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Accepted Article
“Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Clinical aspects and
new animal models of auto-immunity to nodal components”
Prof. Isabel ILLA
ARTHUR ASBURY LECTURE
Unitat Neuromuscular Servei Neurología. Hospital Santa Creu i Sant Pau. Universitat
Autònoma Barcelona. CIBERER
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic
and treatable disorder of the peripheral nerves with clinical and immunological
heterogeneity. It is considered to be an autoimmune disorder resulting from
synergistic interactions of cell-mediated and humoral immune responses against
peripheral nerve antigens although it was only until recently that humoral immune
responses have been identified (Mathey, et al., 2015). Currently, the diagnosis of CIDP
is based on clinical, laboratory and electrophysiological criteria without attention to
immunological findings (Van den Bergh, et al., 2010).
Myelinated nerve fibers consist of four domains: the node, paranode,
juxtaparanode and internode. Each of these domains expresses a large number of site
specific molecules with different functions. Nodes of Ranvier are short gaps in the
myelin sheath where an efficient and rapid propagation of the action potentials occur
(FIG. 1). The paranodal regions sit at the margin of the nodes of Ranvier. This region is
the site where myelin sheath borders (paranodal loops) closely contact the axon and
act as shelters, enabling a high density of Na+ channels at the nodes of Ranvier and of
K+ channels at the juxtaparanodes. Three cell adhesion molecules, contactin-1
(CNTN1) and contactin-associated protein-1 (CASPR1) in the axons, and neurofascin155 (NF155) in the myelin are responsible for the adhesion and the formation of
septate-like junctions (also known as transverse bands) (FIG. 1).
Over the past 5 years, several autoantibodies against proteins of the paranodes
(CNTN1, CASPR1 and NF155) and nodes of Ranvier (NF186/140) have been described
in patients with CIDP. Interestingly, some of these antibodies define specific CIDP
subtypes sometimes referred to as nodopathies and can have diagnostic and
prognostic implications (Querol, et al., 2017). The clinical characteristics associated
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1111/jns.12237
This article is protected by copyright. All rights reserved.
with the presence of these antibodies and data supporting the immunopathogenic role
of the antibodies with implications for treatment will be described below.
Accepted Article
ANTIBODIES TO PARANODAL GLYCOPROTEINS
Anti-CNTN1 antibodies. In 2013 Querol and colleagues described the presence of
antibodies to CNTN1 in four patients with CIDP (Querol, et al., 2013). The importance
of the finding came from the fact that these patients shared a phenotype that
consisted of a predominantly motor neuropathy and an aggressive disease course,
sometimes misdiagnosed as Guillain-Barré syndrome (GBS), with demyelinating
features and early axonal damage. Additionally they shared two unusual features, a
poor response to intravenous immunoglobulins (IVIg) and the finding that the
autoantibodies were predominantly of the IgG4 isotype (Table 1). A study by Miura
and colleagues (Miura, et al., 2015) confirmed, in a series of 533 patients, that 2.4% of
their CIDP cases (n=13) had IgG4 antibodies to CNTN1, 23% of these patients had a
subacute onset, and approximately 60% were minimally response to IVIg. Different
from our initial series, these patients presented with sensory ataxia and 73% had good
response to corticosteroids.
The pathology of this subtype of CIDP has subsequently been described by
different authors. Doppler and coworkers (Doppler, et al., 2015) performed an
immunohistochemical study on dermal myelinated fibers of 4 patients with CNTN1
antibodies and found disruption of the paranodal architecture. Using light and electron
microscopy, Koike and colleagues (Koike, et al., 2017) demonstrated detachment of
terminal myelin loops from the axolemma without classical macrophage-mediated
demyelination antibodies in 1 patient with CNTN1 antibodies. Both studies pointed to
specific pathology at the paranodes, where the antigen is located suggesting its
involvement in the pathogenesis of the neuropathy.
