JNS-13510; No of Pages 5

Journal of the Neurological Sciences xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of the Neurological Sciences

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Paraneoplastic neurological syndromes in lung cancer patients with or

without onconeural antibodies
Margrethe Raspotnig a,⁎, Christian Vedeler a,b, Anette Storstein b
a
Department of Clinical Medicine, University of Bergen, Jonas Lies veg 87, 5021 Bergen, Norway
b
Department of Neurology, Haukeland University Hospital, Haukelandsveien 22, 5021 Bergen, Norway

a r t i c l e i n f o a b s t r a c t

Article history: Background: Paraneoplastic neurological syndromes (PNS) are poorly described in patients without onconeural
Received 19 June 2014 antibodies and in patients with non-small cell lung cancer (NSCLC). We compared the clinical characteristics
Received in revised form 26 October 2014 of PNS in lung cancer patients with and without onconeural antibodies.
Accepted 29 October 2014 Methods: Medical records from patients with lung cancer and neurological symptoms referred for onconeural an-
Available online xxxx
tibody analysis in the period 1995–2004 were analyzed and well-established diagnostic criteria used for the ret-
rospective diagnosis of PNS. Thirty-one patients were diagnosed with PNS and included in the study. Data from
Keywords:
Paraneoplastic neurological syndrome
the Cancer Registry of Norway and follow-up medical data were analyzed.
Onconeural antibody Results: Small-cell lung cancer (SCLC) was the most common lung cancer in the 31 PNS patients (77%, P b 0.01).
Small-cell lung cancer Onconeural antibodies were found in 18 of the PNS patients (58%). Paraneoplastic encephalomyelitis (PEM) was
Non-small cell lung cancer the most common PNS among the seropositive patients (11 of 18 patients), of which 10 had SCLC. Various types
Paraneoplastic encephalomyelitis of PNS were found in the 13 seronegative patients.
The Cancer Registry of Norway Conclusion: Approximately 40% of PNS patients with lung cancer do not have onconeural antibodies. PEM was the
most common PNS in the seropositive patients. Our results underline the importance of recognizing PNS in
patients with NSCLC and those without onconeural antibodies.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction
Paraneoplastic neurological syndromes (PNS) are immune-mediated
disorders that occur in less than 1% of cancer patients [1]. It has been
reported that 50–82% of patients with PNS have onconeural antibodies di-
rected against neuronal proteins expressed by tumor cells [1–3]. PNS are
most frequently associated with small-cell lung cancer (SCLC) [2,4], with
a prevalence of 3–5% [5], but can also be seen in patients with non-small
cell lung cancer (NSCLC). SCLC accounts for 15% of all lung cancers,
whereas NSCLC accounts for 80% [6]. Thus, the less prevalent tumor
type is more prone to be associated with PNS.
The specificity of onconeural antibodies for PNS is high and the
presence of such antibodies defines the neurological disorder as
paraneoplastic [7]. As there are no other markers with high specificity
for PNS, the diagnosis in patients without onconeural antibodies is
often debatable, and the diagnosis of a seronegative PNS is challenging
if no tumor is detected initially.
⁎ Corresponding author at: The University of Bergen, Department of Clinical medicine,
Jonas Lies veg 87, 5021 Bergen, Norway. Tel.: +47 55975045; fax: +47 55975164.
E-mail addresses: margrethe.raspotnig@helse-bergen.no (M. Raspotnig),
Christian.vedeler@helse-bergen.no (C. Vedeler), anette.storstein@helse-bergen.no
(A. Storstein).
The aim of this study was to describe the clinical characteristics of
PNS patients with lung cancer, with special regard to the group without
onconeural antibodies. Seronegative cases have not been described as
thoroughly as antibody positive patients, and previous studies have
usually focused on specific syndromes and not on PNS at a whole in
selected cancer groups.
2. Materials and methods
2.1. Patients
The Neurological laboratory at Haukeland University Hospital, Ber-
gen, Norway, received between 1995 and 2004 sera from 3679 patients
for the analysis of onconeural antibodies. During this time period, the
laboratory was the only one in Norway to perform onconeural antibody
analysis. The national identification numbers of these 3679 patients
were matched to lung cancer data in the Cancer Registry of Norway in
the time period 1990 to 2007, to select patients that were both regis-
tered with a lung cancer diagnosis and tested for onconeural antibodies.
The Cancer Registry of Norway is a national cancer database shown to
have a completeness of close to 99% for the registration of solid tumors
[8]. The selection of patients and PNS epidemiological data from this
population regardless of cancer type has been described previously [4].

http://dx.doi.org/10.1016/j.jns.2014.10.040
0022-510X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Raspotnig M, et al, Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural
antibodies, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.10.040
2 M. Raspotnig et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

Table 1
Clinical characteristics for 31 patients with paraneoplastic neurological syndromes and SCLC or NSCLC.

