Manifestaciones diversas en sistema nervioso periférico con relación a proceso oncológicos o su tratamiento, síndromes paraneoplásicos. Banderas rojas y alertas sobre su detección.

1. Paraneoplastic disorders of the peripheral
nervous system
Jean-Christophe Antoine1,2,3
, Jean-Philippe Camdessanché1,2,3
1. University Hospital of Saint-Étienne, Department of Neurology, Saint-Étienne, France
2. Reference Center for Paraneoplastic Neurological Syndrome, Lyon, Paris and Saint-Étienne, France
3. Rhône-Alpes Reference Center for Rare Neuromuscular Diseases, Saint-Étienne, France
Correspondence:
Jean-Christophe Antoine, CHU de Saint-Étienne, Service de Neurologie, 42055 Saint-Étienne cedex 02, France.
j.christophe.antoine@chu-st-etienne.fr
Available online: 19 April 2013
Clinically overt peripheral nervous system (PNS) involvement is a frequent event in patients
with cancer occurring in 1.7–16% of cases [1,2]. These include compression or infiltration by the
tumour, deleterious effects of treatments, sometimes months or years after their application,
metabolic and nutritional factors, and virus infections favoured by the immunodepression that
frequently accompanies cancer treatment. The term of paraneoplastic neurological syndromes is
restricted to disorders that are not explained by any of the mechanisms mentioned above and
concerns a minority of patients, probably less than 1%. As cancer and peripheral neuropathy are
two frequent conditions that affect millions of patients worldwide, such a negative definition
leaves open the way to possible fortuitous association. However, substantial progresses obtained
over years now allow a clear-cut characterisation of these disorders.
The question of paraneoplastic syndromes of the peripheral nervous system is a multifaceted
problem involving at least four tightly intricate levels of complexity. The first concerns the
different mechanisms by which cancer affects the PNS. The second level is topographic since
many parts of the PNS can be affected including motor, sensory and autonomic neurons, nerve
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e235
Summary
Paraneoplastic neurological syndromes are rare but can affect any part of the peripheral
nervous system (PNS) including motor neurons, sensory ganglia, nerve roots, plexuses, cranial
and peripheral nerves, and neuromuscular junctions. The type of cancer, lymphoma or solid
tumour, is a determinant factor of the underlying mechanism. With solid tumour, antibodies
directed to intracellular (anti-Hu or anti-CV2/CRMP5 antibodies) or surface antigens
(anti-VGCC,or LGI1 and Caspr2 antibodies) have been identified while with lymphoma, the
neuropathy is usually linked to a monoclonal gammopathy. This review discusses the different
etiologies and mechanisms of paraneoplastic disorders of the PNS in patients emphasising their
evaluation, diagnosis and treatment.
In this issue
The discovery of the
Guillain-Barré syndrome and
related disorders
Richard Hughes et al.,
London, United-Kingdom
Pathophysiology of
autoimmune
polyneuropathies
Marinos C. Dalakas, Athens,
Greece
Diagnosis, treatment and
prognosis of Guillain-Barré
syndrome (GBS)
Pieter A. van Doorn,
Rotterdam, the Netherlands
Chronic inflammatory
demyelinating
polyradiculoneuropathy
Peter Y. K. Van den Bergh et
al., Brussels, Belgium
Multifocal motor neuropathy
Raquel Guimarães-Costa et
al., Paris, France
Paraproteinemic
neuropathies
Ricard Rojas-García et al.,
Barcelona, Spain
Paraneoplastic disorders of
the peripheral nervous
system
Jean-Christophe Antoine et
al., Saint-Étienne, France
tome 42 > n86 > juin 2013
http://dx.doi.org/10.1016/j.lpm.2013.01.059

2. roots, plexuses, cranial and peripheral nerves, and the neuro-
muscular junction. The third level corresponds to the cellular
structures that are targeted, neuron cell body, axon membrane
or myelin sheath. The nature of cancer is responsible for the
fourth and last level of complexity since lymphoma and carci-
noma have a different ability to induce paraneoplastic disor-
ders. All of these points have practical consequences for the
diagnosis and management of patients.
