Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis
Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis
Giustino Varrassi . Marios Hadjivassiliou 0 1 2 3 4
0 A. Paladini A. Piroli Department of MESVA, University of L'Aquila , L'Aquila , Italy
1 P. Zis M. Hadjivassiliou Department of Neurology, University of Sheffield , Sheffield , UK
2 P. Zis (&) M. Hadjivassiliou Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield , UK
3 G. Varrassi University of L'Aquila , L'Aquila , Italy
4 P. C. McHugh Centre for Biomarker Research, University of Huddersfield , Huddersfield , UK
Introduction: Paraneoplastic neurological syndromes (PNS) consist of a heterogeneous group of neurological disorders triggered by cancer. The aim of this systematic review is to estimate the reported prevalence of pain in patients with paraneoplastic peripheral neuropathy (PPN). Methods: A systematic computer-based literature search was conducted on PubMed database. Results: Our search strategy resulted in the identification of 126 articles. After the eligibility assessment, 45 papers met the inclusion criteria. Full clinical and neurophysiological data were further extracted and involved 92 patients with PPN (54.5% males, mean age 60.0 ± 12.2 years). The commonest first manifestation of PPN is sensory loss (67.4%), followed by pain (41.3%), weakness (22.8%), and sensory ataxia (20.7%). In 13.0% of the cases, pain was the sole first manifestation of the PPN. During the course of the PPN, 57.6% of the patients may experience pain secondary to the neuropathy. Conclusions: Pain is very prevalent within PPN. Pain specialists should be aware of this. Detailed history-taking, full clinical examination, and requesting nerve conduction studies might lead to an earlier diagnosis of an underlying malignancy.
Paraneoplastic neurological syndromes (PNS)
consist of a heterogeneous group of
neurological disorders triggered by cancer. These
syndromes are caused by mechanisms other than
metastases, metabolic or nutritional deficits,
infections, coagulopathy, or side effects of
cancer treatment such as chemotherapy. The
discovery that many PNS are associated with
antibodies against neural antigens expressed by
the tumor (antineural antibodies) has suggested
that PNS are immune-mediated [
The recommended diagnostic criteria for
] suggest that the cancer has to develop
within 5 years of the diagnosis of the
neurological disorder. This time period has been
based on reports showing that in the majority of
cases the interval between the PNS and the
diagnosis of cancer is less than 5 years.
Paraneoplastic peripheral neuropathy (PPN)
is one of the commonest PNS reported. The aim
of this paper is to systematically review the
presenting manifestations of patients with PPN
and establish the reported prevalence of pain.
This article follows on from the editorial
introduction ‘‘Painful Peripheral Neuropathy and
Literature Search Strategy
A systematic computer-based literature search was
conducted on April 6th, 2017 on PubMed
database. For the search, we used three Medical Subject
Headings (MeSH) terms. Term A was
‘‘neuronopathy’’ or ‘‘ganglionopathy’’ or
‘‘neuropathy’’, term B was ‘‘paraneoplastic’’ and term C was
‘‘first manifestation’’ or ‘‘first symptom’’ or ‘‘initial
symptom’’ or ‘‘first manifestations’’ or ‘‘first
symptoms’’ or ‘‘initial symptoms’’ or ‘‘presenting
symptom’’ or ‘‘presenting symptoms’’ or ‘‘pain’’ or
‘‘painful’’. Limitations included language to be
English and full text to be available. We also
perused the reference lists of the papers in order to
find papers not found through the search strategy.
Inclusion and Exclusion Criteria
To be included in the review, the articles had to
meet the following criteria:
(1) To involve single cases or cases series with
(2) To study human adult subjects.
The following exclusion criteria were applied:
(1) Book chapters, reviews, letters to the editor
and editorials that did not provide new
(2) Papers referring only to autonomic
(3) Papers referring only to cranial
(4) Papers referring only to small fiber
(5) Papers referring to POEMS
(Polyneuropathy, organomegaly, endocrinopathy,
M-protein and skin changes) syndrome.
(6) Papers referring to motor neuron disease.
(7) Papers providing incomplete clinical or
neurophysiological data about the single
Data were extracted from each study in a
structured coding scene using Microsoft Excel
and included information on the article
identification, year of publication, evaluation
period, total number of subjects, gender, age, first
manifestation of the PPN, presence of pain
secondary to the neuropathy,
neurophysiological type of neuropathy, course of symptoms,
type of cancer, and presence of anti-neuronal
We used the International Association for
the Study of Pain (IASP) definitions to classify
pain as neuropathic or not.
