Brain (2000), 123, 1481–1494
Paraneoplastic limbic encephalitis: neurological
symptoms, immunological findings and tumour
association in 50 patients
S. Humayun Gultekin,1,2 Myrna R. Rosenfeld,3,4,** Raymond Voltz,1,* Joseph Eichen,1,**
Jerome B. Posner1,3 and Josep Dalmau1,3,**
1Department of Neurology and the Cotzias Laboratory of
Neuro-Oncology and 2Department of Pathology, Memorial
Sloan-Kettering Cancer Center, 3Department of Neurology
and Neuroscience and 4Division of Neurosurgery, Weill
Medical College of Cornell University, New York, USA
Summary
Paraneoplastic limbic encephalitis (PLE) is a rare disorder
characterized by personality changes, irritability,
depression, seizures, memory loss and sometimes
dementia. The diagnosis is difficult because clinical
markers are often lacking, and symptoms usually precede
the diagnosis of cancer or mimic other complications.
The frequency of antineuronal antibodies in patients
with PLE has not been investigated. We examined the
neurological symptoms and the causal tumours in 50
patients with PLE to determine the utility of
paraneoplastic antibodies and other tests. The diagnosis
of PLE required neuropathological examination or the
presence of the four following criteria: (i) a compatible
clinical picture; (ii) an interval of <4 years between
the development of neurological symptoms and tumour
diagnosis; (iii) exclusion of other neuro-oncological
complications; and (iv) at least one of the following: CSF
with inflammatory changes but negative cytology; MRI
demonstrating temporal lobe abnormalities; EEG
showing epileptic activity in the temporal lobes. Of 1047
patients with neurological symptoms, whose sera or CSF
were examined for paraneoplastic antibodies, 79 had the
presumptive diagnosis of limbic encephalitis, dementia,
cognitive dysfunction, or confusion. Fifty of these patients
fulfilled our criteria for PLE. Pathological confirmation
was obtained in 12 patients. The commonly associated
Keywords: paraneoplastic; limbic; encephalitis; SCLC
Abbreviations: PLE ⫽ paraneoplastic limbic encephalitis; SCLC ⫽ small-cell lung cancer
© Oxford University Press 2000
Correspondence to: Josep Dalmau, MD, Department of
Neurology, University of Arkansas for Medical Sciences,
4301 W. Markham, Slot 500, Little Rock, AR 72205, USA
E-mail: dalmaujosep@exchange.uams.edu
*Present address: Neurologische Klinik, Klinikum
Grosshadern, D-81366 München, Germany
**Present address: Department of Neurology, University of
Arkansas for Medical Sciences, Little Rock, Arkansas, USA
neoplasms were of the lung (50%), testis (20%) and
breast (8%). Neurological symptoms preceded the cancer
diagnosis in 60% of patients (by a median of 3.5 months).
Twenty-five of 44 (57%) patients with MRI studies had
signal abnormalities in the limbic system. Thirty (60%)
patients had antineuronal antibodies (18 anti-Hu, 10 anti-
Ta, 2 anti-Ma), and 20 were antibody-negative or had
uncharacterized antibodies (n ⍧ 4). The combination of
symptoms, MRI findings and paraneoplastic antibodies
established the diagnosis of PLE in 78% of the patients.
Patients with anti-Hu antibodies usually had small-cell
lung cancer (94%), multifocal neurological symptoms
(78%) and a poor neurological outcome. Patients with
anti-Ta (also called anti-Ma2) antibodies were young men
with testicular tumours (100%), frequent hypothalamic
involvement (70%) and a poor neurological outcome. In
the group of patients without anti-Hu or anti-Ta
antibodies, the tumour distribution was diverse, with
cancer of the lung the most common (36%); 57% had
positive MRI. Fifteen of 34 (44%) patients with a median
follow-up of 8 months showed neurological improvement.
Treatment of the tumour appeared to have more effect
on the neurological outcome than the use of immune
modulation. Improvement was observed in 38% of anti-
Hu patients, 30% of anti-Ta patients and 64% of patients
without these antibodies.
1482 S. Humayun Gultekin et al.

Introduction
Based upon prior case reports and their own series, Corsellis
and colleagues first described paraneoplastic limbic
encephalitis (PLE) as a clinicopathological entity 30 years
ago (Corsellis et al., 1968). To date, 137 patients with PLE
have been reported in the English literature, 32 of them
supported by autopsy (reviewed in Table 1). Most reports
have emphasized the clinical and pathological involvement
of the limbic structures, but the majority of patients had
variable involvement of other areas of the nervous system,
mainly the brainstem (Henson et al., 1954; Bakheit et al.,
1990). The diagnosis of PLE is often difficult because
similar symptoms (seizures, memory problems, irritability,
depression, confusion and dementia) can be caused by many
other cancer-related complications, including brain
metastases, toxic and metabolic encephalopathies, infections
(especially with herpes simplex encephalitis) and the side-
effects of cancer therapy (Posner, 1995). In addition,
neurological symptoms frequently precede the detection of the
tumour, further confounding the diagnosis of the neurological
disorder as paraneoplastic in origin.
Antineuronal antibodies, when present in the serum and
CSF, facilitate the diagnosis of PLE and often allow the early
detection of the associated tumour (Alamowitch et al., 1997).
However, the frequency of antineuronal antibodies in patients
with PLE is largely unknown (Dalmau et al., 1999a). We
report the spectrum of neurological symptoms and tumours
in 50 patients with PLE and analyse the utility of the detection
of paraneoplastic antibodies and other diagnostic tests for
this disorder.
Design and methods
The clinical and laboratory data of 79 patients with
presumptive paraneoplastic disorders, including limbic
encephalitis, memory problems, dementia, cognitive dys-
function or confusion, were reviewed. These patients were
identified from a database of 1047 patients with suspected
paraneoplastic neurological syndromes, whose sera or CSF
were examined for antineuronal antibodies at Memorial
Sloan-Kettering Cancer Center. Twelve patients were
examined by the authors (J.B.P., J.D.). Information on the
other patients was obtained from their primary physicians.
The diagnosis of PLE required neuropathological examination
(biopsy or autopsy), or all four of the following criteria: (i)
a clinical picture of short-term memory loss, seizures, or
psychiatric symptoms suggesting involvement of the limbic
system; (ii) an interval of ⬍4 years between the onset
of neurological symptoms and the cancer diagnosis; (iii)
exclusion of other cancer-related complications (metastasis,
infection, metabolic and nutritional deficits, cerebrovascular

Table 1 One hundred and thirty-seven patients with PLE published in the English literature
Reference No. of Tumour type Neurological improvement with Tissue
patients treatment (type)