Classification of paraneoplastic disorders of
the PNS
The known mechanisms by which paraneoplastic disorders may
develop are mostly autoimmune. With carcinoma, the expres-
sion by the tumour of a self-antigen present on different
components of the nervous system may lead to a breakdown
of immune tolerance, activation of auto-aggressive B and T cells
resulting in the production of autoantibodies and cytotoxic T-
lymphocytes [3,4]. Two categories of antigens are now dis-
tinguished, namely intracellular and cell surface antigens [5,6].
This distinction has important consequences since although
antibodies are produced with both types of antigens, it is
probable that they do not have access to their target when
the antigen is intracellular and that T cells are then the main
effectors of the immune process. The situation is different when
the antigen is incorporated in the cell membrane, such as
receptor or ion channel proteins or proteins associated to
them since a number of evidences clearly shows that in this
case antibodies have access to their target and may modulate
the cell surface expression of the protein or by complement
activation damage the cell membrane [5,7]. The practical
consequence is that antibody-mediated disorders are likely
to be better responders to immune treatments than the cell-
mediated ones. Another important difference between intra-
cellular and cell surface antigens is that with the former, the
immune response is almost universally associated with an
underlying tumour, while with the later a cancer may or
may not be present [7].
Two intracellular antigens are specifically associated with para-
neoplastic PNS disorders, namely the HuD and CV2/CRMP5
proteins. HuD is a nuclear and cytoplasmic protein associated
to mRNAs which is widely expressed in neurons of the central
and peripheral nervous system including autonomic neurons
[8]. The CV2/CRMP5 protein is a developmentally regulated
protein which in the adult persists in sensory neurons and in
axons and Schwann cell of the peripheral nerves [9]. Concern-
ing cell surface antigens, two motor axon membrane proteins
of the peripheral nerve are in this category: the voltage-gated
calcium channels (VGCC) of motor nerve terminals which are
involved in acetylcholine release through calcium entry at the
presynaptic level [10] and CASPR2, a protein associated with
potassium voltage-gated channels (VGKC) [11,12].
With lymphoma, the known mechanisms are somewhat diffe-
rent. As a rule, the tumour is responsible for the secretion of
factors that induce the disorders. Usually, this factor is a
monoclonal immunoglobulin produced by malignant plasmo-
cytes (IgG or IgA) or lymphoplasmocytes (IgM). Monoclonal IgM
can behave as autoantibodies reacting in all the identified cases
with a membrane antigen present on the axon or the myelin
sheath. The myelin-associated glycoprotein (MAG) or ganglio-
sides of the axon or neuron cell surface are the main targets of
these antibodies. As with carcinoma, antibodies are likely to be
responsible for the disorder and may occur without malignant
condition that is to say with monoclonal gammopathy of
unknown significance. In other circumstances, the physicoche-
mical properties of the monoclonal immunoglobulin lead to the
formation of amyloid deposits or cryoglobulin precipitates,
which are deleterious for the peripheral nerves. Finally, in a
rare condition, that of POEMS syndrome, the immunoglobulin is
not the pathogenic factor but probably an array of cytokines
produced by the tumour.
Criteria for the diagnosis of paraneoplastic neurological syn-
dromes have been proposed, which does not take into account
neuropathies associated with malignant monoclonal gammo-
pathies [13]. However, these criteria can easily be adapted for
PNS disorders as a whole. Definite paraneoplastic PNS include
three categories of disorders: first, those involving one of the
aforementioned mechanisms, second cases of a well-establis-
hed form of paraneoplastic neuropathy occurring with a tumour
but no identified antibodies, which mainly corresponds to
seronegative sensory neuronopathy, and third neuropathies
that unequivocally improve with the sole treatment of the
tumour. Conversely, any other form of neuropathy which occurs
within 2 years of the diagnosis of cancer can only be provisio-
nally considered as a possible paraneoplastic disorder.
Paraneoplastic disorders of the PNS
associated with antibodies toward
intracellular antigens
Subacute sensory neuropathy (SSN) and other PNS
disorders of the anti-Hu syndrome
SSN depends on the destruction of sensory neurons in dorsal
root ganglia by cytotoxic T-lymphocytes [14]. The onset is
usually subacute or rapidly progressive with paraesthesia and
pain. Sensory loss is mostly multifocal or asymmetrical, and
the upper limbs are almost invariably involved [15,16]. The
face, the chest, or the abdomen may also be concerned.
