PRIMeR

Immune-​mediated neuropathies
Bernd C. Kieseier1*, Emily K. Mathey2, Claudia Sommer3 and Hans-​Peter Hartung1
Abstract | Since the discovery of an acute monophasic paralysis, later coined Guillain–Barré
syndrome, almost 100 years ago, and the discovery of chronic, steroid-​responsive polyneuropathy
50 years ago, the spectrum of immune-​mediated polyneuropathies has broadened, with various
subtypes continuing to be identified, including chronic inflammatory demyelinating poly­
radiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In general, these disorders
are speculated to be caused by autoimmunity to proteins located at the node of Ranvier or
components of myelin of peripheral nerves, although disease-​associated autoantibodies have not
been identified for all disorders. Owing to the numerous subtypes of the immune-​mediated
neuropathies, making the right diagnosis in daily clinical practice is complicated. Moreover,
treating these disorders, particularly their chronic variants, such as CIDP and MMN, poses a
challenge. In general, management of these disorders includes immunotherapies, such as
corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical
criteria and the emergence of more disease-​specific immunotherapies should broaden the
therapeutic options for these disabling diseases.

1
Department of Neurology,
Medical Faculty, Heinrich
Heine University, Düsseldorf,
Germany.
2
Neuroinflammation
Laboratory, Brain and Mind
Centre, University of Sydney,
Sydney, Australia.
3
Department of Neurology,
University of Würzburg,
Würzburg, Germany.
*e-​mail: bernd.kieseier@
uni-duesseldorf.de
https://doi.org/10.1038/
s41572-018-0027-2
Polyneuropathies are common neurological disorders
that can be caused by immune responses against auto­
antigens in the peripheral nervous system (PNS).
Immune-​mediated neuropathies can include acute dis­
orders, such as Guillain–Barré syndrome (GBS)1, which
has several subtypes, including demyelinating (acute
inflammatory demyelinating polyradiculoneuropathy
(AIDP)) and axonal (acute motor axonal neuropathy
(AMAN)) subtypes, or chronic disorders, such as chronic
inflammatory demyelinating polyradiculoneuropathy
(CIDP), multifocal motor neuropathy (MMN) and neuro­
pathies associated with an immunoglobulin M (IgM)
monoclonal gammopathy of undetermined signifi­
cance (MGUS)2. Other immune-​mediated neuropathies
have been identified, many of which are considered as
further subtypes of GBS and CIDP, although many of
these disorders are quite rare (Box 1). In general, periph­
eral neuropathies are characterized by progressive muscle
weakness and are often accompanied by sensory deficits.
Although immune-​mediated neuropathies are fairly
rare, they confer substantial social and economic costs
and affect patients' quality of life (QOL). GBS is con­
sidered a neurological emergency, and patients require
hospitalization and intensive care management, and are
often left with long-​term disabilities, whereas chronic
immune-​mediated neuropathies are typically treated
using expensive immunotherapies over the course of the
disease. Thus, making the right diagnosis is crucial to pre­
vent unnecessary damage to the PNS and to identify the
correct treatment option. In general, diagnosis is based on
clinical manifestations, electrodiagnostic studies and other
supportive evidence, including the detection of autoanti­
bodies for some disorders. Several therapies are available
for management of these disorders, including plasma
exchange and intravenous immunoglobulin (IVIG),
although the specific treatment varies between disorders3.
In this Primer, we consider the clinical features of
acute and chronic immune-​mediated neuropathies and
discuss how these features can be used to differentiate
these conditions from other neurological disorders. We
also summarize the current understanding, diagnosis and
treatment recommendations for these disorders. Given
the large spectrum of clinical subtypes, we focus on GBS,
CIDP, MMN and IgM MGUS polyneuropathies on
the basis of their overall prevalence and the deeper
understanding of these disorders than with other, less
frequent subtypes. We do not cover other forms of neuro­
pathy such as vasculitic neuropathies or POEMS (poly­
neuropathy, organomegaly, endocrinopathy, monoclonal
protein, skin changes) syndrome, both of which are asso­
ciated with a cluster of multisystem clinical features and,
as such, diagnosis relies on a broader clinical spectrum
beyond the features of a neuropathy. In addition, infec­
tious neuropathies are also excluded because this Primer
focuses on autoimmune-​driven polyneuropathies.
Epidemiology
GBS
GBS has an incidence of 0.81–1.89 cases per 100,000
individuals and is the most common cause of acute,
flaccid paralysis worldwide4. No major geographical
variation has been reported in the incidence of GBS5,

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Box 1 | Immune-​mediated neuropathies
Guillain–Barré syndrome and variants
• Acute inflammatory demyelinating polyradiculoneuropathy
• Acute motor and sensory axonal neuropathy
• Acute motor axonal neuropathy
• Acute sensory neuronopathy
• Acute pandysautonomia
Regional variants:
• Miller Fisher syndrome
• Pharyngeal–cervical–brachial variant
Overlap:
• Miller Fisher/Guillain–Barré overlap syndrome
Chronic inflammatory demyelinating polyradiculoneuropathy and variantsa
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
-- Pure motor CIDP
-- Pure sensory CIDP
• Demyelinating neuropathies with monoclonal gammopathy of undetermined
significance other than IgM
• Chronic inflammatory axonal polyneuropathy
• Distal acquired demyelinating symmetric neuropathy
• Multifocal acquired demyelinating sensory and motor neuropathy (also known as
Lewis–Sumner syndrome)
Chronic demyelinating neuropathies distinct from CIDPa
• Multifocal motor neuropathy
-- Multifocal motor neuropathy without conduction block
• Demyelinating neuropathies associated with immunoglobulin M (IgM) monoclonal
gammopathy of undetermined significance with and without anti-​myelin-associated
glycoprotein neuropathies
• Autoimmune neuropathies associated with antibodies to paranodal antibodies
(paranodopathies)
• Chronic ataxic neuropathy with ophthalmoplegia, monoclonal protein, cold
agglutinins and disialosyl antibodies
• Chronic ataxic neuropathy with disialosyl antibodies
a
Collectively, these disorders can be referred to as chronic inflammatory neuropathies.
although incidence might be higher in tropical coun­
tries6. However, substantial regional variation in the
prevalence of the AMAN and AIDP subtypes of GBS
has been reported. AIDP is the main subtype of GBS in
North America, Europe and Australia and accounts
for 60–80% of GBS cases, whereas AMAN accounts for
30–65% of GBS cases in Asia and in Central and South
America7,8. The causes of the regional differences are
unclear but could relate to geographical differences
such as temperature and humidity, genetic susceptibil­
ity, antecedent infection9 or underdiagnosis of AMAN10.
Miller Fisher syndrome (MFS), another subtype of GBS,
accounts for 5% of GBS cases in the Western hemisphere
and up to 26% in Japan11. GBS is more common in men
than in women, with a ratio of 3:2 (ref.12), and occurs
at any age but with a median age of onset of 40 years of
age; incidence increases to 3.3 cases per 100,000 indi­
viduals in those >50 years of age5,13. Overall, GBS has a
recurrence rate of 5%14, although younger patients have
a higher risk of recurrence than older individuals14.
Measures to prevent recurrence are not known.
In 60–70% of cases, the first symptoms of GBS mani­
fest between 1 and 3 weeks after an acute infection,
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usually an upper respiratory tract infection (~40% of
cases) or gastrointestinal infection (20% of cases)15. The
most commonly associated pathogens are Campylobacter
jejuni (particularly for AMAN), Haemophilus influenzae,
Mycoplasma pneumoniae16, cytomegalovirus (CMV),
Epstein–Barr virus and Zika virus17. The 2013–2014
outbreak of Zika virus in Latin America and the Pacific
Islands coincided with a 2–9.8-fold increase in the inci­
dence of GBS compared with the incidence before the
Zika outbreak17. Although a spectrum of clinical mani­
festations is associated with Zika-​virus-associated GBS,
AIDP is the most frequent18.
An association between GBS and vaccination has
been demonstrated only with influenza vaccination (rel­
ative risk 1.41)19; however, the risk of GBS after influenza
infection is ~4–7-fold higher than the risk after influ­
enza vaccination, suggesting that the risk–benefit ratio is
in favour of vaccination20. Some types of surgery, includ­
ing cardiovascular, gastrointestinal and orthopaedic sur­
geries, have been associated with an increased incidence
of GBS21. In addition, immune-​modulating drugs might
precipitate GBS; for example, the triggering of GBS by
tumour necrosis factor (TNF) antagonists has been
described in isolated cases22. Despite several reports of
familial GBS, no significant association between genetic
alterations and GBS predisposition has been demon­
strated. Several candidate genes that have a role in the
innate immune system have been investigated, but no
significant associations were found23. One exception is
a case series of a GBS-​like disease in individuals with a
genetic deficit in protection from complement-​mediated
injury (the p.Cys89Tyr mutation in CD59) and a clinical
response to a complement inhibitor24.
Chronic inflammatory neuropathies
CIDP is the most common immune-​mediated neuro­
pathy, with a reported prevalence ranging from
0.8–8.9 cases per 100,000 individuals from data in eight
countries25. Whether the prevalence differs between
countries has not been ascertained owing to a lack of
systematically collected data. The average age at onset
of CIDP is 48 years of age, and CIDP predominantly
affects men more than women with a ratio of approx­
imately 2:1 (ref.2). Risk factors for CIDP are not known.
Antecedent infections can occur but are rarer in patients
with CIDP (4–30%) than in those with GBS. In contrast
to GBS, which has a strong association with C. jejuni
infections, no particular pathogens associated with
CIDP have been widely identified2.
Population-​b ased studies of MMN are rare, but
several studies have estimated different prevalences
between countries, such as a prevalence of 0.29 cases per
100,000 individuals in Japan, 0.6 cases per 100,000 indi­
viduals in the Netherlands and 0.53 cases per 100,000
individuals in southeast England25–27. The age of onset of
MMN ranges from 20 to 70 years of age, with a median
onset at 40 years of age. MMN is more common in males
than in females, with a ratio of at least 2:1 (ref.26). The
cause of MMN is currently unknown, and no associated
antecedent infections have been reported3.
Paraproteinaemic demyelinating neuropathies are
CIDP variants that often fulfil the diagnostic criteria for
 Primer

