to NF155-AN [55,62,83,89]. F-wave
latencies are prolonged or absent, and CMAP duration is increased with a decreased am-
plitude [55].
Imaging data in these patients is scarce, with only few reports identifying thickening
and gadolinium enhancement in nerve roots on MRI in most patients [90,91]. CSF protein
levels are often highly elevated, whilst the CSF white blood cell count is mostly unremark-
able [62,88,89].
7.4. Therapy
As initially observed, the response to IVIg is generally poor and is attributed to the
predominant IgG4 isotype [82]. In this regard, IgG3 is strongly complement-inducing, and
patients respond better to IVIg therapy. Indeed, Doppler et al. reported four patients with
an acute onset of motor > sensory neuropathy relapsing to severe sensorimotor neuropa-
thy, although initially responding well to IVIg therapy, of which two were screened in the
acute phase and harbored predominant IgG3 [88]. In contrast, corticosteroids usually lead
to a partial to good response, though with an unclear role [82,90]. In treatment-resistant
patients, rituximab showed good and long-lasting response, which was also observed in
children [34,39,57,88].
8. Contactin-Associated Protein 1
Antibodies binding Caspr1 were initially described in 2016 by Doppler and col-
leagues in two patients presenting severe neuropathic pain and a subacute onset, with a
motor-dominant neuropathy resembling CIDP in one patient, while the other presented
with a GBS-like phenotype [4]. Since then, only a few patients with Caspr1 have been
reported, making this a relatively rare type of AN that accounts for 0.2–4% of CIDP diag-
noses [4,44,50,59]. Symptoms are characterized by sensory ataxia, tremors, and a tendency
to a subacute, rapidly progressive, and severe onset [33,39,50]. Neuropathic pain may be
common but has not been reported in all cohorts, and cranial involvement similarly varies
[33,39,50]. Furthermore, autonomic instability with respiratory failure has been reported
in some cases [50].
Reports on age of onset vary, with some authors reporting younger onsets around
the third decade [4,33,91], while others have identified a mean age of onset around the
fifth decade [39]. Very few reports of cases under the age of 18 exist in the literature, two
of which were mentioned by Cortese et al.: their study comprises the clinical characteris-
tics of a 7-year-old female patient with a subacute onset and a 10-year-old female patient
with a more chronic onset, both presenting with weakness of the lower limbs, and one
with additional tremor and sensory ataxia (see Table 4) [33].
At the paranode, stabilized by the adapter protein 4.1B, the transmembrane glyco-
protein Caspr1 forms a cis-complex with CNTN1 and is responsible for hindering the pas-
sage of nodal currents [13,92,93]. The exact antibody epitope is currently unknown; how-
ever, using purified antibodies from a Caspr1-seropositive patient in a cell aggregation
assay and murine sciatic nerve fibers, Cortese et al. demonstrated an isotype-dependent
penetration of the paranodal regions and binding of IgG4, but not IgG1, to the
CNTN1/Caspr1 and NF155 complex, with assumed subsequent function-blocking activity
and disruption of the axo–glial complex [33]. Indeed, both teased fibers and dermal fibers
have shown lengthening of the nodal gab and disrupted paranodal regions [4]. Moreover,
Doppler et al. showed a dispersion of sodium channels in the elongated nodes and para-
nodes, implying a morphological correlate of impaired nerve conduction, with the exact
mechanism thus far unknown [4].
J. Clin. Med. 2024, 13, 5721 18 of 25
Similar to NF155- and CNTN1-AN, IgG4 has so far been identified as a prevailing
subtype [33,39], which, however, has been associated with the more chronic form of the
disease, while IgG3, also found in many patients, is thought to be found in more acute to
subacute stages [4,94]. In line with this, complement deposition was observed in comple-
ment-binding assays of an IgG3-positive patient, while no such depositions were observed
in a patient with IgG4 [4].
Neuropathic pain may be caused by affection of dorsal root ganglia, as initially pro-
posed by Doppler et al. [4]. Analgesic therapy escalation with pregabalin and opioids was
needed in the two initially described patients, whose sera reacted with small transient
receptor potential cation channel subfamily V member 1-positive neurons in cultures of
dorsal root ganglia, though to be involved in pain perception [4].
8.2. Pathology
Subperineurial edema along with severe axonal loss and degeneration have been de-
scribed in sural nerve biopsies [4]. Features characteristic of de- or remyelination, i.e., on-
ion bulbs and thinly myelinated fibers, were not observed in these patients, and T-cell
infiltration was scarce.