Henson et al., 1954 4* SCLC No 0/4¶

Brierley et al., 1960 1† SCLC No Autopsy
Verhaart et al., 1961 1 SCLC No Autopsy
Yahr et al., 1965 1 SCLC No Autopsy
Henson et al., 1965 1‡ SCLC No 1¶
Croft et al., 1965 2§ SCLC No 1, autopsy
Corsellis et al., 1968 3 2 SCLC, 1 non-SCLC No 3, autopsy
Kaplan et al., 1974 1 SCLC No Autopsy
Markham and Abeloff, 1982 1 SCLC Yes, tumour (chemotherapy) None
Carr et al., 1982 1 Hodgkin’s disease Yes, tumour (chemotherapy and None
radiation therapy)
Gritzman et al., 1983 1 Oesophageal cancer No Autopsy
Brennan and Craddock, 1983 1 SCLC Yes, tumour (radiation therapy) None
Duyckaerts et al., 1985 1 Hodgkin’s disease No Autopsy
Case records, 1985 1 Bladder cancer No Autopsy
Yamada et al., 1985 1 Mixed GCT of the testis No 1¶
Cornelius et al., 1986 1 SCLC No Autopsy
Van Sweden and Van 1 Oesophageal cancer No Autopsy
Peteghem, 1986
Camara and Chelune, 1987 1 SCLC No Autopsy
Janati et al., 1987 1 Colon cancer No None
Kawaguchi et al., 1988 1 Mediastinal GCT with No information Autopsy
teratoma elements
Tandon et al., 1988 1 SCLC Symptomatic (haloperidol) Autopsy
Burton et al., 1988 1# Non-seminomatous GCT of the testis Yes, tumour (surgery and None
(predominant embryonic carcinoma) chemotherapy)
McArdle and Millingen, 1988 1 Thymoma No Autopsy
Den Hollander et al., 1989 2 SCLC 1, yes, tumour None
(chemotherapy) 1, no improvement
 Paraneoplastic limbic encephalitis 1483

Table 1 Contd
Reference No. of Tumour type Neurological improvement with Tissue
patients treatment (type)

Newman et al., 1990 1 SCLC, renal cancer No Autopsy

Bakheit et al., 1990 3 2 SCLC, 1 non-SCLC No 3 Autopsy
Dirr et al., 1990 1 SCLC No Biopsy
Ingenito et al., 1990 1 Thymoma No Autopsy
Veilleux et al., 1990 1 Atypical carcinoid No Autopsy
Lacomis et al., 1990 1 Breast cancer No Biopsy
Pfliegler et al., 1990 1 Hodgkin’s disease Yes, tumour (chemotherapy) None
Brashear et al., 1991 1 SCLC No Autopsy
Kodama et al., 1991 2 Breast cancer, thymoma No 2, biopsy
Amir and Galbraith, 1992 1 SCLC Yes, tumour (chemotherapy None
and radiation therapy)
Dalmau et al., 1992 14 SCLC 2, yes, tumour (chemotherapy) None
Baldwin and Henderson, 1992 1 SCLC No Autopsy
Kalkman et al., 1993 1 SCLC Yes, tumour (chemotherapy) None
Panegyres et al., 1993 1 SCLC No Autopsy
Tsukamoto et al., 1993 1 Colon cancer Yes, tumour (surgery) None
Kaniecki and Morris, 1993 1 SCLC Yes, tumour (chemotherapy) None
Sutton et al., 1993 1 SCLC No Autopsy
Cunningham and Burt, 1994 1# Thymoma Yes, tumour (surgery and None
radiation therapy)
Sakai et al., 1994 1 SCLC No information None
Ahern et al., 1994 1# Non-seminomatous GCT No None
of the testis (predominant embryonic
carcinoma)
Cher et al., 1995 1# Breast cancer Yes, tumour (surgery and None
protein A immune absorption)
Antoine et al., 1995 2 Thymoma Yes, tumour (surgery) None
Meyer et al., 1995 1 Neuroblastoma No None
Heidenreich et al., 1995 1 SCLC No Autopsy
Honnorat et al., 1996 2 SCLC No information None
Martin et al., 1996 1 Non-SCLC Yes, tumour (surgery) None
Zacharias et al., 1996 1 SCLC No Autopsy
Deodhare et al., 1996 1 Hodgkin’s disease Yes, tumour (chemotherapy) None
Alamowitch et al., 1997 16 SCLC Yes, 5/15 treated; tumour 1, autopsy
(chemotherapy)
Byrne et al., 1997 1# SCLC Yes, tumour (chemotherapy) None
Nokura et al., 1997 1 Teratoma of the ovary Yes, tumour (surgery) None
Okamura et al., 1997 1 Teratoma of the ovary Yes, tumour (surgery) None
Kaluza et al., 1997 1 Testicular GCT No Autopsy
(seminoma)
Riva et al., 1997 1 Colon cancer No information None
Provenzale et al., 1998 1 SCLC No information None
Wingerchuk et al., 1998 2 Testicular GCT No None
(seminoma)
Lucchinetti et al., 1998 23 SCLC No information None
Bell et al., 1998 1 Renal cell cancer Yes, tumour (surgery) None
Rosenbaum et al., 1998 2 Ovarian cancer, 1, yes, ovarian tumour
Hodgkin’s disease (chemotherapy)
1, no, Hodgkin’s disease 1, biopsy
Hart et al., 1998 1 SCLC No None
Aydiner et al., 1998 1# Teratoma of the ovary No None
Antoine et al., 1999 1 SCLC No information None
Bennett et al., 1999 1# Embryonal carcinoma No None
of the testis
Voltz et al., 1999 8# Testis** Yes, 3/5 treated; tumour 4, biopsy
(3 published twice)†† (all 3 had orchiectomy and
immune modulation)
Stern and Hulette, 1999 1 Small-cell carcinoma of the prostate No Autopsy

*Patients 1, 2, 3, 9; †patient 2; ‡patient 2; §patients 3, 4; ¶pathological findings did not involve the limbic structures; #patients included in
the present series. **4 non-seminomatous GCT, 2 seminomas, 2 mixed GCT; ††3 patients had been published previously (1 by Ahern
et al. (1994), 1 by Burton et al. (1988) and 1 by Bennett et al. (1998). GCT ⫽ germ-cell tumour.
1484 S. Humayun Gultekin et al.