CIDP but are associated with a paraprotein, typically neuropathies, such as cellular infiltration of the periph­
IgM. More than 50% of patients with an IgM para­protein eral nerve, a monophasic clinical course with motor
have anti-​myelin-associated glycoprotein (MAG) IgM deficits and electrophysiological changes, but do not
antibodies28. Paraproteinaemic demyelinating neuro­ exactly recapitulate individual disorders. These mod­
pathies have a prevalence of 1.04–5.1 cases per 100,000 els are often used to provide proof of concepts and are
individuals25,29. Paraproteinaemias are a group of dis­ frequently developed to mimic different aspects of the
orders in which monoclonal plasma cells proliferate disease process; for example, animal models that mimic
(owing to an underlying malignancy, such as multiple the chronicity of CIDP have recently been developed34,35.
myeloma, or the myeloma precursor syndrome MGUS)
and secrete monoclonal proteins (M proteins). The GBS
prevalence of IgM MGUS increases with age, from 3% GBS subtypes are distinguished by their clinical pres­
of individuals >50 years of age to 7.5% of individuals entation, electrophysiology, pathology and a distinct
>85 years of age, with up to 30% developing a neuropathy, underlying pathophysiology. As the demyelinating
and IgM MGUS is the most common paraproteinaemic form, AIDP, and the axonal form, AMAN, are the most
demyelinating neuropathy30. commonly occurring subtypes, they will be discussed in
Notably, most epidemiological studies and clinical more detail here.
trials on chronic inflammatory neuropathies include Substantial advances have been made in identifying
only patients who meet the diagnostic criteria of the pathogenetic autoantibody responses against periph­
European Federation of Neurological Societies and eral nerve targets in some subtypes of GBS, particularly
Peripheral Nerve Society (EFNS/PNS). Owing to this AMAN. Between 30–66% of patients with AMAN had
stringency, the prevalence of these disorders might be a prior infection with C. jejuni36,37, which can result in
underestimated and might not account for patients with an aberrant antibody cross reactivity between lipo-​
atypical phenotypes of the disorder. oligosaccharides (LOSs) on the bacterium and gan­
gliosides on axons — a process known as molecular
Mechanisms/pathophysiology mimicry. However, <1 in 1,000 individuals with a symp­
Immune-​mediated neuropathies are generally con­ tomatic C. jejuni infection are estimated to subsequently
sidered to be immune-​mediated disorders in which develop AMAN38 owing to a combination of host and
humoral and cellular immune responses act synergisti­ microbial factors that determine the production of anti-​
cally to cause nerve damage and neurological dysfunc­ ganglioside antibodies (Table 1). One implicated micro­
tion. Supporting an immune-​mediated aetiology was the bial factor is the sialylation of LOSs, which is determined
identification of autoreactive antibodies and T cells in by the presence of LOS loci that harbour genes involved
sural nerve biopsy samples and in the serum of patients31. in sialylation and that are found in certain stains of
Many of these autoantibodies bind to glycolipids located C. jejuni39; however, infection with one of these strains
in Schwann cells or axonal membranes, or proteins does not always lead to GBS, therefore other factors
located at the node of Ranvier. Although pathogenetic are also involved in the development of disease after
mechanisms that are common to several immune-​ C. jejuni infection. Many studies have attempted to iden­
mediated neuropathies have been identified (Fig.  1), tify host genes that confer susceptibility to GBS after
the precise immunopathogenesis for individual neuro­ infection, although the precise genetic factors have not
pathies — such as how the disease is triggered, or the yet been determined.
identity of specific autoantigens — has yet to be fully Autoantibodies to various gangliosides found in
elucidated. Mechanisms common to several immune-​ axons are used to aid diagnosis of certain subtypes
mediated neuropathies include a peripheral immune of GBS, such as AMAN, acute motor and sensory
response, consisting of the generation of autoantibod­ axonal neuropathy (AMSAN), MFS and pharyngeal–
ies directed towards components of myelin or proteins cervical–brachial variants, and have an accepted role
located at the node of Ranvier, and the breakdown of the in causing nerve injury (Table 1; Fig. 2). In addition, the
blood–nerve barrier owing to secreted chemokines and distribution of the ganglioside in the nerve influences
proteases from activated T cells. Leukocytes and auto­ the clinical phenotype of GBS. For example, GM1 and
antibodies can penetrate the nerve compartment facilita­ GalNAc-​GD1a are expressed predominantly on the
ted by the breakdown of the blood–nerve barrier, where axolemma of motor nerves, particularly at the node of
they can lead to myelin destruction or axonal damage. Ranvier40, and anti-GM1 and anti-​GalNAc0GD1a anti­
Many of the clinical and pathological changes bodies are associated with motor phenotypes. GQ1b
observed in inflammatory neuropathies can be mod­ is enriched in cranial nerves that innervate extraocu­
elled using experimental autoimmune neuritis (EAN) lar muscles, resulting in the ophthalmoplegia seen in
in animals32. In the EAN model, genetically susceptible patients with MFS.
animals, usually inbred mice or rats, are immunized The functional effects of anti-​ganglioside antibodies
with peripheral nerve homogenate, myelin or myelin in GBS have been demonstrated in animal models
components (such as myelin protein P0 and myelin P2 and in nerve biopsy samples. Anti-​GM1 (ref.41) and anti-​
protein or peptides, or lipids such as galactocerebroside) GD1a42 antibodies bind to the nodes of Ranvier, where
or receive adoptive transfer of autoreactive, myelin P2 they disrupt the fine structural arrangements respon­
protein or myelin protein P0 peptide-​specific T cell lines sible for sodium channel clustering, leading to lack of
to induce EAN33. These experimental models resemble sodium channel clustering, slowed axonal conduction
certain aspects of the pathogenesis of inflammatory and loss of function, or they bind to the motor nerve

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Juxtaparanode Paranode Node

BNB Systemic immune compartment

APC Activated
T cell
Ganglioside

Autoreactive Gliomedin
T cell
NrCAM
Plasma cell NF155
MAG
Chemokines, proteases
and adhesion molecules Autoantibody
Kv1.1
Kv1.2 Contactin 1 CASPR1 Nav1.6 Kv7.2
Kv1.4 NF186 Kv7.3
Macrophage
Kv1.6
Apoptosis
Peripheral nervous system

Nerve
cell
TNF, Axon
proteases, Myelin Schwann cell
ROS and microvilli
cytokines

Schwann
cell

Fig. 1 | Pathomechanisms of immune-​mediated neuropathies. Immune-​mediated neuropathies can be triggered by

certain minor infections, which can activate and induce proliferation of autoreactive T cells, owing to a similar structure of
bacterial epitopes and peripheral nerve antigens (molecular mimicry). Autoreactive T cells secrete various cytokines that
stimulate the production of autoantibodies by plasma cells, which can enter peripheral nerves following damage to the
blood–nerve barrier (BNB). Activated T cells cross the BNB through interactions between adhesion molecules on T cells
and the vascular endothelium of endoneurial blood vessels. These interactions allow the adherence of T cells to the blood
vessel wall and cross the BNB by either transcellular or intercellular diapedesis. During this process, activated T cells
secrete metalloproteinases that degrade the basement membrane, which facilitates the possibility for larger molecules as
well as immune cells to cross the BNB. In the peripheral nerve, T cells secrete pro-​inflammatory cytokines, such as tumour
necrosis factor (TNF) and IL-2 (refs248,249), that contribute to the amplification and perpetuation of inflammation within the
nerve by the recruitment of additional immune cells from the periphery as well as by clonal expansion in situ. After the BNB
has become permeable owing to the infiltration of inflammatory cells, soluble factors in serum, such as autoantibodies and
complement, can access the endoneurium of the nerve. Activated macrophages can release mediators, such as pro-​
inflammatory cytokines, reactive oxygen species (ROS) and proteases, that can propagate the inflammatory response and
directly damage Schwann cells and axons. Upon entry to the nerve, autoantibodies can bind to myelin glycoproteins or
proteins at the node of Ranvier or paranodal regions (inset). Several proteins exist at the node and paranodal regions and
have diverse functions, such as maintaining axon–Schwann cell or axon–myelin binding (such as contactin-​associated
protein 1 (CASPR1), neurofascin 155 (NF155) or contactin 1), sodium channel clustering (such as gliomedin) and governing
node organization. Autoantibody binding to these proteins can lead to complement activation, macrophage-​mediated
axonal degeneration or demyelination and disruption to nodal architecture. Long-​term disability is mainly determined
by the degree of axonal degeneration. The immune response is switched off by programmed cell death (apoptosis),
although the mechanisms underlying this process are unknown. APC, antigen-​presenting cell; MAG, myelin-​associated
glycoprotein; NrCAM, neuronal cell adhesion molecule. Inset adapted from ref.80, Springer Nature Limited.

terminals, causing degeneration of the presynaptic nerve
terminal in model systems43 (Fig.  3). The effect of the
bound antibody is largely mediated by complement
fixation, resulting in formation of the membrane attack
complex, although activation of Fcγ receptors on infil­
trating phagocytotic macrophages by antibody–antigen
immune complexes has also been shown to play a role
in macrophage activation, the release of additional toxic
mediators and the phagocytosis of myelin and myelin
debris44. Similarly, anti-​disialosyl antibodies (which
bind to an epitope common to many gangliosides,
including GD1b, GD3, GT1b and GQ1b) bind to the
nodal axolemma in human induced pluripotent stem
cell (iPSC)-derived myelinating neuron–Schwann cell
co-​cultures, resulting in complement-​dependent axonal
degeneration or complement-​independent inhibition of
myelination45. Autopsy studies of nerves from patients
with AMAN have demonstrated IgG and complement
deposition at the node of Ranvier in large motor fibres
and have revealed infiltrating macrophages penetrating
the internodal periaxonal space46. Nodal lengthening
is followed by axonal degeneration, but demyelination
and lymphocyte infiltration are limited47. To summarize,
conceptionally, in AMAN, antibody binding to axonal
target antigens located along the node of Ranvier induces
paranodal myelin detachment, with node lengthening,
sodium channel disruption and altered ion and water
homeostasis, which ultimately, if not stopped, progresses
to axonal degeneration48. Clinically this pathology might
manifest as a continuum on the basis of the relative
presence of a nerve conduction block, which might
revert rapidly, and axonal degeneration49. Indeed, nerve

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conduction block can be assessed using electrophysiol­
ogy as part of the diagnostic work-​up of patients with
suspected AMAN. Most importantly, this concept of a
‘nodopathy’, although initially described in AMAN47,
has also been observed in chronic immune-​mediated
neuropathies, such as CIDP and MMN.
Mechanisms of molecular mimicry in AIDP have
not been established despite the high incidence of ante­
cedent infection in these patients. Extensive searches
for anti-​ganglioside antibodies have resulted in incon­
sistent reports of their presence and/or relevance in
AIDP35,36,50,51. These discrepancies might be due to the
incorrect diagnosis of AIDP (patients with AMAN could
be misclassified as AIDP when diagnosis has been made
without assessment of nerve conduction)52 or the vari­
ous methods used to detect anti-​ganglioside antibodies.
However, patients with GBS that have a demyelinating
phenotype when assessed using nerve conduction stud­
ies (NCS) and who harbour both anti-​ganglioside and
anti-​galactocerebroside antibodies have been reported53.
Nevertheless, the role of autoantibodies in AIDP
remains unclear, and no consistent autoantibody corre­
lations have been reported in patients54 despite extensive
screening of major myelin antigens such as myelin pro­
tein P0, myelin P2 protein and peripheral myelin protein
22 (PMP22)55,56. Moesin, which is expressed on Schwann
cell microvilli, has been suggested as a potential auto­
antigen in CMV-​related AIDP57; however, this obser­
vation was not confirmed in other studies58, although
different methods of antibody detection were used. Some
data suggest that the autoantibody response in AIDP
is directed towards the Schwann cell surface. Indeed,
complement C3d and C5b-9 deposition on the outer
surface of the Schwann cell, but not on the compact
myelin, has been observed in sural nerve biopsy sam­
ples from three patients with AIDP46. On the basis of
these data combined with data from the EAN model,
antibody binding in these specific regions is speculated
to fix complement, most likely derived from serum
complement proteins or produced by infiltrating macro­
phages, which then leads to vesiculation of myelin and
macrophage-mediated demyelination. Serological studies
using indirect immunofluorescence to screen for anti­
body targets found that 24% of patient sera bound to
proliferating, non-​myelinating Schwann cells in vitro59
and 44% of sera from patients with AIDP bound to the
node or paranodal region, as shown by indirect fluores­
cence on teased nerve fibres60, suggesting the presence
of as-​yet unidentified targets at these sites in patients
with AIDP. One target of patient sera has been identi­
fied as contactin-​associated protein 1 (CASPR1), which
is located at the paranodal region61 (Fig. 1). Indeed, anti-​
CASPR1 IgG3 antibodies were detected in the serum of a
patient with GBS, and this response was associated with
severe neuropathic pain61.
CIDP
The clinical heterogeneity of CIDP suggests that dis­
tinct immunopathological mechanisms, such as dif­
ferent patterns of immune responses or specificities
of the antigenic targets, underlie the different subtypes of
the disorder3 (Fig.  3). The pathogenesis of CIDP has
largely been determined through the immunopatho­
logical study of nerve biopsy samples from patients.
These studies have demonstrated inflammatory cells
such as T cells and macrophages that have infiltrated the

Table 1 | Autoantibodies with clinical implications or associations in immune-​mediated neuropathies

Disease Subgroup and/or Antigens Antibody Clinical Refs
phenotype isotype implications
Acute motor axonal Pure motor GM1, GM1b, IgG Guide to GBS 253,254

neuropathy GD1a and subtype

GalNAc-​GD1a
Acute motor and sensory Motor and sensory GM1 and GD1a IgG 255

axonal neuropathy
Miller Fisher syndrome Ataxia, ophthalmoplegia GQ1b and GT1a IgG 225,226

and areflexia
Pharyngeal–cervical– Oropharyngeal, facial and GT1a, GQ1b and IgG 256

brachial variant of GBS neck and shoulder muscle GD1a

weakness
Multifocal motor Motor GM1 and complex IgM Diagnostic guide 257

neuropathy GM1:GalC
Anti-​MAG neuropathy Sensory and ataxia MAG IgM 102

CANOMAD and CANDA Sensory and ataxia GD3, GD1b, GT1b IgM 167,258

and GQ1b
Chronic inflammatory Aggressive onset and initial Contactin 1 IgG4 Poor response to 79,259,260

demyelinating axonal involvement IVIG

polyradiculoneuropathy
Tremor, ataxia and distal NF155 IgG4 243,244,261

motor involvement
Subacute onset, sensory NF186 and NF140 IgG4 Good response to 87

ataxia and conduction block IVIG and steroids

CANDA, chronic ataxic neuropathy with disialosyl antibodies; CANOMAD, chronic ataxic neuropathy with ophthalmoplegia,
monoclonal proteins, cold agglutinins and disialosyl antibodies; GBS, Guillain–Barré syndrome; Ig, immunoglobulin; IVIG,
intravenous immunoglobulin; MAG, myelin-​associated glycoprotein; NF, neurofascin.

