REVIEW

published: 01 October 2021

doi: 10.3389/fneur.2021.706169

Paraneoplastic Neuropathies: What’s

New Since the 2004 Recommended
Diagnostic Criteria
Marco Zoccarato 1*† , Wolfgang Grisold 2† , Anna Grisold 3 , Valentina Poretto 4 ,
Federica Boso 4 and Bruno Giometto 4,5
1
Neurology Unit O.S.A., Azienda Ospedale-Università di Padova, Padova, Italy, 2 Ludwig Boltzmann Institute for Experimental
and Clinical Traumatology Donaueschingenstraße 13 A-1200 Vienna, Vienna, Austria, 3 Department of Neurology, Medical
University Vienna, Vienna, Austria, 4 Neurology Unit, Ospedale S Chiara, Azienda Provinciale per i Servizi Sanitari (APSS),
Trento, Italy, 5 Department of Neurology, University of Trieste, Trieste, Italy

The diagnostic criteria published by the PNS (Paraneoplastic Neurological Syndromes)

Euronetwork in 2004 provided a useful classification of PNS, including paraneoplastic
neuropathies. Subacute sensory neuronopathy (SSN) was the most frequently observed
peripheral PNS, whereas other forms of neuropathy, as sensory polyneuropathy,
sensorimotor polyneuropathy, demyelinating neuropathies, autonomic neuropathies, and
focal nerve or plexus lesions, were less frequent. At the time of publication, the
Edited by:
John Greenlee,
main focus was on onconeural antibodies, but knowledge regarding the mechanisms
University of Utah, United States has since expanded. The antibodies associated with PNS are commonly classified
Reviewed by: as onconeural (intracellular) and neuronal surface antibodies (NSAbs). Since 2004,
Aksel Siva, the number of antibodies and the associated tumors has increased. Knowledge
Istanbul University Cerrahpasa, Turkey
Kelsey Barrell, has grown on the mechanisms underlying the neuropathies observed in lymphoma,
The University of Utah, United States paraproteinemia, and multiple myeloma. Moreover, other unrevealed mechanisms
*Correspondence: underpin sensorimotor neuropathies and late-stage neuropathies, where patients in
Marco Zoccarato
[email protected]
advanced stages of cancer—often associated with weight loss—experience some mild
sensorimotor neuropathy, without concomitant use of neurotoxic drugs. The spectrum
† These authors have contributed
equally to this work
of paraneoplastic neuropathies has increased to encompass motor neuropathies, small
fiber neuropathies, and autonomic and nerve hyperexcitability syndromes. In addition,
Specialty section: also focal neuropathies, as cranial nerves, plexopathies, and mononeuropathies, are
This article was submitted to
considered in some cases to be of paraneoplastic origin. A key differential diagnosis for
Multiple Sclerosis and
Neuroimmunology, paraneoplastic neuropathy, during the course of cancer disease (the rare occurrence
a section of the journal of a PNS), is chemotherapy-induced peripheral neuropathy (CIPN). Today, novel
Frontiers in Neurology
complications that also involve the peripheral nervous system are emerging from novel
Received: 06 May 2021
Accepted: 30 August 2021
anti-cancer therapies, as targeted and immune checkpoint inhibitor (ICH) treatment.
Published: 01 October 2021 Therapeutic options are categorized into causal and symptomatic. Causal treatments
Citation: anecdotally mention tumor removal. Immunomodulation is sometimes performed for
Zoccarato M, Grisold W, Grisold A,
immune-mediated conditions but is still far from constituting evidence. Symptomatic
Poretto V, Boso F and Giometto B
(2021) Paraneoplastic Neuropathies: treatment must always be considered, consisting of both drug therapy (e.g., pain) and
What’s New Since the 2004 attempts to treat disability and neuropathic pain.
Recommended Diagnostic Criteria.
Front. Neurol. 12:706169. Keywords: cancer, tumor type, paraneoplastic neuropathy, onconeural antibodies, surface antibodies,
doi: 10.3389/fneur.2021.706169 mechanisms, therapy

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

INTRODUCTION TABLE 1 | Level of characterization and frequency of mechanisms underlying

paraneoplastic neuropathies.
The paper published in 2004 by Graus et al. (1) on behalf of the
Associations/ Level of characterization Frequency in the
PNS (Paraneoplastic Neurological Syndromes) Euronetwork mechanisms paraneoplastic
provided a useful classification of PNS, including neuropathies. neuropathy
At that time, subacute sensory neuronopathy (SSN) was the spectrum
most frequently observed neuropathy (“classical” paraneoplastic
neuropathy) associated with cancer, while other entities, as Onconeural abs +++ +++