SCLC Sum NSCLC Sum

Onconeural antibodies Onconeural antibodies

+ − + −

Number 15 9 24 3 4 7
Sex Males 5 4 9 1 2 3
Females 10 5 15 2 2 4
Age at cancer diagnosis (years) Mean (min–max) 65 (53–74) 64 (49–80) 65 69 (61–73) 71 (60–76) 70
1-year survival (%) 33 44 38 67 50 57

SCLC: small-cell lung cancer, NSCLC: non-small cell lung cancer.

In the present work, we have studied the subgroup of patients with characterized onconeural antibodies were used for immunohisto-
lung cancer in detail. Ninety-six lung cancer patients were identified chemical staining of rat cerebellar sections, and ten of these 13
and hospital records were obtained for all patients. In the following, sera were also tested for anti-Sox-1, -GAD-65 (immunoblots;
17 patients were excluded; three patients were excluded because of www.ravo.de), -VGCC (radioimmunoassay; www.dld-diagnostika.de)
incomplete medical information and 14 patients because lung biopsy -NMDAR, -Ampa1, -Ampa2, GabaRB1/B2, -CASPR2 and -Lgi1
was inconclusive or not performed. Of the remaining 79 patients, 31 (transfected cells; www.euroimmune.com). In the following, the term
were diagnosed with PNS retrospectively and included in the study. “antibody” refers to “onconeural antibody” as this is the main focus of
Two neurologists evaluated the medical records and made the PNS the study.
diagnosis according to consensus criteria from the Paraneoplastic
Neurological Syndrome Euronetwork [7]. Patients with other possible 2.3. Statistics
neurological explanations for the symptoms, e.g. brain metastasis and
chemotherapy related polyneuropathy, were not diagnosed with PNS. IBM SPSS Statistics for Windows, Version 21.0 (Armonk, NY: IBM
The NSCLC tumors were classified in subgroups according to patho- Corp.) was used for the statistical analysis. P-values b 0.05 were consid-
logical findings [6]. Limited disease in SCLC was defined as tumor re- ered statistically significant. The association between categorical
stricted to one thoracic radiation field, whereas NSCLC was subdivided variables was explored using Pearson' square and Fischer's test. Means
according to the TNM staging system [9]. were compared by the use of Student's t-test. Normal distribution of
data was evaluated with Normal Q–Q plots, Kolmogorov–Smirnov and
2.2. Onconeural antibodies Shapiro–Wilk normality tests and histograms. A binomial test was
used for the analysis of binomial distributed variables. Kaplan–Meier
The sera were analyzed for all well-characterized onconeural plots and log rank test were used to analyze survival.
antibodies (anti-Hu, -Yo, -Ri, -Ma, -CRMP5 and -amphiphysin)
using immunoblot (www.ravo.de), immunohistochemistry and 3. Results
radioimmunoassay [4]. Eleven of 13 available sera without well-
3.1. Patient characteristics
Table 2
Clinical characteristics for 31 patients with paraneoplastic neurological syndromes and Table 1 summarizes the clinical characteristics for the 31 patients
lung cancer, with and without onconeural antibodies. with PNS, by subtype of lung cancer. SCLC was the dominating form of
lung cancer among the PNS patients, occurring in 24 of the 31 patients
Seronegative Seropositive Sum
(n = 13) (n = 18) (77%; P b 0.01). Eighteen (58%) of the PNS patients had onconeural an-
tibodies, 15 (63%) of the SCLC and 3 (43%) of the NSCLC patients. There
Sex Males 6 6 12
Females 7 12 19 were no significant differences in sex, mean age at cancer diagnosis, per-
Median age at cancer 66 (49–80) 67 (53–74) centage of patients with N 1-year survival after cancer diagnosis, or
diagnosis in years mean survival between patients with or without onconeural antibodies
(min–max) in the two cancer groups. Sixty-three percent of the SCLC patients had
Lung cancer SCLC 9 15 24
NSCLC 4 3 7
limited disease at the time of diagnosis, of which 60% had onconeural
PNS PEM 3 11 14 antibodies. Among the patients with NSCLC two patients were in stage
PCD 1 0 1 II, three in stage III and one in stage IV of the disease. Furthermore,
LE 1 1 2 there was no significant influence of onconeural antibody on the pa-
SSN 2 0 2
tients' overall survival in the SCLC group (Kaplan–Meier plot not
LEMS 1 2 3
Neuropathya 2 4 6 shown). This could not be analyzed in the NSCLC group due to the
Myelopathyb 1 0 1 small number of patients.
Other 2 0 2 Twenty-three of the 31 PNS patients were diagnosed with lung
Cause of death Lung cancer 11 7 18 cancer at or prior to the time of referral for onconeural antibodies
PNS 1 2 3
(P = 0.011). We found the mean annual incidence rate of PNS in the
Alive 0 1 1
Unknown 1 8 9 lung cancer patients in the time period 1999–2004 to be approximately
13 per 10,000.
SCLC: small-cell lung cancer, NSCLC: non-small cell lung cancer, PNS: paraneoplastic neu-
rological syndrome, PEM: paraneoplastic encephalomyelitis, PCD: paraneoplastic cerebel-
lar degeneration, LE: limbic encephalitis, SSN: subacute sensory neuronopathy, LEMS: 3.2. PNS in seronegative vs. seropositive lung cancer patients
Lambert–Eaton myasthenic syndrome.
a
Two patients had multiple mononeuropathy (both had sensory-motor affection Clinical characteristics for the 13 seronegative and 18 seropositive
of multiple peripheral nerves, one patient also had autonomic symptoms) and four
had polyneuropathy (three patients had axonal sensory-motor polyneuropathy
patients are listed in Table 2. There was no difference in median age at
and one a pure motor polyneuropathy). cancer diagnosis between the seronegative and seropositive groups.
b
The patient with myelopathy had spastic paraparesis and sensory deficits. Fifteen of the seropositive patients had SCLC (83%; P b 0.01). The type