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GM1 Cer GD1A Cer GT1A
GM1b Cer GD1B Cer GT1b
GM2 Cer GD3 Cer GQ1b
Galactose Glucose N-acetyl galactosamine N-acetyl glucosamine
Fig. 2 | Structure of glycolipids to which antibody responses have been detected in immune-​mediated neuropathies.
Serum antibodies against GM1a, GM1b, GD1a and GalNAc-​GD1a are frequently found in patients with acute motor axonal
neuropathy250, whereas the Miller Fisher syndrome and Bickerstaff brainstem encephalitis variants are associated with
anti-​GQ1b antibodies251. SGPG, sulfated glucuronyl paragloboside.
nerve through the perivascular space or are dispersed
throughout the perineurium and endoneurium62. These
inflammatory cells likely contribute to breakdown of the
blood–nerve barrier. Indeed, disruption of the blood–
nerve barrier has been observed in CIDP and can be
visualized using MRI as gadolinium enhancement at
demyelinative foci in the nerve trunks63 and spinal nerve
roots and plexuses64. Most of these pro-​inflammatory
cells cluster around endoneurial blood vessels and are
predominantly macrophages with fewer CD8+ and CD4+
T cells62. In CIDP, resident and recruited macrophages
act as antigen-​presenting cells that perpetuate the
immune response within the nerve and act as the end-​
stage effector cells of demyelination65. Ultrastructural
studies of nerve biopsy samples from patients with CIDP
have demonstrated macrophages that extend their pro­
cesses between the myelin lamellae, resulting in splitting
and destruction of the myelin66.
Activated CD4+ T cells67, including pro-​inflammatory
T helper 17 (TH17) and TH1 cells68, are increased in the
blood of patients with CIDP. These increases point to
a potential pathogenetic role for these T cell subsets in
contributing to blood–nerve barrier breakdown owing to
their release of pro-​inflammatory cytokines and various
proteinases that affect blood–nerve barrier function and
amplification of the inflammatory response via release
of chemotactic molecules and inflammatory cytokines.
Moreover, differences in immune activation, such as
T cell responses, could partly explain the clinical hetero­
geneity of CIDP. For example, autoreactive myelin-​
specific T cell responses and memory T cell subsets,
CD4+ effector memory T cells and CD4+ central mem­
ory T cells are increased in the blood of patients with
atypical CIDP variants such as distal acquired demyelin­
ating symmetric neuropathy (DADS), multifocal acqui­
red demyelinating sensory and motor neuropathy
(MADSAM; also called Lewis–Sumner syndrome) and
pure motor or sensory CIDP compared with those with
typical CIDP69. In addition, cellular immunoregulatory
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Cer Asialo-GM1 Cer
Cer LM1 Cer
Cer SGPG Cer
SO4
Neuraminic acid Glucuronic acid Cer Ceramide
systems might be dysfunctional or diminished in CIDP70.
Indeed, CD4+CD25highFOXP3+ regulatory T cells from
patients with CIDP have a reduced ability to suppress
proliferative responses of pro-​inflammatory T cells com­
pared with regulatory cells from healthy controls71. CD8+
T cells have also been observed in nerve biopsy sam­
ples and the peripheral blood of patients with CIDP72,73.
Enrichment of these CD8+ T cell clones within the nerve
indicates that the expansion is likely to be antigen driven,
although the antigen responsible is yet to be identified.
CD8+ T cells might have a role in damage of periph­
eral nerve components in patients with CIDP, such as
Schwann cells. Supporting this role of CD8+ T cells is
the upregulation of MHC class I molecules on Schwann
cells74,75. Analysis of the T cell repertoire in patients with
CIDP with and without IVIG treatment found a higher
number of oligoclonal expansions of CD8+ T cells than
of CD4+ T cells, which was reduced after treatment with
IVIG76. This broad activation of CD8+ T cells suggests
a crucial role for this cell type in the pathogenesis of
CIDP and that multiple peptides might stimulate the
antigen-​driven response.
Humoral immune mechanisms, such as antibod­
ies, complement or cytotoxic inflammatory molecules,
might also have a role in CIDP. Supporting this hypoth­
esis is the rapid improvement of some patients after
plasma exchange and the presence of immunoglobulin
and complement on myelin and Schwann cells in sural
nerve biopsy samples from patients77. In addition, the
serum of patients with CIDP who were responsive to
plasma exchange resulted in demyelination and nerve
conduction block in rats, suggesting a role for autoreac­
tive antibodies in CIDP pathophysiology78. Despite these
findings, the role of myelin proteins as autoantigens in
CIDP has not been confirmed. Autoantibody responses
to myelin P2 protein, myelin protein P0, PMP22 and
connexin have been reported in some studies, but other
studies did not detect these responses77. In addition to
these myelin proteins, other potential autoantigens in
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Schwann cell
Paranodal detachment microvilli Demyelination

Unidentified
Myelin antigen
Macrophage
Complement
Autoantibody

Axonal damage
AMAN Glycolipid Ca2+ AIDP

CIDP MMN
CASPR1
Axonal damage
NF186 NrCAM
Contactin 1 Gliomedin Membrane IgM
attack complex
NF155 Unidentified
antigen

Paranodal detachment
T cell
Demyelination

Fig. 3 | The potential role of autoantibodies in immune-​mediated neuropathies. Autoantibodies can cause axonal
damage or demyelination via multiple pathways. In acute motor axonal neuropathy (AMAN), autoantibodies can induce
the formation of the terminal complement complex (also known as the membrane attack complex), which damages the
axon and drives macrophage activation, including macrophage penetration of the internodal periaxonal space;
in addition, paranodal detachment, nodal lengthening, sodium channel clustering and alterations in ion and water
homeostasis can be found. In acute inflammatory demyelinating polyradiculoneuropathy (AIDP) as well as chronic
inflammatory demyelinating polyradiculoneuropathy (CIDP), autoantibodies induce demyelination, which involves
complement and macrophage activation, although the target antigens are better understood in CIDP. In addition, the role
of CD8+ lymphocytes damaging the peripheral nerve has recently been described in greater detail. The in situ activation of
CD8+ lymphocytes might indirectly be co-​mediated via macrophage activation through autoantibodies. In multifocal
motor neuropathy (MMN), autoantibodies facilitate axonal damage and the disruption of sodium channel clustering252.
CASPR1, contactin-​associated protein 1; NF, neurofascin; NrCAM, neuronal cell adhesion molecule. Adapted from
refs1,80,154, Springer Nature Limited.

CIDP include proteins located in non-​compact myelin
and the axoglial junctions at the node of Ranvier, para­
node and juxtaparanode61,77,79,80; disturbances of these pro­
teins can result in impairment of conduction and nerve
conduction block81. Supporting the role of these proteins,
irregularities in the paranodal loops, including vacuola­
tion at the paranodes in the Schwann cell cytoplasm and
abnormal expression and distribution of certain axoglial
proteins, such as diffuse rather than compartmental­
ized expression of the paranodal protein CASPR1, have
been demonstrated in nerve biopsy samples from patients
with CIDP82. In addition, serum from patients with
CIDP binds either to the nodes of Ranvier or to the para­
nodes of teased nerve fibres in 30% of cases60. Further
studies identified some of the target antigens as the
nodal proteins neurofascin 186 (NF186) and gliomedin,
and the paranodal proteins NF155 and contactin 1,
although the antigens are unknown in the remainder of
cases77 (Table 1). In the EAN model, the nodal expres­
sion of NF186 and gliomedin is disrupted before the
onset of clinical signs and demyelination and coincides
with the generation of autoantibodies against NF186
and gliomedin83. These axoglial proteins at the node of
Ranvier play a pivotal role in the compartmentalization
of the myelinated axon into the node, paranode and
internode. Compartmentalization is required for sal­
tatory conduction as it maintains segregation of the
voltage-​gated sodium and potassium channels involved
in the transmission of action potentials. Disruption or
disorganization of these regions can result in slowed
or blocked nerve conduction. In addition, the passive
transfer of anti-​pan-neurofascin and anti-​gliomedin
antibodies exacerbates EAN and causes a decrease in
the clustering of nodal proteins and disorganization
of the nodes of Ranvier77. Nerve biopsy samples from
patients with anti-​NF155 or anti-​contactin 1 antibod­
ies provide evidence that this subgroup is distinct from
those with typical CIDP in that the main pathological
characteristic is paranodal detachment and loss of sep­
tate junctions at the paranode, without macrophage-​
mediated demyelination or onion bulbs (structures that
are formed after repeated episodes of demyelination
and remyelination, which result in concentric layers of
Schwann cells and fibroblasts around the nerve fibre)84,85.
Serum antibodies to the peripheral nerve ganglioside
LM1 were detected in patients with CIDP and found to
be more frequently associated with ataxia, potentially
reflecting the anatomical distribution of LM1 in the