Pain is frequent and sensory loss, affecting especially
deep sensation, often leads to a severe sensory ataxia in
the four limbs. Although if diagnosed late in the evolution,
SSN can be a very disabling disorder, indolent and protracted
courses have been reported [17]. CSF may show elevated
protein concentration, pleocytosis or oligoclonal bands. The
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3. electrophysiological hallmark of SSN is a severe and diffuse
alteration of sensory nerve action potentials with frequently
non-excitable sensory nerves. Motor conduction velocities
are classically normal but are frequently mildly altered
which may be confusing and lead to the inappropriate
diagnosis of axonal sensory-motor neuropathy [18]. Although
SSN occurs with different tumours including breast cancer
and Hodgkin’s disease [19], small cell lung cancer (SCLC)
represents 70–80% of cases. Most patients have anti-Hu
antibodies, which have 99% specificity and 82% sensitivity
for the diagnosis of cancer in patients suspected to have SSN
[20]. If SSN is the most frequent and usually predominant
manifestation of the anti-Hu syndrome, it is isolated in only
24% of patients, the others having various combinations of
central and peripheral nervous system involvement [16].
Other PNS disorders may occur with anti-Hu antibodies [16].
The most frequent is dysautonomia which is frequently asso-
ciated with SSN. It affects the cardiovascular and digestive
systems. Orthostatic hypotension can be very severe and
arrhythmia may explain cases of sudden death. Digestive
pseudoobstruction is also a severe disease that results from
the destruction of autonomic neurons in myenteric plexuses.
Lesion of the lower motor neurons induces motor deficit,
muscle atrophy and fasciculations. As in most cases, patients
simultaneously have SSN, the resulting presentation is that of a
sensory-motor polyneuropathy which since the evolution is
usually rapid and the distribution asymmetrical, may be confu-
sed with a mononeuropathy multiplex. More symmetrical case
with an extensive progression may also be misdiagnosed as
Guillain-Barré syndrome. A predominant or pure motor neuron
syndrome mimicking amyotrophic lateral sclerosis is quite
exceptional [21]. Nerve vasculitis [22] and demyelinating
neuropathy [23] have been reported but they are very unusual
presentations of the anti-Hu syndrome.
Peripheral neuropathy with anti-CV2/CRMP5 and
other onconeural antibodies
Peripheral neuropathy occurs in 57% of patients with anti-CV2/
CRMP5 antibodies and is frequently associated with cerebellar
ataxia, limbic encephalitis or ocular involvement. The neuropa-
thy [24] is different from that of patients with anti-Hu anti-
bodies [25]. It is sensory or sensory-motor and predominates in
the lower limbs. Pain is less frequent. Electroneuromyogram
(ENMG) shows an axonal or mixed axonal and demyelinating
pattern, but the slowing of motor conduction velocities does
not reach the values usually observed in chronic inflammatory
demyelinating polyneuropathies (CIDP) and conduction blocs
are never seen. Nevertheless, when performed, nerve biopsy
may show demyelinated fibers and onion bulb formations [24].
The association of anti-Hu and anti-CV2/CRMP5 antibodies is
not rare. Patients with both antibodies may develop a neuro-
pathy blending the characteristics of the two disorders, in
particular with a mild demyelinating pattern on the ENMG.
SCLC and thymoma are the most frequent underlying tumours
with anti-CV2/CRMP5 antibodies but the prognosis of SCLC is
better with anti-CV2/CRMP5 antibodies than with anti-Hu anti-
bodies [25]. PNS disorders occur only occasionally with anti-Yo,
anti-Ma2, and anti-amphiphysin antibodies and the clinical
pattern of the neuropathy in these cases has not been well
established [26–28].
Paraneoplastic disorders of the PNS
associated with antibodies directed toward
cell surface antigens
The Lambert-Eaton myasthenic syndrome (LEMS)
LEMS is a presynaptic disorder of the cholinergic neuromuscular
and autonomic synapses. It is paraneoplastic in 40 to 60% of
cases usually in association with SCLC [29–31]. Other lung cancer
is rare [29,32–34] and other organ tumour exceptional [30].