sensory polyneuropathy, sensorimotor polyneuropathy, and NSAbs +++ +

demyelinating neuropathies, were less frequent. The other Other – –

immune-mediated
classical peripheral syndrome defined in 2004 was chronic mechanisms
gastrointestinal pseudo-obstruction. Several subsequent works
Hematologic diseases, ++ ++
have reported novel antibody associations, further types of including amyloid
tumor associations, and different types of neuropathy, several Weight loss, cachexia, – +++
of which were not contained in the former classification. A infection
recent update of the classification (2) confirmed the range
NSAbs, Neuronal Surface Antibodies.
of clinical presentations of neurological syndromes typically
associated with cancer (“high-risk neurologic phenotypes”),
including SSN. In this review we aim to provide an update
on mechanisms, antibodies, clinical presentation, and axonal and demyelinating forms, like anti-myelin-associated
management of paraneoplastic neuropathies focusing on glycoprotein (MAG) neuropathy, POEMS (polyneuropathy,
the pathological entities. organomegaly, endocrinopathy, monoclonal-protein and skin
changes) syndrome, and immunoglobulin light-chain (AL)
amyloidosis. MAG and other antibodies targeting myelin-
MECHANISMS associated glycoprotein and glycolipids are deemed to be
The mechanisms underlying paraneoplastic neuropathies (PN) pathogenic (6). Hyperproduction of light chains could have
are manifold and not uniform for individual neuropathies a direct toxic effect but overall leads to the formation of
or tumor types. Although paraneoplastic neuropathies have amyloid deposits with extracellular accumulation of fibrils and
been known for a long time, the autoimmune hypothesis only consequent axonal damage. In addition, hyperviscosity effects
appeared in 1965 when Wilkinson and Zeromski described have been claimed in Bing-Neel syndrome with peripheral
antibodies against neurons in paraneoplastic sensory neuropathy involvement in Waldendström’s macroglobulinemia (7).
for the first time (3). At the core of the autoimmune hypothesis is A number of causes for paraneoplastic sensorimotor
the production of antibodies against neural antigens determined neuropathies, especially in advanced stages of cancer, remain
by an immune response to cancer. obscure and resemble the development of neuropathies
The main focus of the 2004 classification was on onconeural in some general diseases, as infections and critically ill
antibodies, targeting intracellular antigens shared by neuronal conditions (See the paragraph on “Sensory neuromyopathy
and tumoral tissues. The pathogenic role of onconeural and terminal neuropathy”).
antibodies remains unresolved. The most widely recognized By enhancing antitumor immunity, the emerging immune
hypothesis is that T-cell cytotoxicity accounts for neuronal cell therapies, particularly immune checkpoint inhibitors (ICI),
loss in these conditions (4). Today, however, the mechanisms have been associated with a spectrum of immune-mediated
causing paraneoplastic neuropathies by far exceed the spectrum diseases, including neuropathies and rapidly progressive
of onconeural antibodies (Table 1). Some peripheral conditions, polyradiculoneuropathies (8, 9).
e.g., peripheral nerve hyperexcitability syndromes (5), are
mediated by neuronal surface antibodies (NSAbs). The term ANTIBODY AND TUMOR ASSOCIATION
“surface antibodies” indicates antibodies targeting antigens
present on the membrane of neurons, thus producing a potential Several antibodies targeting neural antigens have been described
direct effect, such as ion channel dysfunction. in patients with PN, although this condition is well-known
Immune-mediated mechanisms determine also the rare to occur also without antibodies (1, 10). The 2004 diagnostic
presentations of Guillain-Barré syndrome (GBS), chronic criteria established that onconeural antibodies were consistently
inflammatory demyelinating polyneuropathy (CIDP), and associated with PNS. Still they are now a fundamental marker
vasculitis. Reference is occasionally made to these large groups supporting diagnosis of paraneoplastic neuropathy, commonly
of diseases in a paraneoplastic context. The exact trigger and detected using commercial and in-house tests on cerebellar tissue
relationship between the immune response and cancer is not with specific patterns and recombinant protein-based dot/line
clear, but it is doubtful that the same mechanisms apply to all blotting (11). In 2004, onconeural antibodies were classified as
these entities. “well-characterized” or “partially characterized” antibodies. This
Plasma cell dyscrasia and other hematological entities distinction was based on clinical relevance, number of published
present with a spectrum of different neuropathies of both cases, a recognizable pattern on immunohistochemistry,

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

TABLE 2 | Onconeural antibodies reported in 2004 classification and associated with paraneoplastic neuropathy.

Antibody (antigen) Types of neuropathy Associated tumors Selected published series after 2004 criteria

Hu (ANNA1) SSN; autonomic neuropathy SCLC (12, 13, 17–19)

CV2 (CRMP5) Sensorimotor neuropathy SCLC; thymoma (12, 13)
Amphiphysin Polyradiculoneuropathy, SSN Breast, SCLC (14, 15)
ANNA3 Sensorimotor neuropathy SCLC /
PCA-2/MAP1B Sensorimotor neuropathy; autonomic neuropathy SCLC (16)