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nervous system86. In addition, autoantibody responses
to the nodal proteins NF140 (refs61,87) and the para­
nodal protein CASPR161 have also been demonstrated
in patients with CIDP, but only in a very small number
of patients. Targeting CASPR1 could result in damag­
ing the axoglial junction, whereas NF140 is a neuronal
neurofascin isoform that promotes the assembly of the
node of Ranvier.
MMN
The first descriptions of MMN reported the presence of
anti-​GM1 IgM antibodies and responsiveness to IVIG as
features distinguishing the disorder from amyotrophic
lateral sclerosis (ALS)88. Anti-​GM1 IgM antibodies are
found in 43–85% of patients with MMN89 depending
on the antibody detection method used. The patho­
genicity of these antibodies is unclear, although it is
assumed that their effect is analogous to anti-​GM1 IgG
antibodies in AMAN, whereby they bind at the nodes
of Ranvier and activate complement, which disrupts
sodium channel clustering, leading to conduction block
in electrophysiological studies90 (Fig.  3). Serum from
patients with MMN positive for anti-​GM1 IgM anti­
bodies can activate complement in vitro and in vivo91,92;
anti-​GM1 IgM antibodies that have a high complement-​
activating capacity are associated with more severe
muscle weakness and axonal loss than anti-​GM1 IgM
antibodies with low complement-​activating capacity
in patients with MMN93. Anti-​GM1 IgM from patients
with MMN can also bind to motor neurons differenti­
ated from human iPSCs, leading to disturbed calcium
homeostasis through both complement-​dependent and
complement-​independent mechanisms94, in addition
to complement-​mediated axonal damage, which was
abrogated in the presence of IVIG94.
Nerve biopsy samples from the site of conduction
block in patients with MMN have revealed axonal degen­
eration and loss as well as frequent and prominent regen­
erating fibres95. Collateral reinnervation by surviving
motor units compensates for axonal loss and preserves
compound muscle action potentials (CMAPs)96. In this
study, axonal pathological changes predominated over
myelin pathology; however, other studies have demon­
strated demyelination and onion bulbs97. Intriguingly,
infiltrating inflammatory cells are very rarely reported
in biopsy samples from patients with MMN, posing the
question of how circulating anti-​GM1 IgM antibodies
access the endoneurium98. One possibility is that sera
from patients with MMN contains unidentified humoral
factors that lead to blood–nerve barrier dysfunction via
an increase in vascular endothelial growth factor (VEGF)
secretion from endothelial cells or an unknown IgG that
binds to endothelial cells99. Electrophysiological studies
have suggested that nodal or paranodal dysfunction
contributes to the conduction block observed in patients
with MMN. An immune-​mediated sodium channel
dysfunction has been hypothesized by some, in which
Na+/K+-ATPase pump function is potentially impeded by
antibody binding100,101. Owing to the implicated involve­
ment of nodal regions in the pathophysiology of MMN,
it has been suggested that this disorder should also be
classified as a nodopathy101.
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IgM MGUS polyneuropathies
Approximately 50% of patients with IgM MGUS neuro­
pathy have anti-​MAG autoantibodies, the first antigenic
target to be identified in immune-​mediated neuro­
pathies102. Anti-​MAG antibodies can be detected in the
serum of patients103 and can bind to myelin in nerve
sections 104. Nerve biopsy samples of patients with
anti-​MAG antibodies have demyelination and axonal
loss, and splitting of the outer layers of myelin can be
observed in ultrastructural studies105. These areas of
damage are often colocalized with IgM and complement
(C3d) depositions on the outer rim of the myelin104,106
and on the terminal loops of myelin at the paranodes107.
Furthermore, a study of skin biopsy samples from
patients with anti-​MAG IgM MGUS neuropathy demon­
strated anti-​MAG IgM accumulation within the nerve
perineurium that was associated with axonal degen­
eration and disruption of the axonal cytoskeleton108,
although the precise mechanisms remain unclear. Serum
from patients with anti-​MAG antibodies can cause
demyelination and widening of the myelin lamellae in a
complement-​dependent manner when passively trans­
ferred into experimental models, in which antibodies
in the serum bind to the outer surface of myelin109, the
nodes of Ranvier and Schmidt–Lanterman incisures,
a tube-like compartment of Schwann cell cytoplasm that
crosses the compact myelin and connects the abaxonal
and adaxonal Schwann cell membranes110. Almost all
anti-MAG antibodies cross-​react with the peripheral
nerve glycolipid sulfoglucuronyl glycosphingolipid
(SGPG)111. Unlike MAG, which is expressed in both the
central nervous system (CNS) and PNS, SGPG is exclu­
sively expressed in peripheral nerves, making it a likely
target in peripheral neuropathy. Anti-​sulfatide, anti-​
chondroitin sulfate C and anti-​ganglioside antibodies
can also be found in patients with IgM MGUS30, which
may have similar pathogenetic mechanisms.
Diagnosis, screening and prevention
Patients with immune-​mediated neuropathies pres­
ent with diverse clinical manifestations. Patients with
GBS seek medical help because of rapidly evolving
muscle weakness that can lead to respiratory muscle
fatigue and failure, whereas CIDP can have an insidious
onset and patients can present late in the course of the
disease. The typical presentation of MMN is pure motor
paresis of an upper limb muscle, but symptoms can start
in the lower limbs in rare cases. The following diagnostic
procedures help to rapidly make the correct diagnosis
and assign patients to the optimal treatment (Fig. 4).
GBS
Clinical manifestations. GBS manifests as a rapidly
progressing muscle weakness and sensory disturbance
in arms, legs and, in some patients, facial, bulbar and
respiratory muscles. The typical clinical manifesta­
tions of GBS (that is, whereby symptoms develop after
gastrointestinal or respiratory infections, followed by
neuropathic back pain, distal paresthesias and progres­
sive symmetrical flaccid paresis with a nadir within
4 weeks, in the absence of bladder disturbance) are easily
identifiable. Sensory deficits (such as hypesthesia and
 Primer

Progressive or relapsing pareses with or without sensory deficit and reduced or no tendon reflexes

Duration <2 months Duration ≥2 months

Electrophysiological Electrophysiological and laboratory examination Other family members

examination (including CSF analysis) with similar symptoms

Electrophysiological and Electrophysiological and supportive

Electrophysiological
CSF criteria fulfilled; CSF criteria not fulfilled
criteria fulfilleda
other causes excluded

Signs of inflammation on MRI or

demyelination in biopsy samples
Consider GBS

Consider Consider Consider Consider hereditary

AMAN AIDP CIDP neuropathy

Fig. 4 | Diagnostic algorithm. A clinical duration of symptoms for ≥2 months is the clinical discriminator between Guillain–
Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). As part of the diagnostic
work-​up of patients, nerve conduction studies are carried out to examine for signs of demyelination and can be used to
identify patients with demyelinating diseases (such as CIDP or acute inflammatory demyelinating polyradiculoneuropathy
(AIDP)) or those with axonal pathologies (such as acute motor axonal neuropathy (AMAN)). Signs of demyelination in nerve
conduction studies include a partial conduction block, reduced motor nerve conduction velocity, prolonged distal latency
of the motor nerve and the absence of F-​waves or a prolonged F-​wave latency. In addition to these studies, laboratory tests
such as cell counts and the assessment of protein levels in cerebrospinal fluid (CSF) help to evaluate supportive criteria and
can rule out other causes of disease. For CIDP, pleocytosis of <10 cells μl–1 is a supporting criterion. If other causes of
neuropathy have been ruled out, and the electrophysiological and supportive criteria are fulfilled, patients can begin
term anti-​inflammatory and immunosuppressive therapies. In difficult cases, such as in patients with unfulfilled electro-
physiological and CSF criteria, MRI or nerve biopsy might be helpful to identify demyelinating lesions. aNote that
electrophysiological criteria for GBS might be negative during the first 1–2 weeks.

hypoalgesia) can vary; asymmetrical sensory deficits are
not uncommon, and in rare cases, sensory deficits can
have a pattern with a pseudo-​sensory level suggesting
myelopathy. Approximately 10% of patients with AMAN
have preserved or even exaggerated tendon reflexes112,
which might raise doubt about the diagnosis. Patients
with AMAN more frequently have a preceding C. jejuni
infection, have predominant motor neuropathy with
very little sensory involvement and less frequently have
cranial nerve involvement compared with patients
with AIDP. MFS, characterized by ophthalmoplegia,
areflexia and ataxia, is clinically very distinctive. Other
subtypes of GBS include AMSAN, which manifests
similar to AMAN but with more pronounced sensory
involvement, in addition to a pharyngeal–cervical–
brachial variant16,113, which manifests with rapidly pro­
gressive oropharyngeal and cervicobrachial weakness
associated with areflexia in the upper limbs. The latter has
also been regarded as part of a continuum from GBS to
Bickerstaff encephalitis114.
Diagnostic work-​up. In a typical case of GBS that is
preceded by an infection and by back pain, the diag­
nosis is straightforward. However, several disorders
mimic the symptoms of GBS, and diagnosis can be
more difficult in atypical cases. Diagnostic criteria for
GBS were first developed by the US National Institute
of Neurological Disorders and Stroke (NINDS) in 1978
and were subsequently revised115,116. The latest revision
under the Brighton criteria was developed in response to
the 2009–2010 H1N1 swine flu vaccination campaign116;
these criteria now enable clinical assessment to four
levels of diagnostic certainty.
High protein and albumin levels in the cerebrospinal
fluid (CSF) with normal cell counts (referred to as the
albuminocytologic dissociation) is considered patho­
gnomonic for GBS in patients with the typical clinical
presentation. However, CSF protein and albumin levels
are normal in 50% of patients during the first week after
presentation16, which requires repeat lumbar puncture
to ascertain elevated protein if there are doubts about
the diagnosis. In addition, pleocytosis of 10–50 cells µl–1
is found in ~15% of patients with GBS, which may
confound diagnosis117.
Clinical electrophysiology, particularly NCS, which
can be used to assess for signs of demyelination or axonal
damage, can help to support the diagnosis of GBS and
can identify AIDP and AMAN subtypes (Table 2). NCS
should be performed within the first week after pres­
entation to confirm the diagnosis; however, if nerve con­
duction is within normal ranges initially, NCS should
be repeated >2 weeks after onset as abnormalities might
peak at this time118. At least four motor nerves including
F-​waves (late potentials yielding information on prox­
imal nerve and root segments, which may be affected
early in this polyradiculoneuropathy) and three sensory

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nerves should be investigated to increase the diagnostic
yield16. As AIDP is the most frequent type of GBS in
Europe and North America, detection of demyelination
is important to support the diagnosis, although to date
no final consensus about which neurophysiological cri­
teria are optimal for confirming the diagnosis of GBS
and identifying subtypes has been reached52. The cur­
rent neurophysiological criteria for demyelination are
summarized in Table  2. Nerve conduction velocities
(NCVs) might remain normal until up to 3 weeks after
onset of symptoms; thus, normal NCVs early in the dis­
ease course do not exclude a diagnosis of AIDP119. Signs
of axonal pathology (such as reduced CMAP, amplitude
loss and signs of denervation on electromyography) in
isolation occur in 3–30% of patients with GBS115 and
do not contradict a diagnosis of AIDP. In one study,
24% of patients with an initial diagnosis of AIDP were
rediagnosed with AMAN after NCS were performed10;
however, distinguishing AIDP from AMAN in the early
phase of the disease is not crucial as this does not guide
therapy (see Management).
Nerve biopsy is not recommended for the diagno­
sis of GBS, although it can be used to exclude other
disorders, such as rapidly progressive peripheral nerve
vasculitis. In some patients, even in those without previ­
ous symptomatic infection, associated pathogens can be
isolated from stool or sputum samples, or a correspond­
ing acute humoral response against these pathogens
can be detected in serum and CSF. The most common
pathogens are C. jejuni (found in 20–30% of cases),
CMV (~10% of cases)15,120, Epstein–Barr virus (2–10% of
cases) and M. pneumoniae (1–5% of cases)121. However,
the detection of these pathogens is not specific enough
to aid in the diagnosis of GBS.
Although a number of autoantibodies have been
detected and studied in GBS122 (Table 1), none is of direct
diagnostic value, with the exception of GQ1b antibodies
in MFS. Antibodies against paranodal proteins are asso­
ciated with acute-​onset CIDP79 (that is, a GBS mimic),
but their testing is rarely indicated in acute GBS. New
technologies have begun to identify antibodies that
bind to multiple gangliosides or glycolipids50,51,123. These
antibodies bind to mixtures of different ganglio­sides
arranged as they would be on cell membranes in vivo
rather than binding to individual gangliosides. Screening
patient sera for ganglioside or glycolipid complexes

Table 2 | Characteristics of immune-​mediated neuropathies

Symptoms
Guillain–Barré syndrome
• The first symptoms are
combinations of numbness,
paresthesia, weakness and
pain in the limbs
• Other symptoms include
bilateral weakness of facial
muscles (owing to cranial
nerve involvement) and
autonomic dysfunction
• Limb muscle weakness is
progressive bilateral and
symmetric
• Progression of motor
symptoms over 12 hours to
28 days before a plateau is
reached
Chronic inflammatory demyelinating polyradiculoneuropathy
• Chronic progressive,
stepwise or recurrent
symmetric proximal and
distal muscle weakness and
sensory dysfunction of all
extremities
• Cramps and fasciculations
in the affected limb
Multifocal motor neuropathy
Slowly progressive or
stepwise progressive,
asymmetric limb weakness or
motor involvement that has a
motor nerve distribution
AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy;
CMAP, compound motor action potential; LLN, lower limit of normal. aFeatures of demyelination include prolonged distal motor latency, decreased motor nerve
conduction velocity, increased F-​wave latency, conduction blocks and temporal dispersion269.
Reflexes Nerve conduction study Nerve biopsy sample findings Nerve imaging findings
findings
Generalized In AIDP: • Nerve biopsy is not Nerve enlargement detected
hyporeflexia • Features of demyelinationa (only recommended, although can be using ultrasonography has
or areflexia assessable if the distal CMAP, used in some cases been demonstrated in early
a measure of axonal integrity • Findings from sural nerve biopsy Guillain–Barré syndrome264
amplitude, is >10% LLN) sample and autopsy include
In AMAN and AMSAN: the infiltration of T cells and
• No features of demyelination macrophages in the affected
(or one demyelinating feature nerves, plexus and nerve roots;
in one nerve if distal CMAP segmental myelin destruction
amplitude is <10% LLN) with immunoglobulin and
• Distal CMAP amplitude is <80% complement deposits; and
LLN in more than two nerves prominent, macrophage
• Transient motor nerve infiltration, even in an electro-
conduction block might physiologically normal sural
be present262 nerve263
Absent or Features of demyelinationa • Nerve biopsy is not routine • MRI can detect increased
reduced • Findings from sural nerve signal intensity or contrast
tendon biopsy samples include: signs enhancement in the
reflexes in all of chronic demyelination roots or plexus (>50% of
extremities and remyelination; length-​ patients)64,265
dependent axonal damage; • Nerve ultrasonography
nonspecific inflammatory may show enlarged
infiltrates; and pericapillary nerves266; normalizes with
accumulation of macrophages remission267
Decreased Conduction block Increased number of thinly • T2-hyperintense or
or absent myelinated, large-​calibre fibres; gadolinium-​enhancing
tendon very mild degree of sensory fibre areas in the brachial plexus
reflexes in involvement268 (one-​third of patients)
the affected • Multifocal nerve
limb enlargement on nerve
ultrasonography