Muscle weakness predominates in the proximal lower limbs and
can spread to other skeletal muscles including ocular muscles
[29]. Conversely, respiratory failure is rare [35]. Tendon reflexes
are depressed or abolished. Improvement of strength and
tendon reflexes by exercise is reported in 40% of patients
[36,37]. Autonomic dysfunction is characterized by mouth or
eye dryness, blurred vision, impotence, constipation, impaired
sweating, or orthostatic hypotension [29]. In a subgroup of
patients, LEMS is associated with paraneoplastic cerebellar
degeneration or with the anti-CV2/CRMP5 syndrome [38].
ENMG abnormalities in LEMS consist in the reduction of
compound motor action potentials (CMAP), a decrement supe-
rior to 10% in case of low frequency repetitive stimulation (3–
5 Hz) and increment superior to 100% after brief (20 to 60 s)
maximum voluntary muscle contraction or high frequency
repetitive stimulation (2–50 Hz) [39]. Presence of autoantibo-
dies directed to voltage-gated calcium channels (VGCC) is a
main point for the diagnosis of LEMS as these antibodies are
present in 85 to 90% of patients and reach 100% in case of SCLC
[40–42]. A direct role of anti-VGCC antibodies in the pathophy-
siology of LEMS through a presynaptic bloc of axonal signal has
been demonstrated [39] as well as the transfer of the disease
by the serum of the patients in case of pregnancy [43–45] or in
animal models [41].
Neuromyotonia and peripheral nerve
hyperexcitability (PNH)
Acquired neuromyotonia, PNH, and Isaacs’ syndrome encom-
pass abnormal muscle activities generated in motor nerves like
cramps, stiffness, twitching, spasms, or abnormal muscle rela-
xation [46]. In some patients, PNH is associated with motor
weakness, paresthesias, hyperhidrosis and/or central nervous
involvement including confusion, sleep disruption, mood chan-
ges, and hallucinations reaching in these particular cases the
diagnosis of Morvan’s syndrome [47]. Diagnosis is based on
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4. ENMG recording of fibrillation potentials, fasciculation poten-
tials, myokimia organized in doublet, triplet or multiplet, myo-
kimic discharges, neuromyotonic discharges at rest, and post-
effort or post-electric stimulus discharges [48].
Neuromyotonia is associated with thymoma in 15% of cases,
less frequently with SCLC and occasionally with Hodgkin’s
disease or plasmocytoma [47]. Dysimmune mechanisms sug-
gesting a direct role of voltage-gate potassium channel anti-
bodies have been supported by several experiments [49,50],
but contactin-associated protein-2 (CASPR2) is now known to
be the immune target even if numerous patients do not
develop abnormal antibodies [12,46,51]. In Morvan’s syn-
drome, the central nervous system involvement is probably
linked with LGI1 antibody which occurs more frequently with
limbic encephilitis [52,53].
Peripheral neuropathies in patients with
malignant monoclonal gammopathies (MG)
Monoclonal immunoglobulins associated with malignant clo-
nal proliferations of B-lymphocytes represent 25–30% of all
MG. IgM isotype is associated with lymphoplasmocytic lym-
phoma (Waldenström’s disease), IgG with lymphocytic leu-
kaemia or lymphoma and IgG, A, or D with multiple myeloma.
The overall risk of developing malignancy in patients with MG
of unknown significance is about 1% per year but increases
with age [54].
Amyloidosis occurs in 20–40% of patients with multiple mye-
loma. It is most frequent with l light chains with a k/l ratio of
about 1/3. Peripheral neuropathy reveals amyloidosis in one
fourth of the cases and usually presents as a painful sensory
or sensory-motor neuropathy mainly affecting small fibers
[55,56]. Carpal tunnel syndrome, macroglossia, purpura,
nephrotic syndrome, renal insufficiency, congestive heart fai-
lure, and orthostatic hypotension are frequent [57]. About
70% of patients have at least two organ involvements at
presentation [58]. Some atypical presentation of the neuropa-
thy may occur including cases mimicking CIDP [59]. A rare
presentation with monoclonal IgM and lymphoplasmocytic
lymphoma is that of amyloidomas in roots and plexus
[60,61]. Demonstration of amyloid deposits may be difficult
and necessitate several biopsies. Cryoglobulins associated
with lymphoma are mostly of type I (monoclonal IgG/IgM
component only). Mononeuritis multiplex or sensory-motor
neuropathy with vasculitis is the most frequent manifestation
followed by Reynaud’s phenomenon, and skin and renal
changes [62,63].