Table 2 Tumours associated with paraneoplastic limbic Table 3 Clinical features

encephalitis
Symptom No. of
Type of tumour Current series English literature patients
(50 patients) (72 patients)
Loss of short term memory 42
Lung cancer 25 (50%) 43 (59%) Seizures 25
SCLC 20 (40%) 39 (54%) Temporal lobe, ‘psychomotor’ 10
Non-SCLC 5 (10%) 3 (4%) Generalized only 6
Atypical carcinoid tumour – 1 (1%) Mixture 9
Testicular germ-cell tumours 10 (20%) 4 (6%) Acute confusional state 23
Breast cancer 4 (8%) 2 (3%) Psychiatric abnormalities 21
Hodgkin’s disease 2 (4%) 5 (7%) Affective changes 7
Immature teratoma (ovary) 2 (4%) 2 (3%) Hallucinations 5
Thymoma 1 (2%) 5 (7%) Disinhibition/personality changes 3
Other 4* (8%) 11† (15%) Mixed 6
Positive paraneoplastic 2‡ (4%) – Hypothalamic* 11
antibodies without identifiable Hyperthermia 4
tumour Weight gain 2
Endocrine dysfunction 1
*Includes 1 adenocarcinoma of the colon, 1 adenocarcinoma of Hypersomnia 7
the ovary, 1 chronic myeloid leukaemia and 1 plasma cell Cognitive dysfunction 7
dyscrasia; †includes 3 adenocarcinomas of the colon, 2 Apraxia 3
carcinomas of the oesophagus, 1 small-cell cancer of the ovary, 1 Aphasia 1
small-cell cancer of the prostate, 1 renal cancer, 1 cancer of the Calculation, abstract thought 1
bladder, 1 neuroblastoma and 1 mediastinal germ cell tumour (1 Visual recognition 1
patient included in the group of SCLC also had a renal cell Abulia 1
cancer); ‡1 patient had anti-Hu antibodies and the other had anti- Cerebellar symptoms 9
Ma antibodies. Brainstem abnormalities 13
Other* 21
Sensory loss 8
Lethargy, stupor 6
Autonomic dysfunction 4
disorder or side-effects of therapy) that may cause symptoms
Basal ganglion signs 2
of limbic dysfunction; and (iv) at least one the following: Paresis 3
CSF with inflammatory changes (pleocytosis, oligoclonal Olfactory and taste change 2
bands, increased immunoglobulin content or increased protein Myoclonus 1
content in the absence of measured immunoglobulin); MRI Frontal release signs 1
showing unilateral or bilateral temporal lobe abnormalities *Some patients had more than one symptom.
on T2-weighted images or atrophy on T1-weighted images;
and EEG showing slow- or sharp-wave activity in one or
both temporal lobes. Patients with PLE
Serum (and CSF when available) was examined for Twenty-three women and 27 men, ranging in age from 11 to
antineuronal antibodies using immunoblots of human 75 years (median 55 years), were included in the study.
neuronal protein extracts, recombinant paraneoplastic proteins Neurological dysfunction developed before the tumour
(HuD, CDR62, Nova-1, Ma1 and Ma2) and immuno- diagnosis in 29 patients (median 3.5 months, range 0.5–33
histochemistry on sections of human and rat cerebral cortex, months) and after the tumour diagnosis in 19 (median 5
as reported previously (Dalmau and Rosenfeld, 1995; Voltz, months, range 1–48 months). Two patients had no tumour
1999). The presence of anti-CV2 antibodies was examined identified during the course of the disease; one had anti-Hu
using immunohistochemistry with rat brain tissue fixed in antibodies and the other anti-Ma antibodies (see Discussion).
paraformaldehyde (Honnorat et al., 1996). The associated tumours are shown in Table 2. Cancer of
the lung (50%), particularly small-cell lung cancer (SCLC)
(40%), and testicular germ-cell tumours (20%) were the
most frequently found neoplasms. Thirty-eight patients had
Results localized disease and 5 had distant metastasis; no staging
Among 79 patients with the presumptive diagnoses of limbic information was available for five patients.
encephalitis, memory problems, dementia, cognitive dys- Neurological symptoms developed over days or weeks in
function or confusion, 50 fulfilled our criteria for PLE. 41 (82%) patients. Slower development of symptoms, over
Twelve of these 50 patients have been reported previously months, occurred in 8 patients; for 1 patient the evolution of
(Ahern et al., 1994; Cunningham and Burt, 1994; Cher et al., symptoms was not known.
1995; Alamowitch et al., 1997; Aydiner et al., 1998; Burton Presenting symptoms included memory loss and confusion
et al., 1997; Bennett et al., 1999; Voltz et al., 1999). (24 patients), seizures (6 patients; 3 psychomotor, 1 focal
 Paraneoplastic limbic encephalitis 1485

Fig. 1 MRI findings in PLE. Note the bright signal (arrows in A and B) in the medial aspect of the
temporal lobes. In A, the more intense signal in the right temporal lobe corresponds to oedema after a
brain biopsy (shown in Fig. 2).

Table 4 Diagnostic tests

MRI CSF Paraneoplastic EEG
antibodies

50 patients Abnormal*: 28 Abnormal†: 40 Positive: 30 Abnormal‡: 27

with PLE Normal: 16 Normal: 9 (18 Hu, 10 Ta, 2 Ma) Normal: 6
Not available: 6 Not available: 1 Atypical: 4 Not obtained: 17
(5 had CT study) Negative: 16
29 patients Abnormal§: 10 Abnormal¶: 10 Atypical: 3 Abnormal#: 4
without PLE Normal: 12 Normal: 5 Negative: 26 Normal: 5
Not available: 7 Not available: 14 Not available: 20

*‘Abnormal’ indicates unilateral (10) or bilateral (15) temporal lobe abnormalities on T2-weighted
sequences; in 5 of these 25 patients the lesions showed contrast enhancement. Three patients without
temporal–limbic MRI findings had white matter abnormalities in other regions: 1 multifocal, 1 diffuse,
and 1 perithalamic and deep white matter changes. †‘Abnormal’ indicates inflammatory changes,
including increased proteins (24/47), pleocytosis (24/47), increased IgG synthesis (15/15) and
oligoclonal bands (10/13). ‡‘Abnormal’ indicates temporal epileptic focus (unilateral 10; bilateral 3),
periodic lateralized epileptiform discharges (2), general non-specific slowing (9) and abnormal but not
specified (3). §Abnormal findings include temporal abnormalities (5) detailed in the text, multifocal
white matter lesions (1), cerebral or cerebellar atrophy (3) and frontal lobe metastasis (1). ¶Detailed in
the text. #These include diffuse, non-specific slowing (3) and posterior triphasic waves (1).