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Box 2 | Predicting the clinical course and treatment response of GBS
mEGOS — modified Erasmus GBS Outcome Score
Captures:
• Age
• Preceding diarrhoea
• GBS disability score 2 weeks after hospitalization
Scores range from 1 to 7 and predict the clinical outcome after 6 months; a higher score
corresponds to worse prognosis.
EGRIS — Erasmus GBS Respiratory Insufficiency Score
Captures at time of hospital admission:
• Days between clinical onset of weakness
• Facial and/or bulbar weakness
• MRC sum score
The scoring system ranges from 0 to 7, with corresponding chances of respiratory
insufficiency within the first week after hospital admission from 1% to 91%.
ΔIgG
• Increase in serum IgG levels 2 weeks after treatment with intravenous immunoglobulin
Larger increase is associated with a better clinical outcome.
GBS, Guillain–Barré syndrome; IgG, immunoglobulin G; MRC, Medical Research Council.
increases sensitivity compared with using single mol­
ecules in the detection method but is not yet widely
available clinically owing to the complexity of the assays.
Although associations between anti-​ganglioside com­
plex antibodies and clinical phenotypes are still emerg­
ing, they can give some insight into clinical subtypes,
progression and management54.
Differential diagnosis. Increased CSF cell counts (par­
ticularly >50 cells µl–1) can indicate infection with CMV
or lyme borreliosis, or can suggest HIV radiculitis, trans­
verse myelitis or poliomyelitis. Blood tests can exclude
hypokalaemia as a rare cause of acute muscle weakness
and vitamin B6 deficiency, such as in the context of levo­
dopa pump treatment124. If patients have asymmetric
muscle weakness, then vasculitic neuropathy, lyme
borreliosis, diphtheria and poliomyelitis should be con­
sidered, whereas in patients with pure motor weakness,
myasthenia gravis, polymyositis and dermatomyositis,
poliomyelitis, hypermagnesaemia, porphyria, botulism
and lead or organophosphate poisoning should be ruled
out16. NCS are helpful to rule out disorders that are not
caused by neuropathy (such as myasthenia gravis or
myositis), even if these studies do not prove demyelin­
ation. Spinal MRI can be used to exclude spinal cord com­
pression injury or transverse myelitis. Leptomeningeal
malignancy, especially in patients with lymphoma, can
also mimic GBS and is not always associated with an
increased CSF cell count, such that spinal MRI may
be needed125.
Prognostic tools. Various prognostic algorithms have
been developed to predict the clinical course of GBS
(Box 2). The so-​called modified Erasmus GBS Outcome
Score (mEGOS) captures patients' age, preceding diar­
rhoea and GBS disability score 2 weeks after hospital
entry; increased age, the presence of preceding diar­
rhoea and increased disability scores all correspond
to worse prognosis126. The Erasmus GBS Respiratory
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Insufficiency Score (EGRIS) predicts the development
of respiratory insufficiency within 1 week after hospital
admission and is based on the number of days between
the onset of muscle weakness and hospital admission,
clinical assessment by the Medical Research Council
(MRC) sum score indicating the extent of muscle weak­
ness and the presence of facial and/or bulbar weakness,
altogether indicating severity of disease and, therefore,
the likelihood of respiratory insufficiency127. Both meas­
ures have recently been assessed in a Japanese multi­­
centre cohort of patients with GBS and could reliably
predict respiratory insufficiency128.
CIDP and CIDP subtypes
Clinical manifestations. As in GBS, the clinical mani­
festations of CIDP include an acquired progressive
symmetric sensorimotor neuropathy. However, in con­
trast to GBS, CIDP must be progressive for ≥8 weeks
to fulfil the diagnostic criteria. Motor deficits dominate
in patients with CIDP, and proximal and distal muscle
weakness should be present for diagnosis; distal promi­
nence is often present. Hyporeflexia or areflexia is pres­
ent in most patients129. Facial nerve involvement is found
in 10–15% of patients whereas 5% have oculomotor
nerve involvement, although cranial nerve involvement
or autonomic involvement is rarer in patients with CIDP
than in those with GBS. Sensory deficits occur in up to
90% of patients129,130; pain can be the initial symptom
in rare cases131, although it is present in up to 70% of
patients in the long term132. About half of patients devi­
ate from this typical manifestation and have severe dis­
tal sensory involvement, asymmetrical muscle weakness
or substantial cranial nerve involvement. Up to 10% of
patients have subclinical signs of CNS involvement or
central demyelination in neurophysiological studies
or MRI133,134.
CIDP subtypes include pure motor CIDP or pure
sensory CIDP, which are both believed to comprise
~10% of CIDP cases; few reports broaden this spec­
trum to include axonal variants of CIDP (that is, chronic
inflammatory axonal polyneuropathy (CIAP))135. Some
forms of initial pure sensory CIDP can progress to
include the development of motor symptoms after a
few years. The distal subtype of CIDP, DADS, is charac­
terized by pronounced paresis of the small hand and
foot muscles and often a severe sensory afferent deficit
with unsteady gait136 and is frequently associated with
a monoclonal gammopathy. Anti-​MAG antibodies can
be detected in approximately two-​thirds of patients
with DADS, which might prompt a diagnosis of IgM
MGUS neuropathy. In patients with DADS, clinical
neurophysiology shows marked distal demyelination
in motor nerves, indicated by greatly prolonged distal
motor latencies. The response to immunotherapy in
patients with DADS and other IgM-​associated neuro­
pathy is on average worse than in classical CIDP137.
MADSAM neuropathy is a chronic progressive multi­
focal asymmetric neuropathy with signs of demyelin­
ation. MADSAM is considered a CIDP subtype by some
clinicians but as a separate immune-​mediated neuro­
pathy by others. In this disorder, the upper extrem­
ities are dominantly affected, without a generalized
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Box 3 | Autoantibodies in CIDP: implications for diagnosis and management
Intense focus on anti-​paranodal antibodies in patients with chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP) has led to defined subgroups of patients
with common clinical phenotypes. For example, anti-​contactin 1 antibodies have
been found in 2.4–8% of patients with CIDP55, and those positive for contactin 1
immunoglobulin G4 (IgG4) are poor or partial responders to intravenous
immunoglobulin (IVIG) therapy and are characterized by certain clinical characteristics,
including rapid onset, early axonal damage and motor predominance, sensory ataxia
and tremor55. Anti-neurofascin 155 antibodies have been found in 4–18% of patients
with CIDP193,244,246, and patients with anti-​neurofascin 155 IgG4 antibodies are poor or
partial responders to IVIG and have characteristic clinical phenotypes, including a
disabling tremor and distal motor neuropathy with ataxia. Antibodies to contactin-​
associated protein 1 have been associated with Guillain–Barré syndrome-​like and
CIDP-​like disease with prominent pain61. The detection of these patient subgroups is
important, as these patients might respond better to plasma exchange and anti-​B cell
therapies, such as rituximab, than to standard CIDP treatment247. Still, the overall
number of patients with paranodal antibodies is very low, making a definite statement
on incidence, clinical phenotypes and treatment responses difficult. Setting up an
international registry capturing this group of patients might be a helpful strategy to
better understand this subgroup of CIDP.
areflexia138. The distinction of MADSAM from MMN is
therapeutically relevant as MADSAM might respond to
steroids or IVIG whereas MMN is not steroid sensitive
(see Management).
Diagnostic work-​up. The diagnosis of CIDP is less
straightforward than that of GBS137 (Table 2). No defini­
tive test or biomarker is available for CIDP; accordingly,
several diagnostic criteria have been developed, pri­
marily for use in clinical trials. These criteria are com­
posed of clinical, laboratory and electrophysiological
parameters. Electrophysiological criteria are designed
to detect demyelination, although these should be
used only in conjunction with results from clinical and
labora­tory findings owing to the presence of demyelin­
ation in other neuropathies. Axonal pathologies, whether
primary or secondary to demyelination, are common
and do not exclude the diagnosis of CIDP. At least
15 different sets of diagnostic criteria for CIDP have
been published139, of which the criteria of the EFNS/
PNS had the best sensitivity and specificity 137,139.
However, the sensitivities and specificities of each cri­
terion differ between studies, and some of the criteria
sets differentiate between probable, possible and defi­
nite CIDP, which also leads to different sensitivity and
specificity values.
Elevated CSF protein in conjunction with normal or
only mildly elevated CSF cell count (<10 cells µl–1) is a
supportive criterion for CIDP. Although older studies
reported elevated CSF protein in ~90% of patients with
CIDP3,140, this may not hold true if current clinical and
electrophysiological criteria are used and in chronic
progressive forms141. In addition, >50 white cells µl–1 in
the CSF rules out a diagnosis of CIDP. A clinical pic­
ture of CIDP, sometimes with an acute onset, may be
found in patients with antibodies to the paranodal pro­
teins NF155, contactin 1, or CASPR1 (refs61,80) (Box 3).
Neuropathies with this constellation have been named
‘paranodopathies’. The distinction is of importance
because symptoms may respond better to plasmaphere­
sis and B cell therapies than to standard CIDP treatment.
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Nerve and root imaging are starting to be integrated into
the routine diagnostic work-​up of CIDP (Table 2). Nerve
biopsy (usually of the sural nerve) is not part of the rou­
tine work-​up in CIDP but can be carried out in patients
with atypical clinical manifestations2 or to search for
an alternative diagnosis if patients have no response to
immunotherapy142. Ultrasonography or MRI can guide
nerve biopsy if the sural nerve is not affected and fasci­
cular biopsy of a mixed nerve is considered. MRI-​guided
fascicular biopsy of the sciatic nerve and of the lumbar
or brachial plexus has been described, has demonstrated
abnormalities in patients with CIDP and has few adverse
effects, although data are lacking regarding the exact
clinical yield in comparison to other methods143. Corneal
confocal microscopy, which is available in collaboration
with ophthalmological departments, has been suggested
as an additional technical method in diagnosing and
monitoring CIDP144.
The presence of several clinical or laboratory features
can be used to exclude a diagnosis of CIDP. Clinical
manifestations or other disorders that exclude CIDP
diagnosis include retinitis pigmentosa; ichthyo­sis; evi­
dence of a hereditary disorder or an adequate toxin
exposure; a sensory level indicating a spinal cord lesion;
sphincter dysfunction; hypocholesterolaemia; vitamin
B12 deficiency; untreated hypothyroidism; porphyria;
electrophysiological findings of myasthenia gravis
myopathy or anterior horn disease; and biopsy sample
evidence of a storage disease, vasculitis or amyloidosis.
Differential diagnosis. One of the clinical challenges is
the distinction between CIDP with acute onset and GBS.
Acute CIDP and GBS have similar clinical presentations
during the first 4 weeks, particularly if patients with GBS
present with treatment-​related symptom fluctuations.
The differentiation of acute CIDP and GBS is impor­
tant as treatment strategies and prognosis differ (see
Management)145. Although patients with acute CIDP
seem to exhibit a higher frequency of sensory symptoms
than those with GBS, the clinical differentiation of both
entities remains difficult146. The differential diagnosis of
paediatric-​onset CIDP from hereditary neuropathies is
challenging and genetic testing may be needed. Given
the limited number of cases reported thus far, children
diagnosed with CIDP have a more favourable long-​term
course than adults with similar treatments147. Distal sym­
metric polyneuropathy is the most common neuropathy
seen in patients with diabetes mellitus. However, these
patients can also develop CIDP, and whether diabe­
tes mellitus predisposes to CIDP is controversial. The
different treatment strategies of CIDP and distal sym­
metric polyneuropathy mandate for a thorough clinical
differentiation of diabetic and immune-​mediated neuro­
pathies148. Infrequently, patients with primary axonal
neuropathies, such as vasculitis149 or hereditary amyloid­
osis150, can reveal electrophysiological abnormalities
in the range of a demyelination similar to that observed in
patients with CIDP151. Late-​onset hereditary neuropa­
thies of the Charcot–Marie–Tooth (CMT) type often
fulfil the CIDP diagnostic criteria but do not respond
to CIDP therapies150, such that, when the diagnosis is
in doubt, genetic testing with a panel for demyelinating