With Waldenström’s macroglobulinemia, the monoclonal IgM
can behave as a peripheral nerve antibody. The neuropathy is
similar to that which more frequently occurs with MGUS IgM. In
5 to 45% of patients, the reactivity is directed against MAG
[64,65] and the light chain isotype is k. The neuropathy is
typically a chronic distal mostly sensory neuropathy. Pain,
tremor and ataxia are frequent. Electrophysiology shows a
predominantly distal demyelinating pattern demonstrated by
a decreased terminal latency index under 0.3 [66,67]. Nerve
biopsy when it is performed may show a typical widening of
the most peripheral myelin lamellae and intra-myelin IgM
deposits. Other reactivity is fairly rare in general and especially
with lymphoma. IgM reacting with disialosyl gangliosides occur
with a predominantly sensory neuropathy and ophtalmoplegia
[68,69], and reactivity with GM1 with multifocal motor neu-
ropathy [70,71].
POEMS (polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, skin changes) syndrome is a rare
multisystem disorder occurring with osteosclerotic myeloma
[72,73]. A chronic sensorimotor predominantly distal axonal
and demyelinating neuropathy and a monoclonal component
are mandatory to establish the diagnosis [73]. The component
is usually an IgG (more rarely an IgA) and the light chain of the l
isotype. Oedema including papilla oedema, ascites and ana-
sarca, pulmonary hypertension, renal failure, thrombotic
events, and congestive heart failure are part of the syndrome.
Cytokines including IL-6, TNFa and especially VEGF are over-
produced. Several studies have showed the great help provided
by a dosage of plasma VEGF level for the diagnosis of POEMS
syndrome when the presentation is incomplete [74–76].
Usually very high levels of VEGF are detected but some patients
may present with mild or even low levels.
Beside these well-characterized situations, there exist other
neuropathies for which the link with the gammopathy is still
unclear [77]. In Waldenström’s disease, a large spectrum of
peripheral neuropathy may occur [78]. An unspecific distal
predominantly sensory neuropathy may represent a majority
of cases [64]. The pattern of the neuropathy is axonal or
demyelinating. Observations of endoneural immunoglobulin
deposits in nerve biopsies suggest that the MG may be dele-
terious for nerve fibers without the necessary formation of
amyloid deposits [71,79]. Neuropathy with non-sclerotic mye-
loma that do not depend on amyloidosis are rare and most of
the reported cases have an axonal pattern [80].
Possible paraneoplastic peripheral
neuropathies
Since the concept of paraneoplasia has been fully developed in
the first half of the XXth century, varieties of neuropathies other
than those listed above have been reported as paraneoplastic.
These include cases of Guillain-Barré syndrome, CIDP, mono-
neuritis multiplex, lower motor neuron diseases, brachial ple-
xopathy and sensory or sensory-motor axonal polyneuropathy
[81]. In a study, neuropathies occurring in a short delay with the
discovery of cancer tended to be inflammatory including Guil-
lain-Barré syndrome, CIDP, and neuropathies with vasculitis
[82]. With lymphoma, demyelinating neuropathy is the most
frequent pattern, but axonal neuropathy with microvasculitis
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5. and lower motor neuron disease have also been reported
[83,84].
None of these cases have one of the identified onconeural
antibodies and a link between the neuropathy and the tumour
has not been demonstrated. Improvement of a neuropathy
following treatment of the tumour is a major criterion of the
diagnosis of paraneoplastic disorders, but reported cases are
few. They include lower motor neurone diseases [85,86],
vasculitic neuropathies [87], and CIDP [88]. An epidemiological
approach is another way to demonstrate a link between cancer
and neuropathy. But studies are few and the published ones
may not be free of statistical bias. For example, an Italian group
found increased incidence of cancer in a cohort of patients with
Guillain-Barré syndrome [89], but no specific tumour was
observed. This is a general feature of neuropathies without
onconeural antibodies, which strikingly contrasts with the
overwhelming incidence of SCLC in patients with onconeural
antibodies.