This article is based on previously conducted
studies and does not involve any new studies of
human or animal subjects performed by any of
A database was developed using the IBM SPSS
Statistics (version 23.0 for Mac). Frequencies
and descriptive statistics were examined for
each variable. The primary outcomes of
interest were the proportion of patients who
experienced pain as a first manifestation of the PPN
and the proportion of patients who
experienced pain during their PNS. Further
comparisons between groups were made using
Student’s t test for continuous data and
Chisquare test for categorical data. A value of
P\0.05 was considered to be statistically
This search strategy resulted in the
identification of 126 articles. After the eligibility
assessment, 81 articles were excluded. In total, 45
papers met the inclusion criteria and were used
for this review [
]. These studies were
published between 1984 and 2017. Figure 1
illustrates the study selection process.
Full clinical and neurophysiological data
were further extracted from 42 papers and
involved 92 patients with PPN (54.5% males).
The age of the patients ranged from 18 to
81 years (mean 60.0 ± 12.2 years). The
demographic and clinical characteristics of these
patients are summarized in Table 1.
Epidemiological Characteristics of PPN
Although PPN is said to be the commonest PNS
(34.9%), followed by encephalomyelitis (23.8%)
and cerebellar degeneration (20.6%) [
is sparse epidemiological data on the prevalence
of neurophysiologically confirmed PPN. The
reasons for this are two-fold. The available
studies to date are either in cohorts of patients
with known malignancy and neuropathic
symptoms or in patients who are seropositive
for well-characterized paraneoplastic
antibodies. A correct prevalence study of PPN should
include a large cohort of patients with newly
diagnosed malignancy all of whom should be
evaluated for the presence of PN with nerve
conduction studies, even in the absence of
neuropathic symptoms and paraneoplastic
Fig. 1 PRISMA chart
Lucchinetti et al. [
] estimated that out of
162 patients seropositive for anti-Hu antibodies
(anti-neuronal antibodies usually associated to
small-cell lung carcinoma), 72.8% presented
with neuropathic symptoms. Most commonly,
the patients presented with pure sensory
(40.1%), followed by mixed sensory and motor
(30.2%) and pure motor symptoms (2.4%) [
However, no neurophysiological data were
provided in this study.
In another series of 150 patients with a
biopsy confirmed SCLC, Elrington et al. [
estimated that the prevalence of sensory
symptoms was 16% and the prevalence of motor
symptoms 44%. However, a definite neuropathy
was confirmed with nerve conduction studies
only in one patient (0.7% of the total study
Graus et al. [
] presented a series of 200
patients, seropositive for anti-Hu antibodies,
and estimated that 54% were present with
predominantly sensory neuropathy and 4.5% with
sensorimotor neuropathy. However, no
information was given about whether nerve
conduction studies were done in all patients, and
what type of neuropathy these patients
Clinical Manifestations of PPN
The commonest early manifestation of PPN is
sensory loss (67.4%), followed by pain (41.3%),
weakness (22.8%), and sensory ataxia (20.7%).
In 39.1% of the cases, the presenting
complaints included more than one symptom.
However, in 13.0% of the cases, pain was the
sole first manifestation of the PPN. During the
course of the PPN, 57.6% of the patients
reported pain secondary to the neuropathy. In the
majority of these patients (96.2%), the pain was
directly related to the neuropathy (considered
as neuropathic) as described in the papers
included in this review; however no validated
tools were used to systematically assess and
record other neuropathic symptoms
accompanying pain. A minority of patients reported pain
indirectly related to the neuropathy (not
neuropathic), secondary to painful muscle cramps.
Temporal Evolution of PPN and Pain
Most reports classified PPN as acute, sub-acute
or chronic/progressive. Acute were those
neuropathies that evolved within 1 month,
sub-acute were those that evolved between 1 and
6 months, and chronic the neuropathies that
slowly kept progressing beyond 6 months.
Based on these reports, we estimated that PPN
are sub-acute in the majority of cases (64.1%),
followed by chronic (22.8%) and acute (13.0%).
Neurophysiological Types of PPN and Pain
Large fiber neuropathy can be axonal or
demyelinating. In axonal neuropathy, axons are
affected usually in proportion to their length
(length dependent). In demyelinating
neuropathy, the myelin sheath around axons is
affected, and as a result, the ability of the axons
to speedily conduct electrical impulses is
impaired. The latter leads to slow or no
conduction (conduction block). Sensory
neuronopathy, or ganglionopathy, is another large
fiber peripheral neuropathy, in which the cell
bodies of the sensory neurons located in the
dorsal root ganglia are affected. Finally, in pure
motor neuropathy, there is involvement of only
the lower motor neurons [
Demyelinating neuropathies were reported
in 13% of PPN cases. Among the axonal PPN
(87%), the most common neurophysiological
type was asymmetrical sensory ganglionopathy
(27.2%), followed by symmetrical sensorimotor
neuropathy (23.9%), symmetrical sensory
neuropathy (21.7%), pure motor neuropathy
(7.6%), and mononeuritis multiplex (6.5%).
Figure 2 illustrates how common is pain based
on the neurophysiological type of the PPN.