availability of immunoblotting confirmation, and absence/low of these associations thus needs further characterization and
frequency in patients without cancer. The 2021 update of confirmation before being considered relevant in the diagnostic
diagnostic criteria (2) classifies the antibodies associated approach to PN (Table 3).
with paraneoplastic diseases in three groups according to the In 2016, antibodies against 1,4,5-trisphosphate receptor type
frequency of association with cancer (high- >70%, intermediate-, 1 (ITPR1) were characterized in patients with autoimmune
and low- <30% risk antibodies), but in this review, we use the cerebellar ataxia; this antibody was also found in three patients
former nomenclature. with sensorimotor polyneuropathy, associated in two cases
Well-characterized antibodies associated with paraneoplastic with malignancy (adenocarcinoma of the lung and multiple
neuropathies included anti-Hu (ANNA-1), anti-CV2 (CRMP5), myeloma) (24).
and anti-amphiphysin antibodies. Since 2004 the literature has Antibodies targeting neurofilament light chain (NfL)
confirmed that these three markers are consistently associated have been reported as markers of ataxia and encephalopathy
with the PN spectrum (12–19) (Table 2). SSN with anti-Hu accompanying various cancers, especially neuroendocrine
antibodies is considered the most frequent PN (10). It is lineage neoplasms (25). Six out of 21 of the reported patients
often the predominant manifestation of anti-Hu multifocal manifested with peripheral or cranial neuropathy.
encephalomyelitis (paraneoplastic encephalomyelitis), which in Anti-KLHL11 is a recently described antibody identified in
10% cases can also manifest with dysautonomic symptoms, patients with brainstem encephalitis or cerebellar symptoms
as hypotension, dysrhythmia, or intestinal pseudo-obstruction related to testicular and ovarian cancer (26, 27). A recent
(20). Two extensive case series have compared anti-Hu with retrospective study of 32 patients manifesting a distinctive
anti-CV2 neuropathy (12, 13). Anti-CV2 neuropathy seems to pattern of subacute paraneoplastic myeloneuropathy, associated
be characterized more frequently by sensorimotor involvement with several neoplasms, identified the presence of anti-
and by asymmetric polyradicular involvement. SCLC has amphiphysin (8), anti-Hu (5), anti-CV2 (6), anti-Yo (1), anti-
been confirmed as the most frequent cancer associated with PCA2 (2), and one case of anti-KLHL11, or combinations of
both anti-Hu and anti-CV2 antibodies. Anti-amphiphysin these (28).
antibodies are rare and associated with a broad spectrum of Very recently, a further antibody reaction against Leucine
neurological manifestations, especially in women with breast Zipper 4 (LZUP4) was described in 28 patients with germ cell
cancer or SCLC. Peripheral involvement includes sensory tumors (e.g., seminoma); four patients were affected with motor
neuronopathy, sensorimotor neuropathy, polyradiculopathy, neuronopathy and polyradiculopathy (29).
and neuromyotonia (14, 15). In this context, the characterization of antibodies against
Partially characterized antibodies in 2004 included ANNA- Sry-like high mobility group box 1 (SOX1) deserves mention.
3, a very rare reactivity reported in some cases of sensory, In 2005, anti-glial nuclear antibody (AGNA) was identified
sensorimotor and autonomic neuropathy (21), anti-Zic4—a as a marker of PNS-related lung cancer. The most frequent
marker of cerebellar degeneration described in some cases clinical association was LEMS, but SSN and sensorimotor
of neuropathy, usually with concomitant antibodies (anti-Hu neuropathy were also reported (30, 31). SOX1 was identified
and/or anti-CV2) (22)—and anti-PCA2, which in the earlier as the antigen in 2008 (32). As anti-SOX1 antibody is not
large case series (23) was described in both central and a rare finding in patients with SCLC without paraneoplastic
peripheral syndromes, including LEMS and neuropathy. The accompaniments (33), it can more properly be considered
real target of PCA-2 was identified in 2017, consisting of a serological marker of SCLC. Recently, the presence of
a microtubule-associated protein (MAP1B). PN is the most SOX-1 was also advocated in non-paraneoplastic neuropathies
frequent presentation and was reported in about a half of anti- (34, 35), but this finding was not confirmed in a later
MAP1B patients with SCLC (16). work (36).
In the last 15 years, several novel onconeural antibodies In recent years several antibodies directed against NsAbs
related to PN have been reported. Most have been described in have been described, greatly expanding the interest in
individual works, have not yet been confirmed by other research autoimmune neurological diseases. Antibodies against voltage-
groups, and have a limited number of patients. The strength gated potassium channels (VGKC) were first discovered in

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TABLE 3 | Novel antibodies associated with paraneoplastic neuropathy.

Antibody (antigen) Localization (intracellular/surface) Types of neuropathy Associated tumors

AGNA/SOX1 Intracellular Sensory neuronopathy, sensorimotor neuropathy SCLC

ITPR1 Intracellular Sensorimotor polyneuropathy Lung, Multiple Myeloma
KLHL 11 Intracellular Myeloneuropathy Testicular seminoma
LZUP4 (Leucin-Zipper 4) Intracellular Motor neuropathy, polyradiculopathy Germ cell tumors
NfL (Neurofilament light chain) Intracellular Peripheral and cranial neuropathy Neuroendocrine lineage neoplasms
CASPR2 Surface Neuromyotonia, painful neuropathy, Morvan syndrome Thymoma (20–30%)
LGI1 Surface Neuromyotonia, painful neuropathy Thymoma (5–10%)
Netrin 1 receptors Surface Neuromyotonia Thymoma
Morvan syndrome

the 1990s in patients with motor nerve hyperexcitability in a patient with an unknown or occult malignancy, oncological
(neuromyotonia) and hyperhidrosis (37, 38). Anti-VGKC screening must be performed as recommended (51).
antibodies were later described in limbic encephalitis, with
most cases being of non-paraneoplastic origin (39, 40).
In 2010, it was established that anti-VGKC antibodies TYPES OF NEUROPATHIES
actually target two different associated proteins associated
with ion channels, namely, LGI1 and CASPR2 (41, 42). Over the decades, numerous individual observations have been
These antibodies determine a continuous disease spectrum, published. Gradually, a core of generalized neuropathies has
often dominated by central nervous system involvement emerged, in particular, SSN. Several rarer types need to be
(limbic encephalitis) but frequently with relevant peripheral considered, as do focal peripheral nerve lesions. The spectrum
manifestations, including neuromyotonia, dysautonomia, and is probably still incomplete but reflects the present level of
pain (43). Peripheral involvement, especially when isolated, knowledge and experience (Table 4).
is more frequent in CASPR2 than in LGI1 patients; this is
probably due to the higher expression of CASPR2 in the Generalized Neuropathies
peripheral nervous system, in the juxta-paranodal region (44). Subacute Sensory Neuronopathy
Morvan syndrome is another clinical picture associated with SSN is the prototype of PN. It is characterized by asymmetry,
CASPR2 antibodies, in which peripheral hyperexcitability acute/subacute onset in the upper extremities, and pain. The
and dysautonomia coexist with psychiatric disturbances main clinical feature is sensory ataxia. Even though the motor
and sleep dysfunction. Recently, painful manifestations of system is not impaired in terms of strength, sensory loss results
LGI1 and CASPR2 autoimmunity have been highlighted. in ataxia and severe disability. The disease quickly progresses
Sometimes pain is the cardinal symptom, especially in CASPR2 to a plateau phase, and has little or no tendency to improve.
patients (45–47). As regards the associated tumors, anti-LGI1 Electrophysiologic study reveals absent sensory responses; motor
diseases are rarely paraneoplastic, whereas a tumor, mostly responses can be minimally altered (52). The neuropathology
a thymoma, can be detected in 20–30% of patients with consists of inflammation in the dorsal root ganglia (DRG)
CASPR2 autoimmunity. In patients with double positivity and is often associated with posterior column degeneration.
(anti-LGI1/anti-CASPR2), the likelihood of cancer is higher (up The therapeutic approaches are manifold (53) and usually
to 44%) (47). immune modulation is recommended, although no evidence-
Finally, a further surface reaction against Netrin-1 receptor based recommendations exist. SSN is a disabling condition
has recently been described in patients with thymoma affected by and persons affected remain completely dependent. SSN is
Morvan syndrome or neuromyotonia and myasthenia gravis; the not entirely specific and has been observed as an idiopathic
clinical relevance of this reactivity, which can be found together occurrence or in other autoimmune conditions as Sjogren’s
with CASPR2, needs further specification (48, 49). syndrome. The DRG can be affected by toxicity, as through
Tumor association reflects antibody association (see Tables 2, platinum compounds and pyridoxine overdosage, but the extent
3). The most frequent malignancy associated with PN is SCLC. of the clinical symptoms is not the same as in Hu-associated
However, other lung cancers, like adenocarcinoma, are not rare. paraneoplastic SSN. SSN has also been observed in association
Other associated malignancies are breast and ovarian cancer, with other PNS as cerebellar degeneration, PEM, brainstem
and thymoma. Prostate cancer is an infrequent finding in the involvement, limbic encephalitis, Lambert–Eaton myasthenic
neurological paraneoplastic context, considering the frequency syndrome, and motor neuropathy. Patients may have evidence
of the neoplasm, although cases of SSN have been reported with of autonomic involvement. A rare combination with myositis
Hu antibodies (50). When the diagnosis of PNS is performed has been described (54). For the clinician, the appearance of an