Electrophysiological examinations in patients with Caspr1 show slightly varying re-
sults, with normal to slowed nerve conduction velocity, as well as prolonged distal motor
and F-wave latency [4,22]. However, compound muscle and sensory nerve action poten-
tials were shown to be preserved, all in all, indicating a demyelinating neuropathy [4,22].
Additionally, conduction block has also been reported [22,36].
CSF analysis reveals highly elevated protein levels [4,22,36]. Moreover, symmetric
root hypertrophy and marked T2-signal hyperintensity have been reported on MRI [4,91].
8.4. Therapy
As seen in other ANs, the administration of IVIg shows a low response rate in most
patients with few exceptions, potentially mirroring antibody isotypes [4,33,39,50,94]. Ster-
oids has proven beneficial when administered in combination with further immunother-
apy, and the response to rituximab is generally good [4,33,94].
9. Contactin 1/Contactin-Associated Protein 1 Complex

It remains uncertain whether or not antibodies targeting solely the CNTN1/Caspr1
complex constitute a separate AN subgroup compared to isolated Caspr1-AN or CNTN1-
AN. Querol et al. initially described a patient presenting with sensory disturbances and
weakness, showing electrophysiological features fulfilling the criteria of CIDP [3]. On ex-
amination of the patient’s serum using CBA, antibodies bound solely to cells co-express-
ing the CNTN1/Caspr1 complex, but not when the two CAMs were transfected separately,
leading the authors to postulate the presence of a conformational epitope of the complex
[3].
Subsequently, Pascual-Goñi et al. aimed to provide further elucidation in the debate
on epitope-specificity and, using CBAs, identified 15 patients with a CIDP-like clinical
picture with immunoreactivity against the CNTN1/Caspr1 complex, but not to cells trans-
fected with CNTN1 or Caspr1 alone [95]. In contrast, reactivity for Caspr1 and
CNTN1/Caspr1 were each measurable using ELISA, leading the authors to conclude that
the antibodies in fact primarily target Caspr1, yet with enhanced specificity upon co-trans-
fection of both CAMs. Indeed, clinical, paraclinical, and other laboratory findings resem-
ble those of Caspr1-AN, with half of the patients initially diagnosed as GBS, with ataxia,
cranial nerve involvement, and neuropathic pain. Neurophysiological testing revealed
features attributed to acquired demyelination with non-uniform slowing of motor nerve
conduction and an increase in F-wave latency. Most patients also showed signs of acute
J. Clin. Med. 2024, 13, 5721 19 of 25
denervation with spontaneous activity and low-amplitude CMAP, hinting at axonal in-
volvement. The predominant IgG isotype identified in sera was IgG4 (10/13), while IgG3
was found in the rest. Elevation of CSF protein levels was identified in all patients, and
nerve root enhancement was a common finding on MRI. Histopathological examination
revealed subtotal loss of myelinated fibers, subperineurial edema, and a relatively unre-
markable density of small axons. Inflammatory infiltrates were rare, and there were no
onion bulb formations. The response to IVIg was usually poor, although three IgG3-posi-
tive patients showed a partial response. The majority (90%) patients treated with rituxi-
mab improved, albeit slowly and gradually.
Several aspects of this study can be seen as beneficial, as these findings raise ques-
tions about the sensitivity and specificity of diagnostic methods. In addition, they empha-
size the use of a second diagnostic test, as recommended by the EAN/PNS, and urge di-
agnostic staff to be aware of variations.
10. Discussion and Conclusion