facial twitching, 1 focal motor with secondary generalization,
1 generalized tonic-clonic), hypothalamic dysfunction (6
patients; 3 hypersomnia, 2 hyperthermia, 1 panhypo-
pituitarism), psychiatric abnormalities (6 patients; 5
depression, 1 hallucinations), and symptoms of involvement
of other areas of the nervous system (7 patients; 3 sensory
neuronopathy, 2 cerebellar ataxia, 1 dizziness, 1 diplopia).
For 1 patient, information about presenting symptoms was
not available.
Table 3 shows the main symptoms during the course of
the disease and the total number of patients having each
symptom. Overall, 47 patients developed short-term memory
loss (22 patients), seizures (25 patients) or both (20 patients).
Among the 25 patients with seizures, 10 had temporal lobe
or psychomotor seizures, 6 generalized seizures, and 9 a
combination of seizure types. Only 3 patients did not have
seizures or short-term memory loss: two developed a
confusional state without epileptic activity on EEG and the
other developed hypothalamic dysfunction characterized by
diabetes insipidus, loss of libido and hypothyroidism. In
these three patients the MRI showed mesial temporal changes
compatible with PLE.
Forty-nine patients had neuroimaging studies (44 MRI and
5 CT) (Table 4). The most frequent MRI abnormalities were
1486 S. Humayun Gultekin et al.
Fig. 2 Pathological findings in a patient with anti-Ta-associated limbic encephalitis. Biopsy of the temporal lobe showing perivascular
and parenchymal inflammatory infiltrates (A; haematoxylin–eosin, ⫻200) and multiple perineuronal infiltrates of CD8⫹ T-cells
(B; diaminobenzidine–haematoxylin, ⫻400).
identified on T2-weighted images and involved the mesial
aspect of one (10 patients) or both (15 patients) temporal
lobes (Fig. 1). In 5 patients, the mesial-temporal MRI
abnormalities enhanced after contrast administration. A
biopsy from the enhancing area obtained in 4 patients showed
inflammatory infiltrates and neuronal loss (Fig. 2). In addition
to the temporal lobe findings, 8 patients had MRI
abnormalities in other areas: 4 in the brainstem, 4 in the
hypothalamus, 1 in the thalamus, 1 in the cingulate gyrus
and 1 in the basal frontal lobe; none of these abnormalities,
except 1 in the hypothalamus, enhanced with contrast
material. Three patients without temporal–limbic MRI
findings had abnormalities involving other areas of the
nervous system (Table 4).
The CSF was examined in 49 patients, and 40 showed one
or more of the following abnormalities: 24 of 47 had
pleocytosis (⬎5 cells/mm3; range 9–100 cells/mm3, median
29); 24 of 27 had elevated proteins (⬎45 mg/dl; range 47–
170, median 74); 10 of 13 had oligoclonal bands; and 15 of
15 had intrathecal synthesis of IgG. Only 7 patients had
increased proteins as an isolated finding. None of 49 patients
had malignant cells in the CSF (Table 4).
Paraneoplastic antibodies were identified in the serum,
CSF, or both, of 30 patients (60%): in 18 patients they were
anti-Hu antibodies, in 10 they were anti-Ta antibodies (also
known as anti-Ma2 antibodies) and in 2 they were anti-Ma
antibodies (Figs 3 and 4). Four patients had antineuronal
antibodies that have not been characterized: the serum from
a patient with breast cancer reacted with several proteins in the
30–40 kDa range expressed predominantly in the cytoplasm of
hippocampal pyramidal cells; the serum from a patient with
non-SCLC reacted with several proteins in the range of 40–
60 kDa expressed in the cytoplasm of neurons and Purkinje
cells; the serum from a patient with ovarian cancer showed
selective diffuse reactivity with the neuropil, but was negative
in immunoblot studies; and the serum of a patient with non-
SCLC showed faint labelling of the neuronal cytoplasm
with negative immunoblot findings. Sixteen patients had no
antineuronal antibodies. None of the sera contained anti-CV2
antibodies.
Overall, 39 (78%) patients had temporal lobe abnormalities
on MRI studies and/or positive paraneoplastic antibodies in
their serum. When the abnormal findings in one or both of
these tests were combined with the detection of abnormal
CSF, the number of patients with at least two abnormal tests
was 49. The remaining patient, with Hodgkin’s disease, had
brain biopsy findings supporting the diagnosis of PLE.
On the basis of the presence or absence of anti-Hu
and anti-Ta antibodies, we established three immunological
groups of PLE patients. For practical purposes the two
patients with anti-Ma antibodies and the 4 patients with non-
characterized antineuronal antibodies were included in the
group of patients without antibodies (Table 5). In 6 patients
(3 anti-Hu, 3 anti-Ta) the detection of these antibodies led
to the diagnosis of the paraneoplastic syndrome and assisted
in identifying the underlying tumour.
Of 18 patients with anti-Hu antibodies, 16 had SCLC,
1 was reported to have adenocarcinoma of the lung (the
tumour was not examined by us), and no tumour was identified
in another patient. All patients with anti-Ta antibodies had
testicular germ-cell tumours. In the group of patients without
antibodies or with atypical antibodies, 8 (36%) had cancer
of the lung (4 SCLC), 4 adenocarcinoma of the breast,
2 immature teratoma, 2 Hodgkin’s disease, 1 plasma cell
dyscrasia, 1 malignant thymoma, 1 adenocarcinoma of the
colon, 1 chronic myeloid leukaemia and 1 ovarian cancer
(Table 5).
Seventy-eight per cent of patients with PLE and anti-Hu

Fig. 3 Immunohistochemical analysis of antineuronal antibodies in PLE. Sections of normal human brain immunolabelled with normal
human serum (A) and serum from patients with PLE and anti-Hu antibodies (B), anti-Ta (also called anti-Ma2) antibodies (C) and
atypical antineuronal antibodies (D).
antibodies had symptoms suggesting dysfunction of areas of
the nervous system distant from the limbic system (brainstem,
cerebellum, dorsal root ganglia, cerebral cortex, spinal cord
and autonomic nervous system) (Table 5). These areas were
less likely to be involved in patients without antibodies or
with atypical antibodies (41%).
Compared with the anti-Hu patients (median age 61.5
years), the anti-Ta patients were younger (median age 34
years) and had more restricted involvement of the limbic
system and brainstem (80%); only 2 patients had other
symptoms (1 with involvement of the basal ganglia and 1
with cerebellar dysfunction). As part of the limbic symptoms,
70% of these patients had severe hypothalamic dysfunction
(clinical details of these patients have been reported elsewhere
(Voltz et al., 1999). Unlike patients with anti-Hu antibodies,
the anti-Ta patients did not develop signs of dorsal root
ganglion involvement or myelitis.
Pathological examination of the brain was obtained in 12
patients: 8 had a brain biopsy and 4 an autopsy. In all
Paraneoplastic limbic encephalitis 1487
instances, the main findings were perivascular cuffing and
interstitial infiltrates of lymphocytes, microglial proliferation,
gliosis and neuronal degeneration (Fig. 2). Three autopsy
studies had results of detailed neuropathological examination
showing chronic encephalitis without viral inclusion bodies
that was not restricted to the limbic regions.
Clinical follow-up was available for 34 patients (median
8 months, range 1–84 months) (Table 6). Treatment of the
tumour appeared to be associated with improvement of the
neurological syndrome in 11 of the 15 patients (73%) in whom
this assessment was possible. Eighteen patients received one
or more immune modulatory treatments for the paraneoplastic
disorder: 12 corticosteroids (60–100 mg prednisone), 4
cyclophosphamide, 4 intravenous immunoglobulin, 5 plasma
exchange, and 1 removal of plasma IgG by immunoadsorption
with a protein-A column. Four of these 18 patients (22%)
had partial neurological improvement closely related to the
dates when they were treated with immune modulation,
although all 4 had simultaneous treatment of the tumour.
1488 S. Humayun Gultekin et al.

Table 5 Immunological subsets of paraneoplastic limbic encephalitis

Clinical features Anti-Hu Anti-Ta No antibodies or other
(18 patients) (10 patients) antibodies* (22 patients)

Sex 9 M, 9 F 10 M 8 M, 14 F
Age range (median) (years) 28–70 (61.5) 22–45 (34) 11–75 (57)
Predominant tumour 16 SCLC 10 testicular 8† lung (n ⫽ 4 SCLC)
(no tumour found) (1) (1)
Limited stage tumour 14/15 9/10 15/18
Neurological symptoms 14 7 8
before tumour diagnosis
Symptoms
Limbic alone 4 3 13
Limbic–brainstem alone 2 5 0
Outside limbic–brainstem§ 12 2 9
Hypothalamic deficits 2 7 2
Psychiatric symptoms 5 6 10
Abnormal MRI 7/14 9/9 12/21
Abnormal CT 1/2 0/1 0/2
Abnormal CSF 16/18 8/10 16/21
Final neurological outcome: improvement¶ 5/13 3/10 7/11

*Sixteen patients had no antineuronal antibodies, 2 had anti-Ma antibodies and 4 had antineuronal
antibodies that are uncharacterized. †The remaining 13 patients had adenocarcinoma of the breast (4),
teratoma (2), Hodgkin’s disease (2), plasma cell dyscrasia (1), malignant thymoma (1), adenocarcinoma
of the colon (1), chronic myeloid leukaemia (1) and ovarian cancer (1). §Includes limbic dysfunction
and symptoms involving brainstem and/or one or more of the following: basal ganglia; cerebellum;
dorsal root ganglia; cerebral cortex; spinal cord; autonomic nervous system. ¶Irrespective of the
treatment used.

Table 6 Neurological outcome in 34 patients with PLE

Improved Stable Deterioration

Treatment of the tumour only 11 2 1

Immune modulation only 0 0 4
Treatment of the tumour and 4 6 4
immune modulation
No treatment 0 0 2

recovery). Improvement was observed in 5 of 13 (38%)

patients with anti-Hu antibodies, 3 of 10 (30%) with anti-Ta
antibodies and 7 of 11 (64%) without detectable antibodies
(Tables 5 and 6).