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TABLE 4 | Classification of paraneoplastic neuropathies.

Types of PN neuropathies Sub-classification Comments

Generalized neuropathies Subacute sensory neuronopathy Highly indicative of a PN cause- although also observed in other conditions
Sensory neuropathy Unspecific
Sensorimotor neuropathy Unspecific
Sensory neuromyopathy and terminal neuropathy Historic terminology
Motor neuropathy Rare
Multiplex neuropathy Vasculitis is rare
Myeloneuropathy Possibly new entity
Autonomic neuropathies Incidence uncertain
Rarer and disputed entities Small fiber neuropathy Incidence unclear, except for hematologically-associated types
Cryoglobulinemic neuropathy
Hyperexcitability syndromes
Paraproteinemia and AL amyloid
Focal nerve lesions Cranial nerves Individual cases
Nerve plexus
Mononeuropathies

SSN constitutes a strong recommendation to search for cancer, neuropathy (CIPN) is the most likely differential diagnosis. In
particularly SCLC. plasma cell dyscrasia and associated hematological diseases, a
spectrum of neuropathies has been described, including SMN
Sensory Neuropathy (see below).
A pure sensory neuropathy is less specific for a paraneoplastic
disease, and opinions regarding paraneoplastic etiology are Sensory Neuromyopathy and Terminal Neuropathy
controversial. Patients present with sensory symptoms in the Paraneoplastic sensory neuromyopathy is usually a late effect
typical glove-stocking distribution, often with neuropathic pain of cancer on the peripheral nervous system. It presents as a
and a variable degree of incoordination (55). Onset is usually symmetric sensorimotor neuropathy, is usually mild, and can
more insidious, following the length-dependent distribution. The be associated with type 2 fiber muscle atrophy. It is not specific
most likely causes of a pure sensory neuropathy are autoimmune for individual cancers, is often associated with weight loss, and
diseases (e.g., Sjögren) and toxic and metabolic neuropathies. can be a general sign of advanced cancer. The sensory loss
The distinction between SSN and sensory neuropathy can be affects all qualities. Muscle weakness occurs in proximal and
difficult; even in the 2004 classification it was not always certain distal muscles (with so-called “intermediate sparing”). It is slowly
how precise the distinction could be. Subacute or acute onset progressing. Concomitant factors as chemotherapy or diabetes
may resemble SSN. An attempt to differentiate ataxic from more need to be ruled out. There is no specific antibody association
painful sensory neuropathies was made by Oki et al. (18) and may at present. The nomenclature is historic and was not contained
help in differentiation. in the 2004 classification. However, in clinical practice, this type
of neuropathy can be observed in advanced cancer patients.
Sensorimotor Neuropathy The term “terminal neuropathy” refers to mild sensorimotor
Sensorimotor neuropathy (SMN) is generally the most frequent neuropathies observed in progressive general diseases, in
yet enigmatic neuropathy in terms of specific characteristics advanced stages, including cancer, with or without concomitant
and etiology. The term implies a combination of sensory and use of neurotoxic drugs. This type of neuropathy can be likened
motor symptoms of varying degrees. No specific or characteristic to a common occurrence in patients with severe infections, i.e.,
clinical items have been defined. Patients with SMN usually weight loss, and its origin is probably different. For example,
do not have severe neurological impairment. SMN has been sarcopenia and cachectic neuropathy have been described in
observed as a paraneoplastic condition, also in association with association with diabetic neuropathy (58, 59).
onconeural antibodies (55, 56). The differential diagnosis is wide
and ranges from other causes as alcohol, diabetes, and chronic Motor Neuropathy
idiopathic axonal polyneuropathy, particularly in individuals Pure motor neuropathy is rare. The term “lower motor neuron
aged over 55 years (57). disease” has been used to identify patients with subacute
Yet individual cases with SMN presenting as the first sign development of generalized flaccid paresis with sparing of
of cancer have been described. Practically speaking, SMN is long tracts and bulbar muscles (60). This entity has been
uncharacteristic and the suggestion is to first exclude other described infrequently and is not well-characterized. Only a few
possibilities before embarking on an extensive tumor search. cases were collected in the PNS Euronetwork database (61),
At a later stage of the cancer, chemotherapy-induced peripheral corresponding to <1% of identified patients. The term “lower