Please cite this article as: Raspotnig M, et al, Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural
antibodies, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.10.040
 M. Raspotnig et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx 3

Table 3
Patients with paraneoplastic neurological syndromes, lung cancer and onconeural antibodies.

Patient number Sex Age at referral for analysis for Tumor histology PNS Antibody
onconeural antibodies (years)

1 F 70 SCLC PEM (myelopathy, optic neuritis) CRMP-5, Hu

2 F 70 SCLC PEM (brainstem encephalitis, sensory-motor polyneuropathy) CRMP-5
3 M 73 SCLC PEM (brainstem encephalitis, cerebellar dysfunction, LE) CRMP-5
4 F 58 SCLC PEM (extrapyramidal symptoms, SSN) CRMP-5
5 M 66 SCLC PEM (brain stem encephalitis, myelitis) CRMP-5
6 F 65 SCLC PEM (LE, sensory-motor polyneuropathy) Amphiphysin, Hu
7 F 67 SCLC LEMS Hu, CRMP-5
8 F 53 SCLC Sensory-motor polyneuropathy Hu
9 F 73 SCLC PEM (LE, SSN) Hu
10 F 58 SCLC PEM (LE, SSN) Hu
11 F 73 SCLC PEM (LE, SSN) Hu
12 F 68 SCLC PEM (LE, SSN) Hu
13 M 69 SCLC LE Ma2
14 F 74 SCLC Sensory-motor polyneuropathy Ri
15 M 54 SCLC LEMS Amphiphysin
16 F 76 Adenocarcinoma PEM (extrapyramidal symptoms, autonomic neuropathy) CRMP-5
17 M 62 Adenocarcinoma Sensory-motor polyneuropathy Hu
18 F 74 Large-cell carcinoma Cerebellar symptoms and motor neuropathy Amphiphysin

PNS: paraneoplastic neurological syndrome, F: female, M: male, SCLC: small-cell lung cancer, PEM: paraneoplastic encephalomyelitis, LE: limbic encephalitis, SSN: subacute sensory
neuronopathy, LEMS: Lambert–Eaton myasthenic syndrome.