Patients without PLE

Fig. 4 Immunoblot analysis of human neuronal proteins with
serum from patients with PLE. Lanes correspond to the same sera
examined by immunohistochemistry in Fig. 3. Lane NHS
corresponds to serum from a normal individual.
Irrespective of the treatment used, neurological symptoms
progressed in 11 patients (resulting in death in 6), remained
stable in 8 and improved in 15 (14 partial recovery, 1 full
The sera of 29 patients affected with memory loss, cognitive
dysfunction, or seizures, but who did not fulfil our strict
criteria for PLE, were examined for antineuronal antibodies.
There were 16 men and 13 women with a median age of
64.5 years (range 29–92 years). Thirteen patients had cancer:
neurological symptoms developed before the tumour
diagnosis in 5 patients (median 12 months, range 1 month
to 6 years) and after the tumour diagnosis in 8 (median 3.5
years, range 1–19 years). Tumours included SCLC in 2
patients, non-SCLC tumours in 2 patients, renal cell cancer
in 2 patients, breast cancer in 1 patient, adenocarcinoma of
the parotid gland in 1 patient, testicular germ-cell tumour in
1 patient, lymphoma in 1 patient, multiple myeloma in 1

patients and lung nodules (without biopsy) in 2 patients. No
systemic tumour was identified in the other 16 patients after
a median follow-up of 12 months (range 1 month to 8 years).
CSF was examined in 15 patients: 4 showed inflammatory
abnormalities, 6 showed increased proteins only and 5 were
normal (Table 4). Three patients harboured atypical antibodies
that reacted with neurons; none of these antibodies was
similar to any of the 4 atypical antibodies found in the PLE
patients. The other 26 patients were negative for antibodies.
MRI was obtained in 22 patients. Temporal lobe
abnormalities were identified in 5 patients, whose final
diagnoses were: herpes simplex encephalitis in 2 patients
(1 associated with glioma); metastasis of renal cell cancer
in 1 patient; bilateral temporal lobe abnormalities with
frontoparietal and periventricular white matter changes in
1 patient with non-caseating bone marrow granulomatosis of
uncertain significance; and bilateral temporal lobe T2-
weighted abnormalities with contrast enhancement in 1 patient
with primary CNS lymphoma, who eventually developed
involvement of the left basal ganglia and occipital lobe.
The final diagnoses of the patients without MRI
abnormalities in the temporal lobes included 1 of each of
the following: viral encephalitis; primary CNS lymphoma;
Creutzfeldt–Jakob disease; ischaemic cerebrovascular
disease; psychiatric disorder with pseudodementia; frontal
lobe metastasis; and intracranial hypertension due to remote
subarachnoidal haemorrhage; and 17 patients had primary
degenerative dementia (either of the Alzheimer type or of
unknown cause).
Discussion
In 1960, Brierley and colleagues described three patients
suffering from ‘subacute encephalitis of later adult life mainly
affecting the limbic areas’ (Brierley et al., 1960). At autopsy,
the first patient had a small leiomyoma of the left kidney but
no other evidence of malignancy. The second patient had
several mediastinal and hilar lymph nodes ‘extensively
replaced by oat-shaped cells, appearing identical to those
seen in anaplastic bronchial carcinoma’; no tumour was
found in the lungs or elsewhere in the body. The third patient
had ‘an encapsulated mass at the root of the right lung’
which consisted of fibrotic lymph nodes. Although one of
the authors had previously reported patients with a ‘mental
disorder associated with primary lung carcinoma’ (Charatan
and Brierley, 1956), they believed that it was ‘most unlikely
that this finding [lung cancer in patient 2] is in any way
related to the encephalitis but its occurrence should be noted’.
They also noticed that a lung cancer had been clinically
suspected in patient 3 but they failed to consider that the
fibrotic lymph nodes may have represented a remitting
tumour. In 1961, Verhaart described two patients with
inflammatory lesions of the medial temporal lobe and nerve
cell loss in the brainstem and cerebellum, both of whom had
tumour in the mediastinal lymph nodes but no identifiable
pulmonary lesion (Verhaart, 1961). In 1962, Störring and
Paraneoplastic limbic encephalitis 1489
colleagues described a patient with ‘undifferentiated bronchial
carcinoma and an encephalitic-like picture in the limbic
system’ (Störring et al., 1962). In 1965, Yahr and colleagues
reported a patient with ‘encephalopathy associated with
carcinoma’ who had SCLC and limbic system inflammatory
changes (Yahr et al., 1965). In 1967, Ulrich and colleagues
reported a patient with SCLC and neuronal degeneration
in Ammon’s horn and elsewhere with some perivascular
lymphocytic cuffing (Ulrich et al., 1967).
The name limbic encephalitis was coined by Corsellis and
colleagues (Corsellis et al., 1968) when they reported three
additional patients and extensively reviewed the prior
literature, including those patients first reported by Brierley
and colleagues (Brierley et al., 1960). This description of
limbic encephalitis generated more reports, and by 1990
Bakheit and colleagues were able to report three new patients
with PLE, and reviewed the extant literature, which consisted
of 16 cases that had been verified clinically and pathologically
(Bakheit et al., 1990). Once the relationship between cancer
and the nervous system lesion had been established, three
pathogenic hypothesis were advanced: (i) a (not further
defined) degeneration of the nervous system in which the
inflammatory infiltrates were a secondary ‘reaction to the
tissue breakdown’ (Verhaart, 1961; Ulrich et al., 1967); (ii)
a viral infection (Corsellis et al., 1968); and (iii) an immune-
mediated response against the nervous system (Russell, 1961).
The third hypothesis is the currently accepted one.
Despite the now fairly large number of patients reported,
the diagnosis of PLE remains difficult. The presenting
symptoms may be different from those considered typical of
the disorder (i.e. short-term memory loss, seizures, and mood
or behavioural changes). In 27% of our patients these
symptoms were not part of the presentation of the
paraneoplastic disorder. Usually, patients are not known to
have cancer, as occurred in 60% of our patients. Symptoms
resembling PLE are frequent in cancer patients and may
result from multiple different metastatic and non-metastatic
complications (Clouston et al., 1992; Hosaka and Aoki, 1996;
Spiegel, 1996; Porta-Etessam, 1999). In fact, a 1956 report
of a ‘mental disorder associated with primary lung carcinoma’
described three patients who probably suffered from hepatic
encephalopathy (Charatan and Brierley, 1956). With the
exception of the anti-Hu antibody in some patients with
SCLC and the anti-Ta antibody in patients with testicular
tumours, there are no known serological markers of PLE. In