CMT may be needed. In addition, some therapies, such
as amiodarone, can cause a demyelinating neuropathy
mimicking CIDP152.
As the clinical presentations of GBS reach their
nadir within 4 weeks and in >8 weeks in CIDP, a gap
evolved for those immune-​mediated neuropathies in
which progressive motor and/or sensory deficits pre­
sented with a time to nadir between 4 and 8 weeks.
These neuropathies are called subacute inflammatory
demyelinating neuropathies (SIDPs)153, bridging the
gap between GBS and CIDP. Diagnostic criteria are
similar, including elevated high spinal fluid protein
level (>55 mg dl–1) and inflammatory cells in the nerve
biopsy sample.
MMN
Clinical manifestations. MMN is characterized by slowly
progressive or, less frequently, episodic asymmetric
paresis that follows the distribution of individual nerves
and starts most often in the arms, without obvious sen­
sory loss10. The ulnar, median, radial and tibial nerves
are most commonly affected. Weakness of muscles
innervated by the same nerve can differ considerably
within patients, indicating an irregular pattern of nerve
involvement154. Proximal pareses are the main symptom
in only 5% of patients and leg pareses in 10% of patients.
The early stages of MMN are characterized by paresis
without muscle atrophy, but muscle atrophy is pro­
nounced at later stages of disease155. Fasciculations may
be observed. Muscle strength might deteriorate in cold
temperatures and after exercise. Reflexes are attenuated
within the paretic regions, although complete areflexia
and hyperreflexia are rare. In addition, approximately
half of patients have muscle cramps and fasciculations,
whereas cranial nerve involvement is observed only in
2% of patients154. Mild sensory symptoms might develop
over time in ~20% of patients156, although pain or
autonomic symptoms are not part of the syndrome.
Diagnostic work-​up. Diagnostic criteria for MMN are
based on clinical, electrophysiological and laboratory
characteristics10,157. Conduction block demonstrated in
NCS in motor nerves outside entrapment sites (such as
the carpal or cubital tunnel) supports the diagnosis of
MMN. Although the presence of conduction block has
an important role in the diagnosis of MMN, its definition
varies between expert groups and in the sets of diagnos­
tic criteria. Whether the presence of conduction block
is obligatory for the diagnosis of MMN is debated, and
the EFNS/PNS diagnostic criteria allow for a diagnosis
of possible MMN in the absence of conduction block158.
The detection rate of conduction block in patients with
MMN depends on the number of nerves investigated,
and conduction blocks in proximal nerves might be par­
ticularly difficult to detect. Patients with MMN with and
without evidence of conduction block may respond to
IVIG treatment159.
In addition to conduction block, other signs of
demyelination, such as prolonged distal motor laten­
cies and slowed NCV, are variable in patients with
MMN. Denervation and regeneration potentials can
be detected using electromyography in paretic muscles
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depending on the extent of secondary axonal degen­
eration. In contrast to findings in patients with CIDP,
CSF shows moderately elevated protein in only 30%
of patients, which is not diagnostically helpful160. No
sensory deficits are typically observed in clinical or
electrophysiological testing.
Differential diagnosis. The differential diagnosis of
MMN includes early stages of motor neuron disease;
however, the clinical manifestation of MMN differs from
motor neuron disease by slow disease progression and
the absence of upper motor neuron and bulbar signs.
The differential diagnosis of MMN from lower motor
neuron disease might be more difficult; in this case, clin­
ical follow-​up and response to immunoglobulin therapy
provide the most useful information. Pure motor CIDP
and MADSAM might be considered in patients with
suggestive MMN. Hereditary neuropathy with pressure
palsies is usually easy to distinguish from MMN as this
disorder preferentially affects compression sites.
MGUS neuropathy
Neuropathy with MGUS is a heterogeneous condition.
Because MGUS can co-incidently be present in axonal
neuropathies of any aetiology, and in CIDP, the clini­
cal manifestations are not dependent on the presence of
MGUS. There are a few typical syndromes with neuropathy
and specific types of MGUS that are discussed below.
MGUS can be detected in 5% of the population
>70 years of age; in 90%, the paraprotein is of the IgG
or IgA type161. By definition, for a diagnosis of MGUS,
the paraprotein level must be <3 g dl–1 and the plasma
cell composition of the bone marrow is <10%. MGUS
must be distinguished from other conditions that are
associated with IgG or IgA monoclonal gammopathy,
such as POEMS syndrome, immunoglobulin light-​chain
amyloidosis, lymphoma and cryoglobulinaemia.
As neuropathies occur in 6.6% of the population
>60 years of age162, the co-​occurrence of monoclonal gam­
mopathy and neuropathy is coincidental and does not
indicate that the MGUS is causal to the neuropathy. Most
experts consider a neuropathy that fulfils the diagnostic
criteria for CIDP in a patient with an IgG or IgA MGUS
as classical CIDP. Similarly, in a patient with a mild axonal
neuropathy and concomitant IgG or IgA MGUS, the
co-​occurrence is usually considered coincidential and
the neuropathy is diagnosed as idiopathic, which has a
good prognosis and needs no specific therapy163. In other
patients, a causal connection between the paraprotein and
the neuropathy is assumed. The best-​defined subtype of
MGUS neuropathies is that associated with anti-​MAG
antibodies, which are found in up to half of the patients
with IgM MGUS. Most patients with anti-MAG anti­
bodies have the DADS phenotype with paresis of the
small hand and foot muscles (see above). Enzyme-linked
immuno­sorbent assay (ELISA) is more sensitive than
western blot for the detection of anti-​MAG anti­bodies164.
Their titre does not correlate with disease seve­rity.
Another screening test for anti-MAG antibodies is indi­
rect immunohistochemistry with patient serum on a nerve
preparation. NCS show a prolonged distal latency out
of proportion with conduction slowing in intermediate
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segments of the nerves along the upper and lower no further benefit171. IVIG is usually administered over
limbs. Nerve biopsy is not mandatory in the diagnostic 2 consecutive days; this single course is usually sufficient
work-up of anti-MAG neuropathy, but data from earlier in patients with GBS and does not require consecu­
electron microscopy studies indicate that there might tive courses in classical courses of GBS. Further trials
be enlarged spaces between the myelin lamellae165. are needed to establish the optimal dose of IVIG38 for
In patients presenting with suspected MGUS neuro­ the treatment of GBS, whether additional infusions
pathy, and in whom anti-​M AG antibodies are not are beneficial in patients with severe GBS or patients
detected, screening for other antibodies against chon­ with a clinical relapse within 8 weeks after initial dis­
droitin sulfate, gangliosides, sulfatides, sulfated or ease manifestation and to determine whether IVIG is
cytoskeletal proteins and heparin disaccharide can be effective in patients with mild GBS170,172. Change in
performed using western blot or ELISA166. The presence serum IgG 2 weeks after IVIG might represent a bio­
of these antibodies increases the likelihood of a patho­ marker for treatment response173. The clinical use of
genetic link between the paraprotein and neuropathy; IVIG is mostly safe; however, adverse effects such as
however, their diagnostic importance is uncertain. Other hypersensitivity reactions, haemolytic anaemia, asep­
IgM antibodies have been associated with MGUS neuro­ tic meningitis and thromboembolism may occur in
pathy, including anti-​G D1b, anti-​G D2, anti-​G D3, rare instances, whereas with plasma exchange adverse
anti-​GT1a, anti-​GT1b, anti-​GQ1b, anti-​GM2 or anti-​ events related to the use of citrate (hypocalcaemia and
GalNac-GD1a antibodies. IgM antibodies that bind to metabolic alkalosis) and haemodynamic changes are
the disialosyl epitope of several gangliosides such as not uncommon.
GD1b, GD2, GD3, GT1a, GT1b and GQ1b are associated Corticosteroids are not effective for the treatment
with chronic ataxic neuropathy. A chronic ataxic neuro­ of GBS regardless of whether they are used alone or in
pathy with ophthalmoplegia and bulbar involvement, combination with other therapies174. Owing to the pro­
also named chronic ataxic neuropathy with ophthal­ posed role of complement in GBS, the anti-​C5 human­
moplegia, M proteins, cold agglutinins and disialosyl ized monoclonal antibody eculizumab has been trialled
antibodies (CANOMAD), is observed in connection in patients with severe GBS175,176. However, the two trials
with asialoganglioside antibodies167. Anti-​trisulfated evaluating this drug included a small cohort, which pre­
heparin disaccharide antibodies cause a painful sensory cludes statistically valid assessment of efficacy. However,
axonal neuropathy or motor neuropathy168. these trials do indicate that eculizumab is well tolerated
in patients with GBS and that larger, multicentre, inter­
Management national trials are warranted. Mechanical ventilation,
The mainstay of treatment for the immune-​mediated often for months at a time, is required in the most severe
neuropathies is immunotherapy — particularly for acute cases of GBS in which patients develop tetraparalysis and
disorders but also for chronic variants. The low preva­ respiratory failure. At present, the treatment strategies
lence of these diseases makes it difficult to accumulate for AMAN and AIDP do not differ in clinical practice.
sufficient clinical trial data to qualify as class I evidence.
As such, recommendations for many therapies are based CIDP and CIDP subtypes
IVIG, plasma exchange and corticosteroids. Randomized
on case series or smaller open-​label studies. In addition
to immunotherapy, physiotherapies can improve clinical controlled studies (reviewed in ref.177) demonstrated
disability in patients. that plasma exchange and IVIG are of clinical benefit
in patients with CIDP, and other evidence from clinical
GBS trials, case series and anecdotes from clinical practice
The first-​line treatments for GBS are plasma exchange suggests that corticosteroids are also effective in these
and IVIG, both of which have proven clinical effi­ patients178–180. Indeed, IVIG, plasma exchange and corti­
cacy as shown in numerous double-​blinded, placebo-​ costeroids represent the mainstay of first-​line treatment
controlled clinical trials (reviewed in ref.169). These for CIDP and have a similar level of clinical efficacy.
therapies improve motor deficits in patients with GBS, IVIG treatment resulted in a significant clinical
in addition to cranial nerve involvement and sensory improvement of motor symptoms in patients with
deficits at a similar rate. Plasma exchange is a process CIDP compared with placebo181. However, the limitation
whereby the patient’s plasma is removed and discarded of earlier studies was a short observation period. The
and is replaced by donor plasma or a plasma substitute, ICE (IVIG-​C CIDP efficacy) study182 addressed some
whereas IVIG involves the intravenous delivery of puri­ of these limitations and evaluated the use of IVIG in a
fied, donor immunoglobulins into the circulation. No randomized, double-​blind, placebo-​controlled trial for
difference in the efficacy of plasma exchange or IVIG in 24 weeks, followed by a secondary round of randomi­
patients with GBS has been reported170. In patients with zation and an extension of 24 weeks. This study was the
mild GBS, two plasma exchanges administered 2 days first to demonstrate a significant clinical improvement
apart shortened the time until onset of motor recovery with long-​term IVIG therapy compared with placebo.
compared with patients not receiving plasma exchange, However, questions still remain on the optimal dose for
whereas administering four plasma exchanges every patients as well as timing and duration. Individual clini­
other day was superior to administering two plasma cal patient responses differ and require adequate clinical
exchanges in terms of the time to walk with assistance monitoring as well as dose adaptation. Similarly, the
and muscle strength recovery in patients with mod­ clinical effect of plasma exchange usually lasts only for
erate to severe GBS; additional plasma exchanges had weeks, sometimes months, and therefore may require