Experimental data further supports the immunopathogenicity of anti-CNTN1
IgG4 antibodies. Using an in vitro model Labasque and coworkers (Labasque, et al.,
2014) demonstrated that patient IgG4 anti-CNTN1 antibodies disrupt the binding of
the CNTN1-CASPR1 complex to NF155. Using cell aggregation assays they showed
that the binding activity of the NF155–CNTN1–CASPR1 complex was functionally
blocked and that the CNTN1 antibodies induced alteration of paranodal junctions in
This article is protected by copyright. All rights reserved.
myelinated neuronal cultures. An animal model recently published by Manso and
coworkers (Manso, et al., 2016) revealed that intraneural injections of the antibodies
into preparations of sciatic nerve progressively and specifically disrupted the
Accepted Article
paranodal axo-glial junction. The effects were extremely specific for anti-CNTN1 IgG4
as none of the controls including IgG1 or IgG4 immunoglobulins against other antigens
(e.g., CASPR2) were able to penetrate the paranodes or produce paranodal disruption.
Furthermore, the chronic infusion of antibodies induced progressive clinical
deterioration combined with gait ataxia and electrophysiological worsening in animals
with experimental autoimmune neuritis (EAN). The pathological analysis of the nerves
did not show demyelination, axonal degeneration, or immune infiltration. Instead, the
animals showed a selective loss of the paranodal specialization in motor neurons
characterized by the disappearance of the CNTN1/contactin-1/NF155 complex. These
studies clearly indicate that IgG4 anti‑CNTN1 antibodies play a pathogenic role in
CNTN1 antibody positive CIDP (CNTN1+CIDP).
Anti-NF155 antibodies. Antibodies to different isoforms of neurofascin were first
reported in patients with GBS and CIDP (Devaux, et al., 2012; Pruss, et al., 2011; Yan, et
al., 2010). Subsequently, antibodies specific to the NF155 isoform were found in a
small group (<3%) of patients with CIDP (Ng, et al., 2012) but the phenotype(s)
associated with anti-NF antibodies was not defined.
Studies by Querol and colleagues (Querol, et al., 2014) and confirmed by others
(Devaux, et al., 2016; Ogata, et al., 2015) have demonstrated that patients with CIDP
and anti-NF155 antibodies have a distinct phenotype. Our study (Querol, et al., 2014)
indicated that patients are young, have predominantly distal weakness, ataxia, often a
very disabling low-frequency tremor (3-5 Hz) and demyelinating features on
neurophysiological studies (Figure 1). Interestingly, and similar to CNTN1+CIDP
patients, patients with NF155 antibodies have a poor response to IVIg and the
autoantibodies are predominantly of the IgG4 subtype. Ogata and colleagues (Ogata,
et al., 2015) indicated that up to 18% (9/50) of their patients with CIDP had antibodies
to NF155 but not to NF186 and confirmed the phenotype, the poor response to IVIg,
and the IgG4 subclass of the autoantibodies. They also reported the MRI findings of 7
patients; all had marked symmetric hypertrophy of the cervical and lumbosacral
This article is protected by copyright. All rights reserved.
roots/plexuses that was greater than seen in anti-NF155 antibody-negative CIDP
control patients. The sural nerve biopsy of two patients showed occasional paranodal
demyelination, but no inflammatory cell infiltrates or onion bulbs. Devaux and
Accepted Article
colleagues (Devaux, et al., 2016) screened a large cohort of patients and confirmed the
phenotype in 7% (38/533) of CIDP patients. They also described that 8% of their NF155
antibody positive patients had demyelinating lesions in the CNS.
A pathogenic role of anti-NF155 antibodies is supported by the morphological study
recently performed by Koike and coworkers (Koike, et al., 2017) in 9 sural nerve biopsy
specimens from CIDP patients with these antibodies. Using electron microscopy they
observed detachment of terminal myelin loops from the axolemma at the paranodes
in the NF155 antibody positive patents that was not seen in antibody negative CIDP
patients. They also found a positive correlation between the frequencies of axo–glial
detachment at the paranode and axonal degeneration. In a study of two patients with
anti-NF155 antibodies, Vallat and coworkers (Vallat, et al., 2017), found selective loss
of septate-like junctions at all paranodes examined and the interposition of cellular
processes between the paranodal loops and the axolemma. These alterations suggest
that anti-NF155 antibodies specifically disrupt the NF155–CNTN1–CASPR1 complex at
the paranodes.