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

motor neuropathy” has been also used in conjunction with Rarer and Disputed Entities
plasma cell dyscrasia and myeloma (62, 63), in hematological Small Fiber Neuropathy
malignancies, and as a sequelae of local RT. Small fiber sensory neuropathy (SFN) has not been part of the
classical paraneoplastic spectrum. A recent study suggests that
paraneoplastic causes can amount to 3% of SFN in association
Multiplex Neuropathy with onconeural antibodies that were not further specified (77).
Despite being described in individual cases, paraneoplastic SFN has been documented in cases of Morvan syndrome (78).
mononeuropathy multiplex is a rarePNS (64, 65). Although examples of SF involvement have been described in PN
Mononeuropathy multiplex is generally associated with in solid cancers (79) and hematological diseases (80), it remains
vasculitis. Chronic dysimmune neuropathies, as multifocal unclear whether the SF involvement is exclusive, or part of a
motor neuropathy (MMN), have been reported as PN (66), while general neuropathy syndrome.
rare cases of asymmetric neuropathies have been observed in
AL amyloidosis (67) and in association with Waldenstrom’s
disease (68). Recently observed complications of ICI therapies Immune-Mediated Neuropathies
also include reports of vasculitis (69). Notably, also other tissues From the large, growing number of immune-mediated
can be involved by vasculitis as a clinical sign, e.g., skin vasculitis neuropathies, GBS, CIDP, and also rarely MMN have been
(70) and digital ischemia (71). mentioned to appear as a paraneoplastic phenomenon. In the
PNS Euronetwork database, the incidence of this conjunction
was low. The occurrence of both GBS and CIDP seems higher in
Myeloneuropathy hematological conditions (81, 82) and has also been described to
The simultaneous involvement of the spinal cord and be associated with other cancer types (74, 83) and with axonal
peripheral nerves is termed myeloneuropathy. The usual loss. The occurrence of MMN as a PNS has been reported but
underlying etiologies include B12 or copper deficiency, seems to be extremely rare (84, 85).
inflammatory/infectious diseases, and toxic diseases. This is a Practically speaking, the appearance of either GBS or
fairly new term in conjunction with PNS, which is not contained CIDP does not necessarily point to an underlying malignancy.
in classical descriptions. A recent paper (28) has described a Conversely, GBS may occur during the course of the disease
number of cases that could be the basis for further considering in cancer patients with solid tumors (86) but can be the
its inclusion in the PNS classification. The series consists of 34 presenting phenotype in lymphoma or leukemia, and may be
patients with various antibodies and cancers, especially SCLC called “paraneoplastic” in these circumstances.
and breast adenocarcinoma. Clinically they had a subacute, As a new development and based on immune mechanisms,
asymmetric presentation with sensory (e.g., paresthesias and several immune-mediated neuropathies, also resembling GBS,
impaired proprioception) and motor signs, as asymmetric have been described to occur in conjunction with immune
weakness, and long tract signs. Pain and bladder dysfunction therapies, in particular with ICIs (9, 87).
were frequent clinical findings. The concomitant presence of
hyporeflexia and hyperreflexia at different sites was found in 81%
of patients. MRI imaging showed spinal hyperintensity, which in Cryoglobulinemia
about a half of patients was longitudinally extended. One third Cryoglobulinemia can occur as part of lymphoproliferative
of patients showed lumbar nerve-root enhancement. Previous disease as in MGUS, macroglobulinemia, multiple myeloma
descriptions of similar syndromes are available (72, 73). (MM), leukemia, CLL, and immunoblastic lymphadenopathy.
In addition to acrocyanosis, digital necrosis and purpura may
occur. Likewise, signs of hyperviscosity, as thrombosis, can
Autonomic Neuropathy be associated. Cryoglobulins are monoclonal IgG, often IgM,
Autonomic features can be associated with several types of and rarely light chain. Cryoglobulinemic neuropathy has been
neuropathy. Symptoms can result in orthostatic hypotension, described as paraneoplastic, with IgM precipitation (88) and
urinary symptoms, sweating abnormalities, intestinal pseudo- other conditions. Except for lymphoproliferative diseases, where
obstruction, gastrointestinal dysmotility, and subacute the coexistence has been noted, it does not seem to be a
dysautonomia. Dysautonomia is typical of AL amyloid frequent association.
neuropathy. It has likewise been observed in several
paraneoplastic forms of PN (74) and small fiber neuropathy
(75). Another important aspect is the association of autonomic Hyperexcitability Syndromes
symptoms with other PNS, in particular with LEMS, but also in Abnormal muscular activity with cramps, twitching and stiffness
conjunction with paraneoplastic hyperexcitability syndromes as characterizes neuromyotonia and hyperexcitability syndromes.
Morvan syndrome. In addition to areflexia, stocking-like sensory Electromyographic findings are typical (89). Acquired forms are
loss, and areflexia, autonomic symptoms also appear. Autonomic considered immune mediated and can be found with underlying
ganglionopathies have been observed in conjunction with ICI neoplasms, including in seronegative cases. Neuromyotonia can
therapy (76). Notably, autonomic disturbances are also well- also present with symptoms and signs of sensorimotor and motor
described in other common causes of neuropathy, as diabetes or neuropathy, with no clear mechanisms (90). Neuropathic pain is
neuropathies associated with systemic autoimmune diseases. a frequent finding in Morvan syndrome (see above) (91).