the current study, 60% of the patients had paraneoplastic
antibodies in their serum (see below). Identification of these
antibodies, when combined with characteristic MRI findings,
helped establish the diagnosis of PLE in 78% of the patients.
Symptoms of involvement of areas of the nervous system
distant from the limbic system (particularly the brainstem
and cerebellum) are frequent in patients with PLE. This
occurred in 60% of our patients and similar findings were
recognized by Bakheit and colleagues, who found that only
6 of 19 (32%) patients had isolated limbic encephalitis
(Bakheit et al., 1990).
1490 S. Humayun Gultekin et al.
Typical MRI findings of PLE include unilateral or bilateral
mesial temporal lobe abnormalities that are best seen on T2-
weighted images. On T1 sequences, the temporal–limbic
regions may be hypointense and atrophic, and may sometimes
enhance with contrast injection. These abnormalities,
although well known (Dirr et al., 1990; Lacomis et al., 1990),
had not been examined in a large series of patients. In our
study, 64% of the patients with PLE had abnormal MRI
studies, which in 89% of the cases showed the changes
indicated above. Patients with herpes simplex encephalitis
may have similar MRI findings in the early stages of the
disease. However, these patients usually develop prominent
signs of oedema and mass effect involving one or both
inferior–medial temporal lobes, the inferior frontal lobes and
the cingulate gyrus. In addition, gyral enhancement is present
in more than half of the patients and signs of haemorrhage
are not uncommon (Demaerel et al., 1992; Kapur et al., 1994).
CSF analysis assists in making the diagnosis of PLE in
two ways. First, a negative cytological analysis for malignant
cells in combination with the absence of meningeal
enhancement on the MRI helps exclude leptomeningeal
metastases. Secondly, the detection of inflammatory
abnormalities (pleocytosis, intrathecal synthesis of IgG,
oligoclonal bands) supports the diagnosis of an inflammatory
or immune-mediated neurological disorder; 64% of our
patients had one or more of these abnormalities. We did not
find any patient with antibodies present only in the CSF;
however, two patients had barely detectable serum anti-Ta
titres, while the CSF titres were several orders of magnitude
higher (data not shown).
The EEG has limited usefulness in making the diagnosis
of PLE, but it is useful in assessing whether changes in the
level of consciousness or behaviour are related to temporal
lobe seizures. In a review of 19 patients, Bakheit and
colleagues identified temporal lobe seizures in only one
patient (Bakheit et al., 1990). In our study, the incidence of
EEG abnormalities was limited by the fact that only patients
in whom seizures were suspected received EEG evaluation.
Nevertheless, among the 35 patients with EEG studies, 45%
had epileptic activity.
Symptoms resembling PLE may result from several
disorders, including systemic lupus erythematosus (Glanz
et al., 1998; Stubgen et al., 1998), Wernicke–Korsakoff
encephalopathy with or without cancer (De Reuck et al.,
1981; Engel et al., 1991), toxic effects of doxifluridine (an
antineoplastic agent) (Heier and Fossa, 1986) and herpes
simplex encephalitis (Aimard et al., 1979; Perentes and
Herbort, 1984). Two of our patients with PLE were initially
considered to have herpes simplex encephalitis and received
treatment with acyclovir without neurological improvement.
However, patients with herpes simplex encephalitis usually
develop acute or subacute mental confusion and seizures that
often lead to stupor or coma. The MRI findings (see above)
and the presence of red blood cells in the CSF point to the
diagnosis of herpes simplex encephalitis, which diagnosis can
be confirmed by PCR (polymerase chain reaction) analysis of
the CSF or brain biopsy (Cinque et al., 1996).
Symptoms and pathological findings of limbic encephalitis
have been reported in the absence of cancer (Brierley et al.,
1960; Langston et al., 1975; Horoupian and Kim, 1982;
Daniel et al., 1985; Kohler et al., 1988; Kepes et al., 1990).
We believe that in most cases a cancer was present but not
detected. In one of our patients with PLE and life-threatening
neurological deterioration, the family consented to right
orchiectomy because of the detection of serum anti-Ta
antibodies and ultrasound findings of a mild abnormality in
the right epididymis (consistent with epididymitis). The
original pathological evaluation was negative for testicular
cancer, but detailed review of the slides demonstrated
microscopic intratubular germ-cell tumour (Dalmau et al.,
1999b).
We compared the histological types of tumours of our
patients with those reported in the English literature, bearing
in mind two considerations. First, 53 of 137 reported patients
come from three studies of patients selected on the basis
of suffering from SCLC or harbouring anti-Hu antibodies
(Dalmau et al., 1992; Alamowitch et al., 1997; Lucchinetti
et al., 1998). Secondly, 12 of our patients have been reported
previously. Thus, after excluding these 65 patients from Table
1, the remaining 72 patients were compared with the 50
patients of the current study (Table 2). This comparison
revealed a preferential association of PLE with certain
tumours: SCLC, germ-cell tumours of the testis, breast cancer,
Hodgkin’s lymphoma, immature teratoma and thymoma.
The reason for the preferential association of PLE with
certain tumours is unknown. SCLC and testicular germ-cell
tumours express a number of proteins (including the Hu and
Ma proteins) that in normal adult tissues are restricted to
neurons and germ cells of the testis (Carpentier et al., 1998;
Dalmau et al., 1999c; Voltz et al., 1999). In addition, these
tissues are immunoprivileged by the presence of endothelial
barriers and atypical or absent expression of antigen-
presenting molecules (MHC class I) (Haas et al., 1988;
Neumann et al., 1997; Corriveau et al., 1998). These findings
suggest a mechanism whereby the tumour expression of
brain/testis proteins is the trigger of autoimmunity against
the nervous system. This hypothesis is supported by our
study, in which SCLC and testicular germ-cell tumours
were consistently associated with antineuronal antibodies in
patients with PLE. Immunological disturbances have also
been identified in patients with PLE and thymoma (Antoine
et al., 1995), a tumour frequently related to other autoimmune
neurological disorders, including myasthenia gravis and
neuromyotonia (Newsom-Davis and Mills, 1993;
Drachman, 1994).
Thirty of our patients (60%) had positive paraneoplastic
antibodies (anti-Hu, anti-Ta or anti-Ma). We took into
consideration a possible bias of serum referral to our
laboratory for anti-Ta antibody testing. However, only 2 of
the 10 patients with positive anti-Ta antibodies were included
in the study after the discovery of these antibodies (Voltz