of PNS varied largely among the seronegative patients, whereas
paraneoplastic encephalomyelitis (PEM) was the most common PNS
among the seropositive patients, found in 11 of 18 patients (P = 0.04).
PNS etiology remained unacknowledged in eight of 13 (62%) of the
seronegative patients judging from medical records. In four seronega-
tive patients, failure to recognize the etiology as paraneoplastic delayed
the cancer diagnosis.
The cause of death was known in 22 of the 31 PNS patients, of which
18 patients died from lung cancer (82%, P = 0.04). Only 3 patients died
from PNS, two of these had PEM with brainstem involvement.
Detailed features of the PNS patients with or without onconeural an-
tibodies are given in Tables 3 and 4, respectively. Hu- and CRMP5-
antibodies were the most frequent onconeural antibodies in the sero-
positive group. Ten of the 11 seropositive PEM patients (91%) had
SCLC (Table 3). Table 4 describes the various PNS that were associated
with the seronegative patients. Lambert–Eaton myasthenic syndrome
(LEMS) was found in both groups. LEMS was associated with VGCC an-
tibodies, but in this study we did not define anti-VGCC as an onconeural
antibody. None of the tested sera from seronegative lung cancer
patients were positive for anti-Sox-1, -GAD-65, -NMDAR, -Ampa1,
-Ampa2, -GabaRB1/B2, -CASPR2 and -Lgi1, nor did they contain other
anti-neuronal antibodies. Three patients could not be tested due to in-
sufficient amounts of sera.
4. Discussion
We analyzed 31 patients with PNS and lung cancer. The results
showed that SCLC was the dominating subgroup of lung cancer associ-
ated with PNS with and without onconeural antibodies, which is in
line with earlier studies [2,4].
The overall proportion of onconeural antibody positive PNS patients
for all cancer types varies in different reports from 50 to 82% [2,3].
We found approximately 60% seropositivity for well-characterized
onconeural antibodies in PNS patients with lung cancer. This could be
a reliable number as the present material is not likely to be biased to-
wards a seropositive patient sample. As SCLC is strongly associated
with the presence of onconeural antibodies [10] it is noteworthy that
as many as 37% of the patients with PNS and SCLC did not have any
such antibodies.

Table 4
Patients with paraneoplastic neurological syndromes and lung cancer without onconeural antibodies.

Patient Sex Age at referral for analysis for onconeural Tumor histology PNS
number antibodies (years)

1 F 66 SCLC PEM (brainstem encephalitis, cerebellar dysfunction, sensory-motor

polyneuropathy)
2 F 54 SCLC PEM (brainstem encephalitis, cerebellar dysfunction, psychiatric
symptoms)
3 F 61 SCLC PCD
4 M 70 SCLC PEM (brainstem encephalitis, cerebellar dysfunction)
5 F 55 SCLC LEMS
6 M 49 SCLC Lower motor neuron disease
7 M 76 SCLC Multiple mono-neuropathy with autonomic dysfunction
8 F 63 SCLC Myelopathy
9 M 79 SCLC Unilateral chorea
10 F 76 Adenocarcinoma SSN
11 F 60 Squamous cell carcinoma SSN
12 M 73 Squamous cell carcinoma LE
13 M 72 NSCLC (poorly Multiple sensory-motor mononeuropathy
differentiated)

PNS: paraneoplastic neurological syndrome, F: female, M: male, SCLC: small-cell lung cancer, PEM: paraneoplastic encephalomyelitis, PCD: paraneoplastic cerebellar degeneration, LEMS:
Lambert–Eaton myasthenic syndrome, SSN: subacute sensory neuronopathy, LE: limbic encephalitis, NSCLC: non-small cell lung cancer.