Devaux and coworkers (Manso, et al., 2017) recently presented the preliminary results
of the chronic intrathecal exposure of Lewis rats to anti-NF155 IgG4 from CIDP
patients’ plasma. The study showed that anti-NF155 IgG4, but not control IgG4,
induced progressive clinical deterioration, decreased CAPs amplitude and produced a
selective loss of the CASPR1/contactin-1/NF155 complex at paranodes, further
supporting a pathogenic role of anti-NF155 IgG4 in this subtype of CIDP.
In a collaborative study we found that anti-NF155+ CIDP patients associates with HLADRB15 20 times more frequently than in seronegative CIDP(Martinez-Martinez and
coworkers , unpublished observation) (Martinez-Martinez, et al., 2017) further
supporting the idea that patients with these antibodies constitute a distinct subset of
CIDP.
Anti-CASPR-1 antibodies. The presence of anti-CASPR1 antibodies has been reported
by Doppler and colleagues (Doppler, et al., 2016) in two patients with inflammatory
neuropathies, one classified as CIDP, the other as GBS. Both patients were negative for
This article is protected by copyright. All rights reserved.
antibodies to the other two components of the paranodal complex (Contactin-1 and
NF155). One common feature of these patients was the presence of intense
neuropathic pain. The skin biopsy from both showed paranodal disruption on
Accepted Article
myelinated fibers. The isotype of the anti-CASPR1 antibodies in the CIDP patient was
IgG4 and complement activation was absent. In the GBS patient the isotype of the
CASPR1 antibodies was IgG3. The CASPR1+ CIDP patient received rituximab and
achieved clinical stability and disappearance of the autoantibodies. This specific
phenotype and the relationship to pain have not yet been confirmed in other series.
ANTIBODIES TO NODAL GLYCOPROTEINS.
Anti-NF186/140 antibodies. Recently nodal neurofascins were reported by Delmont
and coworkers (Delmont, et al., 2017) as the main targets of autoantibodies in five
patients with IgG reactivity against the nodes of Ranvier; the antibodies were
predominantly IgG4. The serum of the patients showed strong IgG reactivity toward
the nodes of Ranvier on teased nerve fibers without paranodal reactivity. The
neurofascins located at the nodes of Ranvier are NF186 and NF140 while NF155 as
noted above is located at the paranodes.
These patients presented with clinical features distinct from those of patients with
anti-NF155 IgG4 antibodies. Four of these patients had subacute onset of sensory
ataxia and interestingly, in comparison with patients with anti-NF155 antibodies, none
had tremor. Concomitant diseases were present in three of the patients, two with
nephrotic syndrome and one with IgG4 related retroperitoneal fibrosis. The
predominant neurophysiological features were conduction blocks and decreased distal
motor amplitude. Intravenous immunoglobulin and corticosteroids were effective in
three patients, and one patient remitted following rituximab treatment. Of interest, in
two patients, the autoantibodies depleted and the neurophysiological data recovered
after treatment. This recent description further indicates that CIDP is a heterogeneous
autoimmune disorder with multiple immune targets.
Other nodal antigens
Different studies (Querol, et al., 2017) indicate that sera from some patients with CIDP
show reactivity to components of the compact myelin, nodes or paranodes but the
specific antigen target(s) has not been identified.
This article is protected by copyright. All rights reserved.
Treatment of nodopathies.
The primary goal of therapy in patients with immune-mediated neuropathies is to
Accepted Article
improve strength and functional ability. Additional goals include improvement in pain,
sensory loss, gait, and autonomic instability. The EFNS/PNS guidelines (Van den Bergh,
et al., 2010) include as first line treatment plasmapheresis (Plex), corticosteroids, and
IVIg.