Though rare, the most painful type of PPN is
mononeuritis multiplex. Mononeuritis
multiplex is known to occur in many illnesses
including certain types of systemic vasculitis
]. Indeed, in the majority of patients with
paraneoplastic mononeuritis multiplex a nerve
biopsy was performed, showing evidence for
Although pure motor neuropathy is the least
common, it can still be painful. The major
difference in the pain reported in such cases is that
it is muscular in nature, most commonly
because of cramps [
Paraneoplastic Antibodies and Painful PPN
Out of 76 patients with painful PPN tested for
anti-Hu antibodies, 47 were positive (61.8%).
Other antibodies that have been associated with
PPN are anti-amphiphysin and anti-CV2
antibodies. Interestingly enough, patients with
anti-Hu antibodies were more likely to present
with pain as a first manifestation compared to
patients without anti-Hu antibodies (53.2 vs.
24.1%, p = 0.013). Also, patients with anti-Hu
antibodies were more likely to present with pain
secondary to the PPN at any point compared to
patients without anti-Hu antibodies (74.5 vs.
41.4%, p = 0.004).
Cancer Types and Painful PPN
Lung cancer was the commonest cause of PPN
(45.7%), followed by hematological
malignancies (16.3%) and gastro-intestinal tract
malignancies (12.0%). The majority of patients
seropositive for anti-Hu had lung cancer
(66.0%). Detailed data regarding type of
malignancy are shown in Table 1. Cancer type was
not related significantly to pain either as a first
manifestation or during the course of the PPN
ganglionopathy, SMA sensorimotor axonal neuropathy,
SN symmetrical sensory neuropathy, PM pure motor
neuropathy, MMX mononeuritis multiplex
PPN and Cancer Relapse
PNS can be the first manifestation of cancer
8, 17, 20
] and they often precede the
clinical or radiological diagnosis of a local relapse
or distant metastases. Patients with a history of
cancer presenting with peripheral neuropathic
pain, not otherwise explained, can be diagnosed
with PNS when circulating paraneoplastic
antibodies are detected or a PET scan is positive.
Management of pain as a result of paraneoplastic
neuropathy does not differ from the published
guidelines on the management of neuropathic
]. However, it is commonly reported that
treatment for the underlying malignancy
(including tumor resection and/or chemotherapy)
can improve the symptoms [
3, 11, 28, 30, 37
This systematic review and meta-analysis
indicates the following key points:
(1) Pure sensory neuropathy (sensory
ganglionopathies and symmetrical sensory
neuropathies) is the commonest form of
PPN reported. A full neurophysiological
assessment is therefore advisable in all
suspected cases. Such a finding may
prompt searching for an underlying
(2) The commonest first manifestation of PPN
is sensory loss (67.4%), followed by pain
(41.3%), weakness (22.8%), and sensory
(3) Pain is prevalent in PPN, as almost three
out of five patients with PPN will
experience peripheral neuropathic pain at some
point in the course of the PNS. The
majority of the patients will experience
neuropathic pain, but patients with pure motor
neuropathies also experience pain
secondary to cramps.
(4) One out of seven patients with PPN will
experience pain as the sole manifestation.
Therefore, pain specialists should be aware
that they may be the first to encounter
patients whose pain may be a
paraneoplastic phenomenon. Therefore, detailed
history taking, full clinical examination,
assessment—especially of sub-acute onset and of unknown
etiology—may lead to an earlier diagnosis
of an underlying malignancy.
(5) Testing for paraneoplastic antibodies (i.e.,
anti-Hu and anti-CV2), especially in
sensory neuropathies that evolve sub-acutely,
might also be helpful in earlier diagnosis of
(6) PNS can occur as part of cancer relapse and
pain can be the first manifestation in such
cases. Therefore, patients with a past
history of malignancy who present with
neuropathic symptoms, including pain and
have evidence of a PN on neurophysiology
should be investigated further for a
possible relapse. A PET scan might be useful in
the earlier diagnosis of PNS [
(7) Among the papers included in this review,
different terms have been used to describe
the presenting symptoms. The use of
validated tools [
] for assessing the presence
of pain and the quality of the related
characteristics might be useful for future
No funding or sponsorship was received for this
study or publication of this article. All named
authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for
authorship for this manuscript, take
responsibility for the integrity of the work as a whole,
and have given final approval for the version to
be published. Panagiotis Zis has conceptualized
the review. Panagiotis Zis carried out the
systematic literature review and wrote the
manuscript. Antonella Paladini, Alba Piroli, Patrick C.
McHugh, Giustino Varrassi, and Marios
Hadjivassiliou revised and critically appraised the
Disclosures. Panagiotis Zis, Antonella
Paladini, Alba Piroli, Patrick C. McHugh, Giustino
Varrassi and Marios Hadjivassiliou have
nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by any of the
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