In rare cases, autoantibodies have been observed which sug-
gests immune-mediated disorders. Thus, ganglionic acetylcho-
line receptor antibodies have been reported in patients with
acute or subacute and sometimes chronic autonomic neuropa-
thies [90] but these antibodies are not specific of cancer and at
high titer rarely occur in patients with a known tumour although
low or mild level of antibody may be present in several
neurological conditions including with and without cancer
and in patients with small cell lung tumour [91]. In a handful
of cases, a mechanism similar to that of the well-identified
paraneoplastic disorders may be suspected. Thus, a patient
with breast cancer and lower motor neuron disease developed
an antibody reacting with bIV spectrin [92]. Although low levels
of anti-ganglioside antibodies can be found in patients with
neuropathy and tumour probably as a consequence of a natural
anti-cancer immunity [93], anti-ganglioside antibodies have
been specifically linked with both the cancer and the neuropa-
thy in a few patients with melanoma [94,95].
Diagnostic strategy of paraneoplastic
disorders
When and how to diagnose a paraneoplastic
neuropathy?
In more than 80% of cases, the paraneoplastic neurological
disorder antedates the revelation of cancer by month or years
and when the cancer is known, a relapse must be suspected. It
is therefore important to identify those patients for whom an
active search of an underlying tumour is needed. In this way,
there are three main circumstances in which the clinical pat-
terns of the neuropathy imply to consider the possibility of a
paraneoplastic disorder.
The first is when a well-established paraneoplastic disorder
is diagnosed. This includes SSN, LEMS, neuromyotonia and
neuropathies with a well-characterized onconeural antibody.
SSN depends on several etiologies including, genetic, toxic,
dysimmune and paraneoplastic conditions while an important
proportion remains idiopathic. In our personal series, an under-
lying tumour is present in no more than 6% of patients with
definite SSN originating from a single population area (unpu-
blished data). Distinguishing SSN from other sensory neuropa-
thies is nevertheless important owing to its consequence. A set
of criteria relying on easily obtainable clinical and electro-
physiological items has good sensitivity and specificity to
distinguish SNN from other neuropathies [96]. Following a
recently proposed strategy for the etiological diagnosis of
SNN [97], it is recommended to perform systematically a search
for anti-Hu and CV2/CRMP5 antibodies in patients fulfilling the
criteria of SSN. As paraneoplastic SNN can be seronegative, a
search for a tumour must be performed if the evolution is acute
or subacute and the CSF inflammatory. The question of a
paraneoplastic origin may arise in a patient receiving platinum
salts for the treatment of a small cell lung cancer and who
develops subacute SNN. Some clinical features distinguish toxic
from paraneoplastic SNN in particular platinum salt-induced
SNN have a symmetrical distribution and almost spare small
fibers [98,99]. A search for onconeural antibodies may help to
distinguish the two disorders but only high antibody titers are
indicative of a paraneoplastic origin since patients with SCLS
may harbor low level of anti-Hu or anti-CV2/CRMP5 antibodies
[13].
The main difficulty with LEMS is not to miss the diagnosis and
perform a search for potentiation in a patient with peripheral
motor deficit and low amplitude CMAP. As patients with anti-Hu
and especially anti-CV2/CRMP5 antibodies may simultaneously
have LEMS, it is recommended to systematically perform a
search for potentiation when the CMAPs are abnormal. A clinical
score, the DELTA-P score, has been proposed to predict the
paraneoplastic origin of LEMS in a given patient according to the
presence of bulbar weakness, erectile dysfunction, loss of
weight, tobacco consumption, age and Karnosky’s score in
the screened patients [100]. Anti-SOX1 antibodies which are
specific of the tumour may also help to distinguish paraneo-
plastic from non-paraneoplastic LEMS [101,102].