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Plasma Cell Dyscrasia and Paraproteinemia TABLE 5 | Neuropathies associated with hematological diseases.
Plasma cell dyscrasias and paraproteinemias are usually not
Hematological Neurological syndrome
classified among paraneoplastic neuropathies. This is probably disease
due to the inhomogeneous presentations within the different
groups with paraproteinemia. Despite this, several types of MGUS Anti-MAG neuropathy (*), POEMS
neuropathies occur in association with the hematological disease Waldenstrom‘s disease Axonal, demyelinating, anti-MAG
by indirect involvement (not directly neoplastic), resembling neuropathy (*), hyperviscosity syndromes
the pattern of paraneoplastic disease. At least three conditions, Multiple myeloma Axonal, demyelinating, AL amyloid (*)
such as POEMS syndrome, anti-MAG neuropathy, and AL Lymphoma Immune-mediated (*), rarely AL
amyloidosis, have characteristics of paraneoplastic disorders. Leukemia Rarely AL amyloid in CLL (*) and hairy cell
The mechanisms are diverse and range from immunoglobulin leukemia
(IgG) deposition to axonal and demyelinating neuropathies, *Neuropathies which bear similarities with the characteristics of
hyperviscosity issues, and AL amyloid deposition. paraneoplastic syndromes.
Neuropathies related to MGUS are usually sensory-motor,
axonal, or demyelinating. Commonly, IgG or IgA cause
axonal lesions, whereas IgM tends to be associated with
demyelinating features. purpura, congestive heart failure, and orthostatic hypotension are
Waldenstrom’s disease can develop from MGUS and is other typical (but not specific) clinical findings (96) (Table 5).
considered as a low-grade lymphoma (lymphocytoplasmatic
lymphoma). It can be associated with demyelinating Focal Nerve Lesions
neuropathies, sometimes with MAG antibodies. Hyperviscosity Focal paraneoplastic neurological syndromes are rare and usually
mechanisms can also result in a multifocal neuropathy (92). not contained in the classifications. The list of entities provided
Cryoglobulinemia can be associated; AL amyloidosis is rare. here is incomplete and based on observations and case reports,
Multiple myeloma presents with a variety of PN, including lacking consistency and systematic approach. Focal presentations
axonal and demyelinating types with no typical clinical features. include cranial nerve lesions, plexopathies, mononeuropathies
AL amyloidosis is responsible for 30–40% of neuropathies in (e.g., CTS) (97), and also muscle involvement.
myeloma, in particular with λ light chain.
Three phenotypes further illustrate the relationship between Cranial Neuropathies
PNS and plasma cell dyscrasia. Anti-MAG neuropathy results There are numerous reports on paraneoplastic cranial nerve
in a painful sensory neuropathy, predominantly in the legs (CN) lesions (Table 6). Three CNs appear to be preferably
with impaired balance. Progression is slow and leads to affected: the optic, trigeminal, and vestibular nerves. In addition
sensory ataxia. Tremor action is frequently reported. Numerous to lesions of the optic nerve (98, 99), also in combination
investigations have discussed the effects of anti-MAG and the with spinal cord lesions (100), there are several visual
role of sulfoglucuronyl-glycosphingolipid (SGPG) antibodies (6). conditions, as cancer-associated retinopathy (101), melanoma-
Therapy suggestions are controversial, among them anti-CD20 associated retinopathy (102), acquired night blindness, bilateral
drugs, like rituximab, and attempt to neutralize the MAG diffuse uveal melanotic proliferation, bilateral diffuse uveal
antibodies (93). melanotic proliferation, cone dystrophy and achromatopsia, and
POEMS syndrome is considered by many to be a PNS. The photophobia (103).
disease is often rapidly devastating, resulting in neuropathy with Oculomotor nerve lesions are rarely described as a PN. Local
tetraparesis and multi-organ involvement. The neuropathy is M- neoplastic causes and orbital myositis need to be excluded (104).
protein related (Ig A or G) and can cause axonal, demyelinating, However, extraocular muscle involvement has been described in
or mixed neuropathy (61). Often, an isolated osteosclerotic AL amyloidosis, and local AL deposits in the lid may cause ptosis.
lesion can be detected. The distinction between CIDP and The trigeminal nerve can be affected in autoimmune and
POEMS can be difficult and neurophysiological criteria have rheumatoid arthritis. Similarly, sensory trigeminal neuropathy,
been suggested (94). A CIDP-like presentation with pain could or the “numb chin” (105) and “numb cheek” (106) syndrome
be a useful indicator for POEMS. Elevated levels of vascular subtypes, have been reported to be caused by paraneoplastic
endothelial growth factor (VEGF) are found in about two-thirds mechanisms (107, 108). The presence of orofacial pain (109–111)
of patients (95). and neuralgia have been suggested to be of paraneoplastic origin,
Light-chain (AL) amyloidosis is an important differential among other causes. Vestibular damage and neuritis have been
diagnosis in paraproteinemia, Waldenstrom’s disease, multiple described as paraneoplastic phenomena in a few selected cases
myeloma, and several other entities. Clinically, a combination of (112–114). There is a paucity of reports on possible damage to
fatigue, renal impairment, sensory and autonomic neuropathy, the caudal cranial nerves. Local amyloid depositions (115) in
and often also carpal tunnel syndrome (CTS) is suggestive. In the soft palate and tongue (116) need to be considered under
addition to the characteristic sensory, often painful neuropathy, plasma cell dyscrasia. Several cases of possible multiple CN
frequently including autonomic features, focal lesions due to lesions, caused by a potential paraneoplastic mechanism, have
deposits of amyloid are also described. Macroglossia, periorbital been mentioned (117, 118). A similar distribution of affected CNs

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

TABLE 6 | Paraneoplastic involvement of cranial nerves.