Plasmapheresis. Most patients with CIDP show an excellent response to Plex (Eftimov,
et al., 2013). A similar good response to Plex has been reported in patients with nodal
and paranodal antibody+ CIDP with the exception of one patient with anti-NF186/140
antibodies. Good response to Plex is further support for a pathogenic role of the
autoantibodies. However, for maintenance treatment, Plex may be less tolerated than
IVIg or corticosteroids or has more side-effects.
Corticosteroids are considered a first line treatment in patients with CIDP (Van den
Bergh, et al., 2010) as they have been reported to be superior to no treatment in an
unblended randomized control trial and in many observational studies. The EFNS/PNS
task force (Van den Bergh, et al., 2010) recommended a trial of corticosteroids in
patients with significant disability (level C recommendation). In patients with nodal and
paranodal antibodies, corticosteroids are reported effective in approximately 40-60%
of cases (Table 2)
IVIg. The most widely used treatment for CIDP is IVIg (Mehndiratta, et al., 2015) due to
its proven efficacy in approximately 80% of patients. Also, crossover trials have shown
no significant short-term difference between IVIg and Plex or prednisolone.
Contrary to the expected good response, the percentage of patients with nodal and
paranodal antibodies responsive to IVIg is much lower as only around 40% of these
patients respond. An exception are patients with anti-NF186/140+ CIDP for whom a
response of 80% is similar to regular CIDP.
Nodal and paranodal autoantibodies are almost all of the IgG4 isotype and a similar
lack of response to IVIg therapy has been described for other IgG4 mediated diseases.
Antibodies of the IgG4 isotype do not activate complement or bind to Ig Fc domain
receptors, elements that are involved in IVIg action mechanisms (Lunemann, et al.,
2015) . This could account for the lack of response to IVIg of these patients.
This article is protected by copyright. All rights reserved.
Rituximab. A very good response to rituximab, a B‑cell-depleting therapy, has been
reported repeatedly in small series and case reports (Delmont, et al., 2017; Doppler, et
al., 2016; Querol, et al., 2015) in patients with CIDP and IgG4-antibodies who do not
Accepted Article
respond to conventional first line treatments. Importantly, the response is long-lasting
and in those patients in whom the antibodies have been screened a decline of the
antibody titers is observed in parallel to the clinical and neurophysiological
improvement. Of clinical interest, the better responders were patients with short
disease duration, probably due to the presence of less permanent axonal damage
(Querol, et al., 2015).
Although the efficacy of rituximab in patients with IgG4‑related CIDP is supported only
by these small series and case reports, the effectiveness of rituximab in other
IgG4‑mediated diseases with diverse target organs (Diaz-Manera, et al., 2012; Joly, et
al., 2007) strongly supports considering B‑cell-depleting therapies as the treatment of
choice in patients with CIDP and anti‑CNTN1, anti‑NF155, anti-CASPR1 or antiNF186/140 antibodies who have not responded to IVIg or corticosteroids. In patients
with CIDP the effects of rituximab are not as clear (Velardo, et al., 2017). A trial could
demonstrate if rituximab should be used as first line therapy when the presence of
antibodies is confirmed.
Conclusions. The clinical and immunological heterogeneity of CIDP is being unraveled
with the description of specific autoantibodies and their association with disease
phenotypes. The percentage of patients with CIDP in whom specific nodal or paranodal
autoantibodies can be detected is low and to date only Contactin-1, NF155, CASPR1
and NF186/140 glycoproteins have been identified as targets. However, for Contactin1+ CIDP and NF155+ CIDP, morphological as well as in vivo and in vitro studies have
demonstrated a pathogenic role of these antibodies in the immune neuropathies.
Therefore, the detection of antibodies has implications for diagnosis, prognosis,
follow-up, and importantly for treatment selection. On-going research will likely
identify novel antigenic targets revealing that the heterogeneity of CIDP is due in part
to a large number of immune responses that represent small groups of patients.