The second circumstance which is highly suspect of a paraneo-
plastic neurological syndrome although not pathognomonic is
when the peripheral neuropathy is associated with involvement
of the central or autonomic nervous system. Such an association
must therefore be carefully searched for in a patient with
subacute peripheral neuropathy since central and autonomic
nervous system manifestations may be almost asymptomatic.
A subacute and severely deteriorating evolution is a common
feature of paraneoplastic disorders. Therefore, peripheral neu-
ropathies with an unusual, rapid and severe course should be
considered as suspect of a paraneoplastic disorder inasmuch
as the CSF shows cellular inflammatory reaction or local IgG
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6. production. Patients in these circumstances may or may not have
onconeural antibodies. Although there is no validated recom-
mendation for the management of patients when onconeural
antibodies are absent, it may be preferable to search for an
underlying tumour when the neuropathy follows this pattern.
As a rule, axonal distal polyneuropathy or CIDP do not deserve a
specific search for a malignancy except when a monoclonal
gammopathy is detected. The question is opened for nerve
vasculitis for which there exist several case reports or small
series mentioning association with lymphoma or carcinoma
[84,103,104].
A search for monoclonal gammopathy is a common rule in the
management of patients with peripheral neuropathy. A mono-
clonal IgG with l light chain should prompt searching for
amyloidosis or POEMS syndrome according to the clinical pre-
sentation while a k light chain with a monoclonal IgM should
orientate toward a possible autoantibody activity of the mono-
clonal component. Monoclonal cryoglobulins may be difficult to
detect if they are precipitated in the serum sample. In this
circumstance, a low blood complement level is very suggestive
of cryoglobulinemia.
With lymphoma, the most important difficulty is to identify
cases of neurolymphomatosis due to the infiltration of peri-
pheral nerves by the tumour and distinguish them from para-
neoplastic disorders. Pain and a presentation of radiculopathy
are suggestive but the neuropathy may present in many other
forms [105]. FDG-PET scanner may help to detect abnormal
fixation along peripheral nerves, but nerve biopsy is the only
way to ascertain a diagnosis, which is frequently a difficult
decision since proximal nerve trunks, roots or plexus may have
to be analyzed. Furthermore, a close phenotypic study of the
mononuclear cells infiltrate is necessary to demonstrate mono-
clonality and distinguish lymphomatous infiltration from
inflammatory reaction [84].
Tumour diagnosis in patients with definite
paraneoplastic PNS
The strategy in search for the responsible cancer depends heavily
on the nature of the paraneoplastic disorders and the associated
antibodies [31]. In patients with SSN, LEMS, anti-Hu or anti-CV2/
CRMP5, SCLC must be suspected first. The tumour is frequently
limited to small metastatic lymph nodes that may escape detec-
tion by CT scan or lung fibroscopy. A FDG-PET scanner is then
recommended but it should be kept in mind that if the method is
highly sensitive it is not specific [106]. Mediastinal lymph nodes
may be difficult to reach for biopsy and each case must be
carefully discussed with a trained lung specialist or thoracic
surgeon to adopt the safest strategy with the best chance of
rapidly reaching the accurate diagnosis [107]. FDG-PET scanner
has also the advantage of detecting extrapulmonary small cell
tumours that may occur with the disorders listed above. When a
first careful workup is negative, it is recommended to renew it
after 3 to 6 months and then every 6 months for a period of at
least 4 years [31]. With LEMS, 2 years are sufficient since most
cancer appear within this delay [13]. When performing an
extensive search for the underlying tumour, it is not rare to
found a malignancy which is at odd with the expected cancer
(e.g. a colon cancer with an anti-Hu antibody). If an expression of
the onconeural antigen by the tumour is not demonstrated, a
SCLC must still be suspected [16]. With neuromyotonia and CV2/
CRMP5 antibodies, thymoma is an alternative possibility when
other cancers are excluded.