CN Neoplastic Paraneoplastic syndromes Other mechanisms

II Base of the skull Optic nerve neuropathy/neuritis Other immune-mediated causes,

hyper-viscosity
Leptomeningeal carcinomatosis CAR, MAR
III, IV, VI Base of the skull tumors/metastasis Individual cases /
Orbital metastasis
Leptomeningeal carcinomatosis
V Local metastasis, base of the skull Numbness trigeminal nerve, or parts Isolated facial pain, neuralgia
metastasis, mandibular metastasis (chin, cheek)
VIII Leptomeningeal carcinomatosis Few reports on vestibular neuritis /
Caudal CNs Base of the skull metastases Not reported (isolated nerves) Focal amyloid in plasma cell
dyscrasia
Leptomeningeal carcinomatosis
Lesions after the exit of CN of the bony
skull
Multiple CNs Base of the skull metastasis Few reports, not homogeneous /
Leptomeningeal carcinomatosis

CAR, cancer associated retinopathy; MAR, melanoma associated neuropathy.

has been reported as a complication of treatment with immune of chemotherapy, symptoms impacting the quality of
checkpoint inhibitors (119) (see below). life persist in half of patients (128). Alteration of cancer
treatment due to CIPN involves 10–65% of patients; in
Plexopathies up to one third of patients, chemotherapy needs to be
PN causing plexopathies are rare but have been reported in discontinued (129).
individual cases. Most reports date back some years, and new Despite significant variability in susceptibility [depending
investigations, in particular with the aid of imaging techniques, on concurrent diabetes, alcohol consumption, and other pre-
could potentially detect a symptomatic cause. The cervical plexus existing neuropathies, along with genetic factors and older age
is mentioned in regard to the phrenic nerve (120–122). Although at onset (130)], the development of CIPN is generally dose-
there are reports that inflammatory paraneoplastic causes can dependent and thus influenced by different drug schedules and
affect the brachial and lumbosacral plexus, the evidence is based combinations, as well as route of administration. Traditionally,
on individual case reports (123). CIPN involves breast and colon cancer patients undergoing
toxic doses of intravenous (IV) cisplatin and oxaliplatin. The
Mononeuropathies cumulative toxicity mainly affects the DRG and their axons,
In plasma cell dyscrasia, CTS could be a sign of amyloidosis. causing a sensory neuronopathy or dying-back neuropathy; small
The issue of other isolated paraneoplastic mononeuropathies fiber neuropathies can also ensue, while motor, autonomic, and
is uncertain. One report suggests a paraneoplastic ulnar nerve cranial involvement is less common.
lesion (124); there is also mention of a peroneal nerve lesion Most patients develop CIPN in the first three or four
(125). Multiple enlarged nerves (126) have been described cycles of treatment, with gradual progression of symptoms and
in ultrasound as a PNS, but may lack a clinical correlate. subsequent stabilization at or soon after treatment completion.
Deposition of light chains causing individual nerve lesions Patients typically display length-dependent symmetric sensory
has been described (97). In summary, the appearance of a loss (sometimes even leading to ataxia) with prominent acral
mononeuropathy of paraneoplastic origin is not likely, except in sensory symptoms, pain episodes, and reduced dexterity.
the case of CTS associated with AL amyloid. A notable exception is platinum-associated neuropathy, as
oxaliplatin may also cause distinctive acute, transient, cold-
CANCER THERAPY IN DIFFERENTIAL induced dysesthesias after the first infusions, while both
DIAGNOSIS oxaliplatin and cisplatin neurotoxicity usually worsens in the
months following the end of chemotherapy (i.e., the coasting
CIPN is the commonest form of neurotoxicity in cancer phenomenon). CIPN then slowly improves with time, sometimes
patients, causing a chronic neuropathy in about 30% leaving a chronic pain syndrome with dysesthesia, hyperalgesia,
and milder/temporary symptoms in up to 70% of those tactile and thermal allodynia, and spontaneous pain. Acute pain
undergoing traditional chemotherapy (127). In addition to syndrome related to nerve pathology has also been reported
the burden on patients’ quality of life, CIPN can lead to with paclitaxel (131). New anti-microtubule drugs can induce
modifications or discontinuation of oncologic therapy, thus axonal, mainly sensory polyneuropathy, as can older taxanes
impacting on their overall prognosis. Even after cessation [e.g., eribulin and ixabepilone (132)].

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

Recently, advancements in more selective targeted therapies neuropathy (8, 9), small fiber/autonomic neuropathy (145),
and newer agents have improved chemotherapy tolerability sensory neuronopathies, and neuralgic amyotrophy (146, 147).
and overall cancer survival but have not translated into a Despite these findings, ICIs are generally considered safer than
reduction of CIPN cases. Besides having to differentiate CIPN conventional chemotherapy for the peripheral nerve, and ICI-
from other conditions that do not dictate premature treatment induced neuropathies are more likely to have an acute/subacute
discontinuation, the advent of biological agents, known to and non-length-dependent presentation (9, 146).
have more idiosyncratic and off-target side-effects, has further According to current guidelines (148), management requires
added to the neurologist’s diagnostic conundrum. Indeed, CIPN ICI discontinuation and high-dose IV steroid administration,
pathogenesis largely remains to be defined and is still one of followed by slow steroid tapering to avoid relapses related to
the most common dose-limiting complications of antitumor the long-lasting half-life of ICIs (146). Up to 50% of cases
treatment, considering the growing number of cancer survivors (149) could be resistant to steroid therapy and, due to their
who develop late drug-resistant chronic pain syndromes that may severity, require IV immunoglobin (IG), plasma exchange,
heavily impact on their quality of life. or immunosuppressants.