Please cite this article as: Raspotnig M, et al, Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural
antibodies, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.10.040
4 M. Raspotnig et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
A recent published study of seronegative patients with paraneoplastic
cerebellar degeneration (PCD) from the PNS Euronetwork showed that
clinical features were similar in seronegative and seropositive patients
[11]. We found that the clinical characteristics in the seropositive and se-
ronegative patients were quite similar; however, the syndrome distribu-
tion was different in patients with and without antibodies. PEM was the
most common PNS among the seropositive patients, and as nearly all of
them also had SCLC, this was also the most frequent syndrome in this sub-
group of cancer. These results are in accordance with previous studies,
where antibody positive PEM in SCLC patients is well-described and
defined as a clinical entity. However, the most common paraneoplastic
syndrome in SCLC patients is reported to be LEMS, thought to occur in
as many as 3% of SCLC patients [12]. In our study, this syndrome was
found in three patients with SCLC.
In contrast to the seropositive group, no specific PNS phenotype
dominated among the seronegative patients as a whole; on the con-
trary, a wide variety of syndromes were represented. Furthermore, we
found that PNS was not recognized in eight of 13 seronegative patients,
in support of the view that PNS might be underdiagnosed in this group.
Earlier descriptions of PNS in NSCLC are mainly based on case reports
or small series [13–16]. For example, Sabater et al. [16] reported nine se-
ronegative NSCLC patients with PCD. In our study, we found that the
four seronegative NSCLC patients had either peripheral neuropathy/
neuronopathy or limbic encephalitis. Together, the two studies show
that different PNS are associated with NSCLC in patients without
onconeural antibodies.
Our study did not show any difference in survival in regard to anti-
body status. We have previously shown that survival of SCLC is not de-
pendent on the presence of Hu- or VGCC-antibodies [10]. Lung cancer
was the primary cause of death for the PNS patients, in line with earlier
data [2]. In total, only three patients died from PNS, all of which had
PEM.
While data on the incidence of PNS are lacking, we have close to
complete ascertainment of PNS cases associated with lung cancer dur-
ing the study period. Based on these data, we have estimated a mean an-
nual incidence rate for PNS in lung cancer to be approximately 13 per
10,000. The prevalence of PNS is thought to be b1% of cancer patients
in general, but reliable numbers are still missing.
The low number of included patients is a limitation of this study, and
especially data regarding the NSCLC group of patients should be
interpreted with care. The low sample size is partly due to the strict in-
clusion criteria of defined histological sub-classification of lung cancer,
exclusion of patients with brain metastasis and the consensus of two
separate clinicians when diagnosing the patients with PNS retrospec-
tively. However, this inclusion procedure increased the clinical preci-
sion in regard to lung cancer and neurological diagnosis, which is
especially important when diagnosing seronegative PNS.
All seronegative patients with neurological findings that did not cor-
respond to a classical PNS were defined as “possible” and not “definite”
PNS. The close correlation in time between lung cancer diagnosis and
neurological symptoms (less than six months in three out of four pa-
tients) and the thorough exclusion of other diagnoses made it however
very likely that the symptoms were of paraneoplastic origin. Several
studies have shown that a delay of more than four years between PNS
and cancer diagnosis is very infrequent [17,18].
5. Conclusions
In conclusion, our results confirm that the predominant lung cancer
type associated with PNS is SCLC, but also that a significant percentage
of patients with PNS have NSCLC. Patients with onconeural antibodies
are more likely to have SCLC than NSCLC. As many as 40% of the patients
with lung cancer and PNS were seronegative, even patients with SCLC.
We found that patients without onconeural antibodies shared many
clinical characteristics with seropositive patients. The major difference
between the groups was that several different PNS were associated
Please cite this article as: Raspotnig M, et al, Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural
antibodies, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.10.040
with the negative antibody status, whereas PEM was the dominating
syndrome among seropositive patients. Analysis of the diagnostic pro-
cess in patients without onconeural antibodies supports the view that
there is a diagnostic delay. The results emphasize the importance of
awareness for the broad clinical spectrum of seronegative PNS as early
cancer diagnosis and treatment improves morbidity and mortality.
Disclosure of conflict of interest
On behalf of all authors, the corresponding author states that there is
no conflict of interest.
Ethical approval
The Regional Ethics committee, The Norwegian Social Science Data
service and the Ministry of Health and Care Services approved the
study. An exemption was given for obtaining informed consent.
Acknowledgments
We would like to thank biostatistician Karl-Ove Hufthammer, PhD at
the Centre for Clinical Research, Haukeland University Hospital, Bergen,
for the statistical help, Else Marit Løberg, MD at the Department of Pa-
thology, Oslo University Hospital-Ullevål, Oslo, and Lars Helgeland,
MD at the Department of Pathology, The Gade Institute, Haukeland Uni-
versity Hospital, Bergen, for the reconsideration of pathological speci-
men and Mette Haugen at The Neurological laboratory at Haukeland
University Hospital, Bergen, for the help with the antibody analysis.
The study has used data from the Cancer Registry of Norway. The inter-
pretation and reporting of these data are the sole responsibility of the
authors, and no endorsement by the Cancer Registry of Norway is
intended nor should be inferred.
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Please cite this article as: Raspotnig M, et al, Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural
antibodies, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.10.040