With monoclonal gammopathy, the strategy of tumour diag-
nosis depends on the nature of the gammopathy. Wal-
denström’s disease and lymphocytic leukemia are usually
diagnosed by blood cell analysis and bone marrow aspiration
or biopsy. Lymphomas usually require FDG-PET scanner and
lymph node biopsy. A search for a plasmocytic proliferation
necessitates an extensive and careful bone radiographic
screening since particularly with POEMS syndrome the tumour
may present as solitary plasmocytoma. MRI is helpful for the
detection of plasmocytomas in particular when they are located
in the vertebrae. Plasmocytomas are usually not detected by
bone scintigraphy with technecium tracers but may be showed
by FDG-PET scanner [107].
Treatment
Symptomatic treatments
Pain is a frequent manifestation of paraneoplastic neuropathies
and patients may greatly benefit from tricyclic antidepressants,
antiepileptic and sometimes morphinic drugs [108].
The first-line treatment in LEMS is symptomatic and uses 3-4
diaminopyridine which is a validated strategy according to the
2011 Cochrane review [109]. Seizure is a dose-dependent
serious side effect of 3-4 diaminopyridine and must be
taken into account [110]. Perioral tingling, paresthesias, gas-
trointestinal symptoms, and in a few cases, QT interval pro-
longations can be encountered as well. With neuromyotonia,
carbamazepine, phenytoin, lamotrigine and sodium valproate
can be used alone or in combination [111].
Specific treatments
Paraneoplastic disorders with antibodies toward
intracellular antigens
Several studies have tried immunomodulatory or immunosup-
pressant treatments including high-dose steroids, intravenous
immunoglobulins (IVIg), plasma exchanges, cyclophospha-
mide, rituximab or a combination of them in patients with
paraneoplastic disorders associated with intracellular antigen
antibodies [112–115]. These studies are often uncontrolled or
opened and include small numbers of patients with different
paraneoplastic disorders and onconeural antibodies. Some of
them suggest slight improvement or stabilization but as a
e240
J-C Antoine, J-P Camdessanché
tome 42 > n86 > juin 2013

7. whole their results are inconclusive. In a retrospective study of a
large number of patients with anti-Hu antibodies, an early
treatment of the tumour was the only factor significantly
associated with a stabilization of the neurological disorder [16].
Paraneoplastic disorders with antibodies toward
intracellular antigens
The main treatment of paraneoplastic LEMS is, as in the princeps
case, the tumour treatment which usually results in an impro-
vement of the neuromuscular transmission failure [116]. In
case of residual symptoms, prednisone or prednisone–azathio-
prine association is proposed on the basis of an old and small
retrospective study [117]. Plasma exchanges, IgIV and rituxi-
mab may be selectively useful [117,118].
With PNH, tumour treatment sometimes permits disease
control [119]. Clinical improvement and a decrease of auto-
antibody titer and ENMG abnormal activities had been shown
after plasma exchanges [49,119]. In spite of absence of large
trials, IVIg, prednisolone, azathioprine and methotrexate are
proposed as well [111].
Paraneoplastic neuropathies with lymphoma
As with carcinomas, an early treatment of the tumour is the
most efficient way of improving or stabilizing the neurological
disorder. Patients with POEMS or IgM monoclonal gammopa-
thy with antibody activities usually do not or only poorly
respond to steroids, IgIV or plasma exchanges which therefore
are not recommended. With cryoglobulinemia or anti-MAG
IgM, protocols incorporating anti-CD20 antibodies may be
efficient to rapidly reduce the level of the gammopathy. In
case of amyloidosis, the Mayo Clinic group has advocated high-
dose chemotherapy and stem cell transplantation in selected
patients [120] while a French collaborative study have showed
the efficacy of conventional doses of melphalan plus predni-
sone [121]. With POEMS syndrome and systemic plasma cell
proliferation, a treatment similar to that of amyloidosis is pro-
posed while a local radiotherapy is recommended in patients
with solitary or dominant osteosclerotic plamocytoma [122].
Thalidomide, lenalidomide, and bortezomib are interesting
drugs for both amyloidosis and POEMS syndrome but their
neurotoxicity in patients with neuropathy should be taken
into account. Anti-VEGF antibodies have been proposed [58]
forthe treatment of POEMS syndrome but gave conflicting results
[122].
Disclosure of interest: the authors declare that they have no conflicts of
interest concerning this article.
e241
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J-C Antoine, J-P Camdessanché
tome 42 > n86 > juin 2013