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continuous repetition if other treatment modalities,
which are easier to apply, fail in patients.
In a retrospective analysis, intermittent high-​dose
intravenous methylprednisolone (IVMP) improved
muscle strength in patients with CIDP, similar to the
effect observed with IVIG or oral prednisolone in these
patients183. In addition, in another study, patients who
responded to IVMP had longer-​term remission than
those on IVIG184. However, the discontinuation of treat­
ment is higher with IVMP than IVIG owing to ineffi­
cacy or an increased frequency of adverse effects185.
Prospective clinical data regarding the benefit of IVMP
should be obtained before this drug is recommended
as a standard therapy for CIDP. CIAP might res­pond
to immunomodulatory treatment in a similar way
as CIDP186.
Subcutaneous immunoglobulins. The increasing use of
immunoglobulins for the treatment of chronic immune-​
mediated neuropathies, particularly in patients who
require long-​term therapy, has led to interest in admin­
istration of subcutaneous immunoglobulin (SCIG) as
the long-​term application at home might be preferred
by some patients. To date, only two placebo-​controlled,
double-​blind clinical trials and one observational study
have reported on the efficacy and tolerability of SCIG
in patients with CIDP187. The first study demonstrated
the superiority of SCIG compared with placebo in
patients with CIDP who previously responded to IVIG
as assessed by muscle strength and functional abil­
ity169,188. The second randomized, double-​blind, placebo-​
controlled trial demonstrated a significant reduction in
the percentage of patients with CIDP relapse or treat­
ment discontinuation during 24 weeks of treatment with
SCIG compared with placebo189. In a prospective obser­
vational study, an equivalent efficacy of SCIG and IVIG
was demonstrated in these patients who switched from
IVIG to SCIG190. In addition, several case series and case
reports have corroborated the utility of SCIG in patients
with CIDP (reviewed in ref.191). As such, in countries
where reimbursed, SCIG is used as a treatment option
for patients with CIDP. The spectrum of adverse effects
is similar to IVIG, such as tolerability, headache, nausea
and local skin reactions.
IFNβ. IFNβ has numerous immunomodulatory effects
and is used for the treatment of multiple sclerosis, provid­
ing the rationale for the use of this drug in inflammatory
neuropathies.
Anecdotal observations suggest that IFNβ may be
a useful adjunctive therapeutic option in patients with
CIDP. However, in a controlled clinical trial, intramus­
cular IFNβ1a did not exhibit any clinical superiority
compared with placebo in patients with CIDP192.
Classical immunosuppressive drugs. The use of immuno­
suppressive drugs, such as methotrexate, cyclosporine,
mycophenolate mofetil and cyclophosphamide, in
inflammatory neuropathy is based on the assumption
that immunomodulatory agents that are effective in other
immune-​mediated diseases would also be of benefit in
these neuropathies. However, few immunosuppressive
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drugs have been tested in controlled clinical trials, and
the use of these drugs is largely based on anecdotal evi­
dence, which underlines the pressing need for more
rigorous clinical evaluation.
Only a few studies have evaluated the use of metho­
trexate monotherapy in patients with CIDP193. In a series
of ten patients, seven increased muscle strength by
≥2 points on the MRC sum score with weekly low-​dose
oral methotrexate, although three patients deteriorated.
In this study, only two patients had an improvement in
disability, although these patients were also receiving
corticosteroid treatment193. In a randomized controlled
trial of 59 patients with CIDP, no benefit in methotrexate
was demonstrated compared with placebo188. Thus, at
present, data are insufficient to recommend low-​dose
methotrexate as a standard immunosuppressive therapy
in patients with CIDP.
Cyclosporine should be considered only in patients
resistant to more conventional therapies given the
severe adverse effects (nephrotoxicity, neurotoxicity,
hypertension, hyperlipidaemia and diabetes mellitus)
associated with this drug. In one study, three out of
eight patients with CIDP had a clinical improvement, as
demonstrated by assessing muscle strength and walk­
ing speed with cyclosporine A treatment, and no seri­
ous adverse effects were reported194. In another study,
modified Rankin and Inflammatory Neuropathy Cause
and Treatment Group (INCAT) disability scores were
significantly reduced and grip strength was significantly
enhanced in patients with treatment-​resistant CIDP
who received a microemulsion of cyclosporine A, and
these effects persisted for the observation period of up
to 1.5 years195.
Mycophenolate mofetil add-​on therapy stabilized
the clinical condition and permitted a reduction in the
use of previous medications, such as steroids or IVIG
in three patients with CIDP and one patient with IgM
neuropathy in one study196. However, median muscle
strength, sensory or the modified Rankin score, a com­
monly used clinical outcome measure in neurology, did
not change after treatment. Despite the small number of
patients included in these trials, these data do support
the use of mycophenolate mofetil as an add-​on therapy
in immune-​mediated polyneuropathies197.
In addition, high-​dose cyclophosphamide improved
motor strength and QOL (demonstrated using the
36-Item Short Form Survey (SF-36) questionnaire) in
a small study of patients with a subset of severe, refrac­
tory CIDP198. In another series, 11 out of 15 patients
with CIDP had clinical remission for up to 9 years after
monthly pulse intravenous cyclophosphamide for up to
6 months199. However, patients and clinicians are hesitant
to use or prescribe cyclophosphamide for CIDP until
further controlled clinical trials provide sufficient evi­
dence for its efficacy owing to the severe adverse effects
of this drug, such as haemorrhagic cystitis, infertility
and increased risk of infections and cancer. Combining
cyclophosphamide with fludarabine might represent
a potent treatment approach in otherwise treatment-​
resistant patients with CIDP, as demonstrated in a small
case series reporting improvements in motor strength200.
Limited studies have been carried out to evaluate the use
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of azathioprine in CIDP; accordingly, insufficient evi­
dence is available to determine the efficacy of this drug
in patients with this disorder197,201.
Monoclonal antibodies. Monoclonal antibodies can tar­
get specific immunopathogenetic mechanisms that are
common to a number of immune-​mediated diseases
and therefore have the potential to be similarly effective
across a range of disorders. However, unexpected and
severe adverse effects, such as infections or secondary
autoimmune diseases, can arise even years after therapy
has been initiated202, therefore, long-​term monitoring
is warranted.
Alemtuzumab is a humanized monoclonal antibody
that targets CD52, which is expressed by most lympho­
cytes and monocytes. In a single case report, clinical
improvement of motor deficits of a patient with CIDP
with alemtuzumab was noted203. A retrospective study
of seven patients with CIDP who were heavily depend­
ent on IVIG therapy demonstrated a reduction in the
required dose and frequency of IVIG treatment with
alemtuzumab. In addition, two of the seven patients had
prolonged remission, and two demonstrated a partial
response, although no clinical benefit was observed in
the remaining three patients204. Three patients also devel­
oped secondary autoimmune diseases204. Accordingly,
further studies, including studies with larger num­
bers of participants, are needed to evaluate the thera­
peutic potential of alemtuzumab in the treatment of
immune-​mediated neuropathies.
Natalizumab is a monoclonal antibody directed
towards the α4 integrin of the VLA4 antigen that is
expressed on the surface of T cells and blocks the inter­
action between VLA4 and VCAM1 on endothelial
blood vessels, thereby inhibiting the extravasation of
immune cells along the blood–brain barrier as well as
their migration through the extracellular matrix205. In
one case series, natalizumab therapy demonstrated a
variable efficacy in three patients with CIDP who were
unresponsive to first-​line therapies and presented with
severe and frequent relapses over a number of years206.
Some patients demonstrated long-​term improvement,
dramatic improvement over a substantial time frame
or stabilization on clinical measures assessing motor
strength206, whereas patients in another case report did
not have a clinical benefit with natalizumab use207. These
discrepancies reflect the underlying immunopathologi­
cal heterogeneity in CIDP; further evaluation of natali­
zumab will require controlled clinical trials, perhaps in
different subgroups of patients.
MMN
Immunoglobulin therapy. IVIG is the first-​line treatment
for MMN and, in contrast to CIDP, plasma exchange
and corticosteroids are ineffective in these patients208.
The response to treatment with IVIG in patients with
MMN can be maintained in the long term by increas­
ing the induction dose and frequency of administra­
tion209,210. The efficacy of IVIG in patients with MMN
has been demonstrated in randomized, double-​blind,
placebo-​controlled studies and a few case reports211,212.
In one study, 16 patients with MMN demonstrated
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improvements in functional self-assessment, standard­
ized neurological examination and formal strength
testing and NCS with IVIG treatment213.
SCIG could represent an interesting alternative
to IVIG in selected patients with MMN. Indeed, one
single-​blind crossover study demonstrated the therapeu­
tic equivalence of SCIG and IVIG at improving motor
strength in patients with MMN214, although the cohort
size was small (nine patients). Observation of five of
these patients and one additional patient for 24 months
confirmed sustained efficacy and tolerability215. In addi­
tion, one other study demonstrated an equivalent clinical
efficacy in terms of improving motor strength of SCIG
treatments in patients previously treated with IVIG216.
Additional smaller case series or reports have empha­
sized the potential efficacy of SCIG in patients with
MMN191. However, data for the long-​term use of SCIG
in the treatment of MMN are not available.
Monoclonal antibodies. Among the different monoclo­
nal antibodies, evidence for clinical efficacy has been
gathered in MMN only for rituximab. Rituximab is
a mouse–human chimeric antibody that binds to the
CD20 antigen expressed on the surface of pre-​B cells,
mature B cells and memory B cells. Rituximab was orig­
inally used for the treatment of non-​Hodgkin lymphoma
and other neoplastic B cell-​mediated diseases owing to
the function of this drug in eliminating B cell precursors
and B cells from the circulation via antibody-​dependent
cytotoxicity and complement-​dependent cytolysis. In an
open-​label study, six patients with MMN receiving IVIG
therapy were also given rituximab, although rituximab
add-​on therapy did not reduce the required dose of IVIG
or convey any clinical improvement. However, other
studies reported improved motor strength after switch­
ing from IVIG to rituximab217. Thus, controlled studies
are warranted to better understand the clinical value of
rituximab for the treatment of MMN.
MGUS neuropathy
IVIG, PE and corticosteroids. IVIG is not the first-​line
therapy for MGUS neuropathy with anti-​MAG IgM anti­
bodies owing to a lack of compelling evidence of clinical
efficacy. By contrast, smaller studies have suggested a
stronger clinical improvement in muscle strength with
plasma exchange. The evidence for a clinical beneficial
effect for corticosteroids in MGUS neuropathies is rather
poor. In a combination study with cyclophosphamide
for 6 months, no difference was observed in functional
scales compared with placebo218. Patients with MGUS
neuropathy with IgG or IgA antibodies should be con­
sidered indistinguishable from patients with idiopathic
CIDP and should therefore be treated with IVIG, plasma
exchange or corticosteroids.
Monoclonal antibodies. Rituximab has been shown to
be of benefit to patients with polyneuropathies associ­
ated with anti-​MAG antibodies219: six patients out of
nine demonstrated clinical improvement assessed using
the Neurological Disability Score, two remained stable
and one deteriorated219. B cells were depleted in all nine
patients, with a concomitant reduction of anti-​MAG
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antibody titres by >52% in eight patients. A follow-​up assumption on the underlying immunopathogenesis. In
study demonstrated the tolerability of a higher dose of addition, these findings emphasize the complex nature
rituximab and a clinical improvement was demonstrated of the immune responses in peripheral nerve disorders
in four out of eight patients and coincided with improve­ and teach us more about the underlying immunopatho­
ment in motor NCVs and a decrease of anti-​MAG anti­ genesis. With the use of immunomodulatory therapies,
body titres220. In a case series, rituximab stabilized 29% of clinicians should be highly vigilant in monitoring for
patients with anti-​MAG neuropathy and improved motor unexpected complications, even when the drug in ques­
as well as sensory symptoms in 31.5% of patients within tion has proved to be beneficial in clinical trials. Indeed,
the 7–12-month post-​treatment follow-​up period221. the use of these drugs in other immune-​mediated dis­
However, 11% of patients had a transient and revers­ orders, such as multiple sclerosis or rheumatoid arthri­
ible clinical deterioration during or immediately after tis, has shown that severe complications can arise years
treatment, possibly owing to the phenomenon of IgM after therapy.
flare or an increase in pro-​inflammatory cytokines221. In
addition, rituximab was effective in a patient with CIDP Quality of life
and high titres of anti-​sulfated glucuronyl paragloboside QOL is adversely affected in many chronic diseases, but
IgM antibody without M protein222. objectively measuring a patient’s physical, emotional and
Overall, the current assumption based on the avail­ social well-​being is often difficult. Most clinical trials
able data is that one-​third of patients with anti-​MAG IgM involving patients with immune-​mediated neuropathies
MGUS neuropathy will respond well to rituximab, one-​ include outcomes assessing strength and sensory deficits,
third will exhibit a marginal response and one-​third may which are present in 40–50% of patients. Residual dis­
have no response28. To what extent humanized versions ability can persist for many years after recovery from GBS
of rituximab, ocrelizumab or ofatumumab might exhibit or CIDP and can interfere with daily functioning and
clinical efficacy in immune-​mediated neuropathies social activities and, therefore, contribute to a reduction
needs to be explored. in QOL229. Indeed, even 10 years after disease onset, 14%
of patients with GBS have moderate to severe disability,
Physiotherapy whereas a further 50% of patients have minor sensori­
Physiotherapy might be beneficial in improving func­ motor symptoms, indicating that this residual disability
tional limitations and reducing chronic disability in might be permanent230. In addition, one-​third of patients
patients with immune-​mediated peripheral neuropa­ with GBS have long-​term activity limitations231.
thies; however, evidence supporting this therapy is Other factors affecting QOL include fatigue, pain, anxi­
limited. One study demonstrated the feasibility and ety and depression, although these factors are difficult to
acceptability of a 12-week unsupervised, community-​ assess quantitatively232. Fatigue is reported by 40–80% of
based strengthening, aerobic and functional exercise patients with immune-​mediated neuropathies233,234 and
programme in patients with stable inflammatory motor is associated with reduced QOL233 and greater activity
neuropathy223. Significant improvements were seen in all restriction230. In a study by the INCAT group, the average
measures of activity limitation in participating patients Fatigue Severity Scale scores were significantly higher in
and in other factors, such as anxiety, depression and patients with previous GBS, stable CIDP or MGUS poly­
fatigue. The chosen modality of physiotherapy might neuropathy than in healthy controls, and 80% of patients
have a critical role in the functional benefit exerted by scored >5, which is indicative of severe fatigue233. Severe
this therapy. In another study, a high-​intensity physio­ fatigue was experienced by 81–86% of patients with nor­
therapy programme was associated with a significant mal strength or sensation and was not associated with the
improvement in the function of relevant domains of level of disability as ambulatory and wheelchair-​bound
the Functional Independence Measure, such as mobil­ patients were similarly affected. Although many chronic
ity, transfers, sphincter control and locomotion, com­ conditions have a negative effect on mental health235,
pared with a lower-​intensity programme in patients few studies have specifically examined mental health
with chronic GBS224. Other studies support these obser­ in patients with immune-​mediated neuropathies. One
vations225,226. Tailoring the physiotherapeutic interven­ study by 323 members of the Dutch Society of Neuro­
tion, as well as considering patient preference for type muscular Disorders reported depression in 6% of
and location of the strengthening exercises, appears to patients with GBS and in 9% of patients with CIDP236.
be important. Further research is required to understand how fatigue,
pain, anxiety and depression contribute to prognosis in
Failed translation patients with immune-​mediated neuropathies and how
Despite a valid immunological rationale supported by these factors can be effectively assessed in the clinic. An
convincing data from preclinical models, some thera­ inflammatory-​neuropathy-specific survey, the IN-​QOL,
peutic strategies did not demonstrate a clinical benefit or has been developed to assess QOL in patients with GBS,
yielded unexpected adverse effects when applied in the MMN, CIDP and MGUS polyneuropathy237. This instru­
clinic. Examples of these therapeutic strategies include ment combines six commonly used QOL questionnaires
infliximab (a monoclonal antibody targeting TNF)227, and tailors them towards outcomes most relevant to
tacrolimus (FK506; an immunosuppressant)228 or fingo­ inflammatory neuropathies.
limod32. These failures could be driven by various factors, Long-​term disability, fatigue or depression can affect
including less meaningful end points, insufficient sam­ all aspects of patients' lives, including family life, social
ple sizes for detecting the expected result or an incorrect activities or working life132. Up to 30% of patients with