AN comprises a group of neuropathies that clinically resemble CIDP and GBS, with
increasing evidence suggesting a different disease course and therapy response. Moreo-
ver, the age of disease onset seems to vary depending on the targeted epitope, with a trend
towards earlier ages in certain AN subtypes, i.e., NF155-AN [19]. Isolated pediatric cases
have also been described in other AN subtypes and generally resemble the adult pheno-
type [30,33,34,44]. This review uniquely summarizes previously described pediatric cases,
an area that has not been explicitly explored so far. This is particularly relevant for pedia-
tricians since the number of reports in children is increasing and the diagnosis has im-
portant implications for treatment and outcome. Moreover, we summarize current con-
cepts along with experimental and clinical findings on ANs, offering clinicians and re-
searchers an up-to-date overview of this topic (summarized in Figure 1).
Figure 1. Summary of antigens, epitopes, clinical and paraclinical findings in autoimmune nodopa-
thies, including list of pediatric cases [23,29–39,44,59,62,78]. Created in BioRender. Höftberger, R.
(2024) BioRender.com/l96s138.
J. Clin. Med. 2024, 13, 5721 20 of 25
Particular attention should be paid to the diagnostic methods that are used for the
detection of nodal/paranodal antibodies. Unless otherwise stated, this review focused on
studies where patient reports were based on CBA, ELISA, and flow cytometry results, as
recommended by the EAN/PNS (2022), thereby assuming high specificity and sensitivity
in the diagnosis of the respective AN. Results using alternative methods, e.g., Western blot
alone, were regarded as less reliable because of the loss of epitope confirmation and were
therefore not included. Since CBAs are time- and resource-intensive, their implementation
in a diagnostic laboratory can be challenging. Therefore, diagnosis may only be accessible
in specialized laboratories, which might mask a substantially higher number of AN cases
in both children and adults.
Another aspect that might contribute to differing frequencies lies in the patient co-
horts themselves. While some studies recruited the sera of patients fulfilling diagnostic
criteria of different neurological societies [4,36,39], others report findings from a broader
range of patients [60,89]. Furthermore, previous studies were often conducted on pre-ex-
isting highly selected sera instead of samples collected in a manner reflecting clinical prac-
tice [50]. This approach adds to the challenge of comparing cohorts, and it was not fully
considered when scanning the literature, potentially containing a bias regarding frequen-
cies. Additionally, geographical and/or ethnic differences may play a role in varying inci-
dences [50]. This latter aspect may be reflected in, and add valuable information to, the
currently underexplored etiology of these disorders. In this regard, a certain HLA associ-
ation with NF155-AN has been identified [51,52], with substantially higher frequencies
found in East Asian versus Western populations [38,46,50]. Other etiological factors such
as infections, as seen in classical GBS, have only rarely been identified in AN [5,34,37]
Some of the ANs were reported to show a combined central and peripheral nervous sys-
tem involvement, and patients may present an elevated CSF cell count and CSF protein as
well as enhancement in nerve roots on MRI, supporting the hypothesis of intrathecal in-
flammation [23,56,96]. Whether this reflects a specific phenotype of patients with
nodal/paranodal antibodies or more of a coincidence is currently unclear and requires
further investigation. In this regard, the breakdown of the blood–brain and blood–nerve
barriers, with potential exposure to certain antigens and subsequent antibody synthesis,
could be taken into consideration in patients with concomitant inflammatory diseases.
Another important field in AN is the characterization of specific antibody classes and
subclasses, which may provide valuable information on disease activity and the treatment
response [21]. For example, IgG4 is found in the majority of ANs, providing a potential
explanation for the limited IVIg therapy response in many patients and better outcomes
upon B-cell depletion with rituximab [27,29,46,73]. In contrast, antibodies of the subclass
IgG3 were found in a subset of ANs during the initial stage [85]. Complement deposition
is associated with the latter, and cases respond well to IVIg therapy [85]. The evolution of
immunoglobulins due to an indirect class switch was hypothesized but could not be con-
firmed in longitudinal studies [39,94]. Moreover, certain reports include the presence of
IgG2 antibodies to different NF isoforms in pediatric patients; however, the relevance of
this phenomenon is still unclear [30].
Taken together, ANs comprise a novel group of antibody-mediated neuropathies
characterized by a distinct clinical and paraclinical phenotype reminiscent of CIDP or GBS
[3–5]. While often fulfilling the electrophysiological criteria of CIDP, ANs often present
with different disease courses and therapy responses. Moreover, certain constellations of
symptoms and paraclinical as well as laboratory findings may point at the specific epitope,
thereby prompting clinicians to search for AN and guide testing and therapy decisions,
respectively. Although these diseases are mainly described in adults, increasing numbers
of pediatric cases have been reported in recent years [30,34]. Clinical and paraclinical de-
scriptions resemble those of adult findings; however, further studies are needed to char-
acterize these phenotypes in children. In contrast, laboratory parameters, above all, anti-
body status including isotype characterization, may aid individualized therapy guidance
and contribute to the elucidation of differences in pathophysiology in children.
J. Clin. Med. 2024, 13, 5721 21 of 25
Author Contributions: Conceptualization, V.Q., K.R. and R.H.; writing—original draft preparation,
V.Q., K.R. and R.H.; writing—review and editing, V.Q., K.R. and R.H.; visualization, V.Q., K.R. and
R.H.; supervision, K.R. and R.H.; funding acquisition, R.H. All authors have read and agreed to the
published version of the manuscript.”
Funding: This work was partly supported by the Austrian Science Fund (FWF), project number
I6565-B (SYNABS), and the Austrian Society of Neurology.
Conflicts of Interest: The authors declare no conflicts of interest.
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Review

Antibody-Mediated Nodo- and Paranodopathies

1 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna,

45711 Datteln, Germany; kevin.rostasy@uni-wh.de

Keywords: paranodopathy; nodopathy; neurofascin 155; neurofascin 186/140; pan-neurofascin

J. Clin. Med. 2024, 13, 5721. https://doi.org/10.3390/jcm13195721 www.mdpi.com/journal/jcm

2. Anatomy of the Node of Ranvier and Its Antibody Epitopes

symmetric proximal and

symmetric proximal and

symmetric proximal and

4.4. Paraclinical and Laboratory Findings

Similar to NF155-AN, reports on clinical data of NF186-AN describe sensory motor

5.3. Paraclinical and Laboratory Findings

providing indirect evidence of pathogenicity, contrary to the normally appearing par-

6.3. Paraclinical and Laboratory Findings

7.3. Paraclinical and Laboratory Findings

8.3. Paraclinical and Laboratory Findings

9. Contactin 1/Contactin-Associated Protein 1 Complex

10. Discussion and Conclusion

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