Targeted Therapies CAR T Cell Therapy

Tumor-specific antibodies cause similar, unexpected nerve Chimeric antigen receptor T-cell therapies have become standard
injury ranging from mild, predominantly sensory neuropathies treatments of relapsed or refractory hematological malignancies.
(i.e., polatuzumab vedotin and enfortumab vedotin) to Acute neurotoxicity is well-documented and moderate-to-severe
potentially severe motor neuropathy, as seen in lymphoma neurological events are estimated to occur in 20–30% of patients,
patients undergoing brentuzumab (133, 134); these generally with a median time of onset of 5–6 days after infusion
improve slowly upon discontinuation. Neuropathies have also (150–152). Neurological manifestations are associated with
been reported in high numbers during adotrastuzumab cytokine release syndrome, referred to as “immune effector cell-
emtansine treatment (135). Regarding the latest drugs, associated neurotoxicity syndrome,” which identifies a distinctive
such as neurotrophic-tyrosine-receptor-kinase gene and encephalopathy manifesting with stereotypic evolution of a
anaplastic-lymphoma-kinase inhibitors, neuropathy has been specific set of symptoms (152). Very little is known about
described with both larotrectinib [including grade III and IV potential long-term adverse events; however, a case of peripheral
reactions within 3 months of treatment (136)] and lorlatinib neuropathy has been described as a late complication (153).
(137), respectively.
THERAPY
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies The general therapeutic strategy for PNS is based on the
directed against specific molecules on activated immune assumption that the detection of cancer and its removal can
cells whose role is to maintain self-tolerance and prevent improve the neurological syndrome. This is seldom obtained in
autoimmunity, thus enhancing anti-tumor immunity. PN associated with onconeural antibodies. Numerous attempts
Targets include programmed death-1 receptor (nivolumab, have been published for the treatment of SSN. A systematic
pembrolizumab, cemiplimab), its ligand (atezolizumab, review in 2012 concluded that only class IV evidence was
avelumab, durvalumab), and cytotoxic T lymphocyte antigen-4 available for the effect of IVIG, plasma-exchange, steroids,
(ipilimumab). Alongside, ICIs may cause off-target toxicities or immune-suppressive chemotherapy (53). Most individual
called immune-related adverse events (irAEs) (138, 139). recommendations suggest immune-modulating therapies can
Neurological irAEs represent a minor proportion, with an stop the progression of the PN. Given the severe debilitating
estimated incidence of 1–3%, more common after combination outcomes in patients with SSN, these interventions are justified
checkpoint blockade (140, 141). Nevertheless, they are clinically but should be performed very early (e.g., 2 months) after
relevant complications with high-grade toxicity, carrying neurological symptoms onset (154). On the other hand, diseases
significant morbidity and mortality (142), and thus requiring associated with NSAbs are usually responsive to immunotherapy.
prompt identification. Immune-related peripheral nerve This also seems to be confirmed for peripheral involvement in
disorders induced by ICI are highly heterogeneous (8, 9). Cranial syndromes with anti-LGI1 anti-CASPR2 antibodies (47). Steroids
neuropathies and polyradiculoneuropathies have emerged are often the first option, followed by or associated with IVIG
as the most common phenotypes (9). Cranial neuropathies and plasma exchange. Therapies with anti-CD20 treatment (e.g.,
may be isolated or associated with other neurological rituximab), or immunosuppressors like cyclophosphamide, have
manifestations, frequently involving facial and abducens less supporting evidence than do other NSAbs associated diseases
nerves, although any CN may be affected (143) Acute and (e.g., NMDAR encephalitis) (155). Nevertheless, these options
chronic polyradiculoneuropathies mostly include GBS or CIDP can be considered in non-responsive cases and their efficacy has
and usually develop within the first three cycles of therapy been reported (44, 78, 156).
(9, 144). Unlike classical GBS, cerebrospinal fluid analysis often The smaller group of acute immune-mediated neuropathies,
reveals lymphocytic pleocytosis besides hyperproteinorrachia as GBS, CIDP, and vasculitis, usually respond to conventional
(142) and benefits from steroid administration. Other reported immune therapies, approved for the non-neoplastic entity of
ICI-related neuropathies are mononeuritis multiplex/vasculitic the given neuropathy. Paraproteinemic neuropathies and AL

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Zoccarato et al. Paraneoplastic Neuropathies: What’s New

amyloidosis are also treatable to some extent, according to antibodies need more robust evidence to become relevant in
current hematological guidelines. clinical practice, the true novelty has been the discovery of
The appearance of PN has implications not only for cancer NSAbs in diseases with prominent, or coexisting, peripheral
and cancer therapy but also significantly impacts patient involvement, which can be paraneoplastic.
performance, quality of life, and disability. Symptomatic Circulating autoantibodies are commonly considered a
therapy is therefore a cardinal feature of treatment. valuable tool for cancer diagnosis and are frequently requested in
Pain control is a key goal. This can be achieved by clinical practice for patients with unclear neurological peripheral
antidepressants (tricyclic antidepressants and serotonin- symptoms. However, proper adherence to the use of biomarkers
noradrenaline reuptake inhibitors) and by GABA-mimetic is critical in translating recommendations into clinical practice.
drugs (first-line therapy). Second- and third-line drugs At present, circulating classical onconeural antibodies and only a
for neuropathic pain include topical lidocaine and opioids few NSAbs are considered a valuable tool for cancer diagnosis for
(157). Neuromyotonia can respond to antiepileptics patients with paraneoplastic neuropathy.
as carbamazepine, phenytoin, lamotrigine, and sodium Finally, new cancer therapies seem to evoke immune-
valproate (158). mediated neurological syndromes, which may mimic PN, but
Cancer rehabilitation is an important initiative to promote appear at different times during treatment. In the coming years,
specific therapies for patients affected by neurological conditions the study of the mechanisms and effects of these therapies
in cancer. Therapy effects and, due to increased long-term will provide new insights into the relationship between cancer,
survival, persisting effects need to be specifically treated. The immunity and the nervous system.
rehabilitation of neuropathies is generally also heterogeneous,
depending on the focus of deficit and disability. The reference AUTHOR CONTRIBUTIONS
level could be at best adapted and copied from the rehabilitation
of cancer patients with CIPN, which bears similarities with the WG, MZ, AG, and BG conceived and drafted the review. VP
most common phenotype. and FB contributed to draft the review. WG and BG revised
the manuscript for important intellectual content. All authors
CONCLUSION contributed to the article and approved the submitted version.

In summary, since the 2004 classification, several peripheral ACKNOWLEDGMENTS

manifestations have been described, mainly with new antibodies,
in patients affected by cancer. Whereas novel intracellular The authors thank Joanne Fleming for English editing.

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Frontiers in Neurology | www.frontiersin.org 14 October 2021 | Volume 12 | Article 706169