et al., 1998); the other 8 were retrospectively identified from
the 1047 patients in the database.
On the basis of the presence of paraneoplastic antibodies,
we established three immunological subsets of PLE (Table
5) that differ from each other by the age of the patients, the
type of tumour association and some clinical features. The
most distinctive of these include the presence of symptoms
from areas outside the limbic system in most anti-Hu patients
and the frequent hypothalamic and brainstem involvement in
anti-Ta patients. In addition, PLE patients with anti-Ta
antibodies are more likely to have abnormal MRI findings
than other PLE patients.
It is important to note that the group of patients ‘with
no antibodies or with other antibodies’ is an ill-defined,
heterogeneous group that includes patients without
antineuronal antibodies, and 6 patients with antibodies other
than anti-Hu and anti-Ta (4 non-characterized and 2 anti-
Ma). One anti-Ma patient was a woman, without a cancer
diagnosis, who developed confusion, lethargy and T2 MRI
abnormalities involving the medial temporal lobes,
hypothalamus and upper midbrain; the other was a woman
with breast cancer, typical symptoms of PLE, and T2 MRI
abnormalities in the medial temporal lobes. Unlike other
anti-Ma sera that react similarly with both Ma1 and Ma2
proteins (Dalmau et al., 1999c), the sera and CSF of these
two patients showed more reactivity with Ma2 than Ma1
(data not shown). This finding and the data from patients
with anti-Ta antibodies (which recognize Ma2) (Voltz et al.,
1999) suggest that Ma2 contains epitopes related to
autoimmunity associated with limbic dysfunction.
In contrast to most paraneoplastic syndromes of the CNS,
which do not improve with treatment, PLE may respond to
therapy. In our study, 44% of patients with a median follow-
up of 8 months showed neurological improvement regardless
of the type of treatment. Treatment of the tumour appeared
to have more effect on neurological improvement than the
use of immunosuppressive therapies. We found similar results
in the literature review of 137 patients (Table 1). Information
about the response to treatment was available for 107
patients; 25 (23%) had neurological improvement, in 24 the
improvement was attributed to tumour treatment, and in 1 it
was attributed to symptomatic treatment (haloperidol). These
findings, coupled with the high frequency of limited stage
disease (88% of our patients, irrespective of antineuronal
antibody status), underscore the need for prompt detection and
treatment of the tumour, which may improve the neurological
deficits and control the cancer.
We are aware that some of our findings may result from
the design of the study. To explore this possible bias, we
examined the clinical information of a group of 29 patients
with memory loss, cognitive dysfunction or confusion
(considered to be paraneoplastic) whose sera were sent to us
for antineuronal antibody testing. When compared with our
group of 50 patients with PLE, the two main discriminating
diagnostic tests were the MRI studies and antineuronal
antibody testing. None of the 29 patients had paraneoplastic
Paraneoplastic limbic encephalitis 1491
antibodies, and only 2 had MRI abnormalities similar to
those identified in PLE; one had herpes simplex encephalitis,
and the other a primary CNS lymphoma that eventually
showed multifocal areas of enhancement.
From this and previous studies (Table 1), it appears likely
that PLE is an immune-mediated disorder that can be caused
by several types of tumour-induced autoimmunity. When
PLE is suspected, the following tests should be considered: (i)
MRI of the brain without and with contrast; (ii) paraneoplastic
antibody testing of serum and CSF; (iii) CSF studies to rule
out the presence of metastatic cells and demonstrate the
presence of inflammatory abnormalities (oligoclonal bands,
intrathecal synthesis of IgG, pleocytosis); and (iv) EEG
studies, particularly in patients with an acute confusional state
of unknown cause. Patients older than 40 years, particularly if
they are smokers, should be examined for serum and CSF
anti-Hu antibodies; the detection of this antibody confirms
that the limbic syndrome is paraneoplastic and indicates that
the tumour is probably SCLC. In patients older than 40
years without paraneoplastic antibodies, the tumours most
frequently encountered are non-SCLC, carcinoma of the
breast and thymoma; however, the absence of anti-Hu
antibodies does not rule out the possibility that the underlying
tumour is SCLC. Patients younger than 40 years, particularly
if they are male, should be studied for serum and CSF anti-
Ta antibodies; the detection of these antibodies indicates that
the disorder is paraneoplastic and that the tumour is likely
to be located in testis. In patients younger than 40 years
and without paraneoplastic antibodies, the tumours most
frequently involved are Hodgkin’s lymphoma and immature
teratoma. Regardless of the antineuronal antibody status,
MRI studies show T2 abnormalities in mesial temporal
regions in 57% of the patients; these findings, although not
pathognomonic, are highly suggestive of PLE, particularly if
they are associated with inflammatory changes in the CSF.
Although we did not find anti-CV2 antibodies, which are not
consistently associated with PLE, there are 3 reported patients
(2 with SCLC and 1 with thymoma) in whom detection of
anti-CV2 antibodies helped to establish the paraneoplastic
origin of a limbic dysfunction (Antoine et al., 1995; Honnorat
et al., 1996).
From our study and review of the literature, no definitive
treatment is available for PLE. However, early identification
and treatment of the tumour is the approach that appears to
offer the greatest chance for neurological improvement.
Acknowledgements
We thank Drs James Miller, Nicolas Miret, Ian Sutton,
Francesc Graus, Antoine Carpentier, Jerome Honnorat, Jean-
Yves Delattre, Charles F. Bolton, Fred Hochberg, Casilda
Balmaceda, Hakan Gurvit, Joseph Landolfi, Michael Homer-
Ward, Lisa Rogers, Louisa Thoron, Jeffrey Raizer, Bruce
Cree, Daniel Park, Ronald Kanner, Lawrence Haber, Jon
Wilson and Nuno Antunes, for providing clinical information
and Dr Victor Reuter for the pathological evaluation of the
1492 S. Humayun Gultekin et al.
tumour of one of the patients. This work was supported by
NIH grant NS-26064 (J.B.P, J.D.) and the ACS Evelyn Frew
Clinical Research Professorship (J.B.P.).
References
Ahern GL, O’Connor M, Dalmau J, Coleman A, Posner JB, Schomer
DL, et al. Paraneoplastic temporal lobe epilepsy with testicular
neoplasm and atypical amnesia. Neurology 1994; 44: 1270–4.
Aimard G, Boisson D, Trouillas P, Devic M. Encephalites et
encephalopathies aigues amnesiantes. Remarques a propos de 16
observations. Rev Neurol (Paris) 1979; 135: 679–92.
Alamowitch S, Graus F, Uchuya M, Reñé R, Bescansa E, Delattre JY.
Limbic encephalitis and small cell lung cancer. Clinical and
immunological features. Brain 1997; 120: 923–8.
Amir J, Galbraith RC. Paraneoplastic limbic encephalopathy as a
nonmetastatic complication of small cell lung cancer. South Med J
1992; 85: 1013–4.
Antoine JC, Honnorat J, Anterion CT, Aguera M, Absi L, Fournel P,
et al. Limbic encephalitis and immunological perturbations in two
patients with thymoma. J Neurol Neurosurg Psychiatry 1995; 58:
706–10.
Antoine JC, Absi L, Honnorat J, Boulesteix JM, de Brouker T, Vial C,
et al. Antiamphiphysin antibodies are associated with various
paraneoplastic neurological syndromes and tumors. Arch Neurol
1999; 56: 172–7.
Aydiner A, Gurvit H, Baral I. Paraneoplastic limbic encephalitis with
immature ovarian teratoma—a case report. J Neurooncol 1998; 37:
63–6.
Bakheit AM, Kennedy PG, Behan PO. Paraneoplastic limbic
encephalitis: clinico-pathological correlations. J Neurol Neurosurg
Psychiatry 1990; 53: 1084–8.
Baldwin L, Henderson A. Paraneoplastic limbic encephalitis
presenting as acute viral encephalitis [letter]. Lancet 1992; 340: 373.
Bell BB, Tognoni PG, Bihrle R. Limbic encephalitis as a
paraneoplastic manifestation of renal cell carcinoma. J Urol 1998;
160: 828.
Bennett JL, Galetta SL, Frohman LP, Mourelatos Z, Gultekin SH,
Dalmau JO, et al. Neuro-ophthalmologic manifestations of a
paraneoplastic syndrome and testicular carcinoma. Neurology 1999;
52: 864–7.
Brashear HR, Caccamo DV, Heck A, Keeney PM. Localization of
antibody in the central nervous system of a patient with paraneoplastic
encephalomyeloneuritis. Neurology 1991; 41: 1583–7.
Brennan LV, Craddock PR. Limbic encephalopathy as a nonmetastatic
complication of oat cell lung cancer. Its reversal after treatment of the
primary lung lesion. Am J Med 1983; 75: 518–20.
Brierley JB, Corsellis JA, Hierons R, Nevin S. Subacute encephalitis
of later adult life, mainly affecting the limbic areas. Brain 1960; 83:
357–68.
Burton GV, Bullard DE, Walther PJ, Burger PC. Paraneoplastic limbic
encephalopathy with testicular carcinoma. A reversible neurologic
syndrome. Cancer 1988; 62: 2248–51.
Byrne T, Mason WP, Posner JB, Dalmau J. Spontaneous neurological
improvement in anti-Hu associated encephalomyelitis. J Neurol
Neurosurg Psychiatry 1997; 62: 276–8.
Camara EG, Chelune GJ. Paraneoplastic limbic encephalopathy.
[Review]. Brain Behav Immun 1987; 1: 349–55.
Carpentier AF, Voltz R, DesChamps T, Posner JB, Dalmau J,
Rosenfeld MR. Absence of HuD gene mutations in paraneoplastic
small cell lung cancer tissue. Neurology 1998; 50: 1919.
Carr I. The Ophelia syndrome: memory loss in Hodgkin’s disease.
Lancet 1982; 1: 844–5.
Case records of the Massachusetts General Hospital. Weekly
clinicopathological exercises. Case 30—1985. A 52-year-old woman
with a progressive neurologic disorder and a pelvic mass. N Engl J
Med 1985; 313: 249–57.
Charatan FB, Brierley JB. Mental disorder associated with primary
lung carcinoma. Br Med J 1956; 1: 765–8.
Cher LM, Hochberg FH, Teruya J, Nitschke M, Valenzuela RF,
Schmahmann JD, et al. Therapy for paraneoplastic neurologic
syndromes in six patients with protein A column immunoadsorption.
Cancer 1995; 75: 1678–83.
Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon
AM. The role of laboratory investigation in the diagnosis and
management of patients with suspected herpes simplex encephalitis:
a consensus report. The EU Concerted Action on Virus Meningitis
and Encephalitis. [Review]. J Neurol Neurosurg Psychiatry 1996; 61:
339–45.
Clouston PD, DeAngelis LM, Posner JB. The spectrum of
neurological disease in patients with systemic cancer. [Review]. Ann
Neurol 1992; 31: 268–73.
Cornelius JR, Soloff PH, Miewald BK. Behavioral manifestations of
paraneoplastic encephalopathy. Biol Psychiatry 1986; 21: 686–90.
Corriveau RA, Huh GS, Shatz CJ. Regulation of class I MHC gene
expression in the developing and mature CNS by neural activity.
Neuron 1998; 21: 505–20.
Corsellis JA, Goldberg GJ, Norton AR. ‘Limbic encephalitis’ and its
association with carcinoma. Brain 1968; 91: 481–96.
Croft PB, Henson RA, Urich H, Wilkinson PC. Sensory neuropathy
with bronchial carcinoma: a study of four cases showing serological
abnormalities. Brain 1965; 88: 501–14.
Cunningham JD, Burt ME. Limbic encephalitis secondary to
malignant thymoma. Ann Thorac Surg 1994; 58: 250–1.
Dalmau J, Rosenfeld MR. Characterization of neuronal antigens and
antineuronal antibodies. In: Phillips MI, Evans D, editors. Methods
in neurosciences, Vol. 24. Neuroimmunology. San Diego: Academic
Press; 1995. p. 261–71.
Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated
paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical
study of 71 patients. Medicine (Baltimore) 1992; 71: 59–72.
Dalmau J, Gultekin SH, Posner JB. Paraneoplastic neurologic
syndromes: pathogenesis and physiopathology. [Review]. Brain
Pathol 1999a; 9: 275–84.
Dalmau J, Gultekin SH, Posner JB. A serologic marker of
paraneoplastic limbic and brain-stem encephalitis in patients with
testicular cancer [letter]. N Engl J Med 1999b; 341: 1476.