Currently, the diagnosis of CIDP is based on clinical and electrophysiological criteria.
This article is protected by copyright. All rights reserved.
New diagnostic criteria should be developed that incorporate the presence of immune
biomarkers.
Accepted Article
Acknowledgements:
The biomarker studies in CIDP have been supported by grants from: Fondo de
Investigaciones Sanitarias, Ministerio Economia y Competitividad , Instituto de Salud
Carlos III, PI16/01440 to I.I.; The Agence Nationale pour la Recherche and Instituto de
Salud Carlos III CIBERER for the ACAMIN project under the E-Rare-2 (ERA-Net for
Research on Rare Diseases) framework (grant to J.J.D., O.P. and I.I) and The GBS/ CIDP
Foundation to I.I. Special recognition to the investigators Luis Querol and J.J. Devaux.
This article is protected by copyright. All rights reserved.
Accepted Article
Table 1. Characteristics of the CIDP associated to nodal protein antibodies. Summary
of published cases.
ANTICONTACTIN-1
(21 patients)
2.4- 7.5%
ANTINF155
(51 patients)
7 - 18%
ANTICASPR1
(2 patients)
3%
ANTINF186/140
(5 patients)
2%
Onset
Aggressive
acute/ subacute/
chronic
Subacute or
chronic
Acute or chronic
Subacute 4/5
Mean age (range)
60 (33-81)
38 (10-67)
30 (GBS)
69 (CIDP)
61 (2–70)
Clinical features
Severe motor,
sensory ataxia
>Distal weakness,
ataxia, tremor (35 Hz)
Sensory ataxia,
no tremor
Neurophysiological
studies
Demyelinating
features
CSF protein levels
(range)
Yes
Early axonal loss
Yes
>Distal weakness,
distal
hyperesthesia,
pain
Yes
Mean 190 mgr/dl
(70-693)
Mean 250 mgr/dl
(40-600)
CIDP: 520mgr/dl
Nerve biopsy:
Paranodal pathology
without inflammation
Electron microscopy:
Detachment of
terminal myelin loops
from the axolemma
Predominant IgG
isotype
Yes
Yes
Yes
median
179mg/dl,
range 80200g/l
NR
Yes
Yes
NR
NR
IgG4
IgG4
IgG4
IgG4
MRI: hypertrophy of
cervical/lumbosacral
roots/nerves and/or
swelling
Associated diseases
Yes (in 2/2 patients
reported)
Yes (in 7/7
patients
reported)
NR
NR
Demyelinating CNS
lesions
NR
NR
Nephrotic
syndrome (2
patients);
retroperitoneal
fibrosis (1)
NR
% of CIDP patients
Nephrotic
syndrome (1
patient)
NR: Not Reported
This article is protected by copyright. All rights reserved.
8%
Yes
Accepted Article
Table 2
Response to Treatment
Contactin-1
Plasmapheresis Good
NF155
Good
Few non responders
CASPR1
GBS: ND
CIDP: good
IVIg
<40%
<20%-40%
Corticosteroids
20%-73%
25%-70%
Rituximab
long lasting
>80%
long lasting
>80%
CIDP; 1
patient, not
effective
GBS: ND
3/4
CIDP: slight
improvement
in a few
weeks
GBS: ND
CIDP: long
Excellent in
lasting
1 patient
GBS: ND
This article is protected by copyright. All rights reserved.
NF186/140
2/5 patients
improved;
1/5
worsened
3/4
Accepted Article
FIGURE 1.- Schematic representation of the nodal and paranodal components of
myelinated fibers to which antibodies have been described. Neurofascin 186 (NF186) is
located at the nodes and the glycoprotein complex formed by Contactin-1, CASPR1 and
NF155 and is involved in the adhesion between the myelin sheath borders and the
axons at the paranodes.
This article is protected by copyright. All rights reserved.
Accepted Article
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Accepted Article
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