Nature Reviews | Disease Primers | Article citation ID: (2018) 4:31 17

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Primer
CIDP retire early owing to their disability, and patients
with MMN need frequent leave from work owing to
hospital admission for IVIG administration238. Many
patients require long-​term care outside of the clinical
setting as well as additional support from health and
social services239, which can be financially costly over the
course of the disease. Economical self-​management pro­
grammes designed to improve disability, mental health,
social participation and QOL are urgently needed, par­
ticularly for the chronic immune-​mediated neuropathies
in which health-​related QOL among patients with CIDP,
MMN or MGUS polyneuropathies is similarly affected238.
Numerous studies have reported the effect of long-​
term immunotherapy on health-​related QOL. Indeed,
long-​term immunotherapy, by improving strength,
sensation and some neurophysiological parameters,
increases patient activity and participation, thereby
improving health-​related QOL229,240.
Outlook
Although much progress has been achieved in the
field of immune-​mediated neuropathies, many ques­
tions remain that need to be addressed to improve the
treatment of patients with these disabling diseases.
Animal models
Considerable advances have broadened our understand­
ing of the pathogenesis of immune-​mediated disorders
of the peripheral nerve, and many of these advances have
been translated into promising therapeutic approaches
in the EAN model. However, this classical model mimics
only certain parts of an acute demyelinating immune
neuropathy and is induced in rats. Genetically modified
mice would be a more suitable tool to decipher critical
pathogenetic pathways of immune-​mediated damage
to the PNS. Limited protocols are available that allow
the induction of EAN in mice, providing the opportu­
nity to study various pathogenetic aspects in transgenic
models32. Mouse or rat models of AMAN would be an
interesting and useful expansion of the present experi­
mental repertoire. Rabbit models of AMAN have been
generated by immunizing these animals with GD1b
and GM1, although better models may help to further
dissect disease mechanisms of acute AMAN.
Chronic immune-​m ediated neuropathies, par­
ticularly CIDP, are more difficult to mimic in animal
models because EAN represents an acute monophasic
model of disease. Repeated immunization protocols in
rabbits or repeated adoptive transfer of T cells in Lewis
rats prompted a relapsing but not robust clinical course
(reviewed in ref.32). An alternative model was generated
by cross-​breeding mice deficient in the co-​stimulatory
molecule T lymphocyte activation antigen CD86 (also
known as B7-2) with the immune-​mediated diabetes-​
prone non-​obese diabetic (NOD) mouse strain34. Use
of these models might clarify the differences between
self-​limiting immune responses in GBS and progressive
or recurring inflammation in CIDP and other chronic
immune-​mediated neuropathies. However, these models
reflect only parts of complex immune-​driven disorders
and might explain why translation of most of the innova­
tive treatment strategies described in preclinical models
18 | Article citation ID: (2018) 4:31 www.nature.com/nrdp
0123456789();
have failed. As such, specifically for a better understand­
ing of chronic immune-​mediated neuropathies, better
model systems are needed.
Nodopathies
Although the role of nodal dysfunction in AMAN
has been recognized for some time47, the discovery
of autoantibodies to nodal and paranodal proteins in
CIDP has helped focus attention on nodal dysfunction
and pathology across several clinical neuropathies.
Immune-​mediated neuropathies have traditionally been
classified as either axonal or demyelinating according
to certain pathological and electrophysiological charac­
teristics. However, the concept of a nodopathy allows
novel pathogenetic mechanisms to be postulated (for
example, the reversible loss of sodium channel func­
tion due to antibody binding at the node in GBS and
CIDP). Classifying immune-​mediated neuropathies
as nodo­pathies paves the way for individualized treat­
ments across the spectrum of immune-​mediated neuro­
pathies incorporating the use of immune biomarkers
and electro­physiology. For example, antibody responses
might be useful for guiding treatment options in this
subgroup of CIDP patients. Indeed, resistance to IVIG
treatment is in part due to the IgG isotype subclass of
the anti-​NF155–contactin 1 response and its ability to
activate complement. In patients with IgG1–3 subclasses
(which fixes and activates complement), administration
of IVIG could inhibit complement deposition, providing
some therapeutic effect241. However, patients with IgG4
antibody responses that do not fix complement are resist­
ant to treatment with IVIG but do seem to respond to
treatment with rituximab242.
Biomarkers and diagnostic criteria
Important advances have also been made in studying
surrogate markers in patients. With the introduction of
advanced biomarker research tools, the understanding
of the potential pathogenetic role of autoantibodies tar­
geting peripheral nerve antigens is broadening. As pre­
viously mentioned, autoantibodies in GBS that target
gangliosides are predominantly found in axonal variants,
which are less prevalent in the Western hemisphere. The
discovery of autoantibodies that are directed towards
the nodal and paranodal regions of myelinated fibres
and the correlation with certain clinical phenotypes or
response to treatment in CIDP80,242–244 provide a conceiv­
able pattern for future therapeutic strategies in CIDP
research. It seems likely that CIDP, similar to GBS, will
eventually be divided into subtypes on the basis of clini­
cal features and autoantibody response. However, larger
studies are warranted to establish robust differentiation
pathways to be implemented in clinical practice.
Beyond the use of clinical manifestations, better clin­
ical and paraclinical criteria are needed to help predict
the individual clinical course and treatment response of
patients. Anticipating response to therapy in patients
with immune-​mediated neuropathies is difficult. Even
the INCAT electrophysiological criteria, which are well
elaborated for demyelinating neuropathy, cannot pre­
dict a higher rate of response to immunotherapy245. The
lack of reliable clinical measures underlines the need
 Primer

for new ways to conduct clinical trials in this group of
heterogeneous disorders. Innovative trial design and the
use of new end points could enable us to conduct more
treatment trials, perhaps in more clearly predefined
subgroups of patients, which might broaden our rather
limited therapeutic options in these disabling diseases.
Management
Personalized medicine in immune-​mediated neuro­
pathies, as the ultimate step in this development, would
probably require a combination of new models, improved
tools to guide treatment responses and new biomarkers.
Advanced diagnostic techniques for screening and risk
identification might extend the clinical spectrum of
immune-​mediated neuropathies. On the other hand,
markers for sensitivity, efficacy, safety and resistance for
on-​market drugs might make it possible to stratify the
use of the right drug for the right patient at the right time.
Additionally, personalized medicine could also drive
innovation for focused treatment approaches tailored to
the needs of specific subgroups of patients. The appar­
ent imminence of such promising developments offers
hope that progress in the treatment of these disabling
neurological diseases will accelerate in the near future.
Published online xx xx xxxx

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Nature Reviews | Disease Primers | Article citation ID: (2018) 4:31 23
Author contributions
Introduction (B.C.K. and H.-P.H.); Epidemiology (B.C.K.,
E.K.M. and C.S.); Mechanisms/pathophysiology (B.C.K.,
E.K.M. and H.-P.H.); Diagnosis, screening and prevention
(B.C.K. and C.S.); Management (B.C.K., E.K.M., C.S. and
H.-P.H.); Quality of life (B.C.K.); Outlook (B.C.K. and H.-P.H.);
Overview of Primer (B.C.K.).
Competing interests
B.C.K. reports receiving personal fees for consulting for
Grifols and UCB. E.K.M. reports receiving funding from the
GBS/CIDP Foundation International and the National
Health and Medical Research Council of Australia and is a
member of the Scientific Committee of the Trish Multiple
Sclerosis Research Foundation. C.S. reports receiving per-
sonal fees for educational talks for Alnylam, CSL Behring,
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Primer
Grifols, Kedrion, Sanofi-​Genzyme, Shire and Pfizer; personal
fees for consulting for Air Liquide, Alnylam, Astellas,
Baxalta and UCB; and research support to the institution
from Kedrion. H.-P.H. reports CSL Behring fees for serving
on a steering committee and from UCB for participating on
advisory boards.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Disease Primers thanks G. Lauria,
E. Nobile-Orazio, A. Uncini, J. Vallat and the other anony-
mous reviewer(s) for their contribution to the peer review of
this work.