Dalmau J, Gultekin SH, Voltz R, Hoard R, DesChamps T,
Balmaceda C, et al. Ma1, a novel neuron- and testis-specific protein,
is recognized by the serum of patients with paraneoplastic neurologic
disorders. Brain 1999c; 122: 27–39.
Daniel SE, Love S, Scaravilli F, Harding AE. Encephalo-
myeloneuropathy in the absence of a detectable neoplasm. Clinical
and postmortem findings in three cases. Acta Neuropathol (Berl)
1985; 66: 311–7.
De Reuck J, Sieben G, De Coster W, Vander Eecken H. Prospective
neuropathologic study on the occurrence of Wernicke’s
encephalopathy in patients with tumours of the lymphoid-hemopoietic
systems. Acta Neuropathol Suppl (Berl) 1981; 7: 356–8.
Demaerel P, Wilms G, Robberecht W, Johannik K, Van Hecke P,
Carton H, et al. MRI of herpes simplex encephalitis. Neuroradiology
1992; 34: 490–3.
den Hollander AM, van Hulst AM, Meerwaldt JD, Haasjes JG. Limbic
encephalitis. A rare presentation of the small-cell lung carcinoma.
Gen Hosp Psychiatry 1989; 11: 388–92.
Deodhare S, O’Connor P, Ghazarian D, Bilbao JM. Paraneoplastic
limbic encephalitis in Hodgkin’s disease. Can J Neurol Sci 1996; 23:
138–40.
Dirr LY, Elster AD, Donofrio PD, Smith M. Evolution of brain MRI
abnormalities in limbic encephalitis. Neurology 1990; 40: 1304–6.
Drachman DB. Myasthenia gravis. [Review]. N Engl J Med 1994;
330: 1797–810.
Duyckaerts C, Derouesne C, Signoret JL, Gray F, Escourolle R,
Castaigne P. Bilateral and limited amygdalohippocampal lesions
causing a pure amnesic syndrome. Ann Neurol 1985; 18: 314–9.
Engel PA, Grunnet M, Jacobs B. Wernicke–Korsakoff syndrome
complicating T-cell lymphoma: unusual or unrecognized? South Med
J 1991; 84: 253–6.
Glanz BI, Schur PH, Khoshbin S. EEG abnormalities in systemic
lupus erythematosus. Clin Electroencephalogr 1998; 29: 128–31.
Gritzman MC, Fritz VU, Perkins S, Kaplan CL. Motor neuron disease
associated with carcinoma. A report of 2 cases. S Afr Med J 1983;
63: 288–91.
Haas GG Jr, D’Cruz OJ, De Bault LE. Distribution of human leukocyte
antigen-ABC and -D/DR antigens in the unfixed human testis. Am J
Reprod Immunol Microbiol 1988; 18: 47–51.
Hart PE, Schon F, Macsweeney E. Paraneoplastic limbic encephalitis.
J Neurol Neurosurg Psychiatry 1998; 64: 160.
Heidenreich F, Schober R, Brinck U, Hartung HP. Multiple
paraneoplastic syndromes in a patient with antibodies to neuronal
nucleoproteins (anti-Hu). J Neurol 1995; 242: 210–16.
Heier MS, Fossa SD. Wernicke–Korsakoff-like syndrome in patients
with colorectal carcinoma treated with high-dose doxifluridine (5⬘-
dFUrd). Acta Neurol Scand 1986; 73: 449–57.
Henson RA, Russell DS, Wilkinson M. Carcinomatous neuropathy
and myopathy: a clinical and pathological study. Brain 1954; 77:
82–121.
Henson RA, Hoffman HL, Urich H. Encephalomyelitis with
carcinoma. Brain 1965; 88: 449–64.
Paraneoplastic limbic encephalitis 1493
Honnorat J, Antoine JC, Derrington E, Aguera M, Belin MF.
Antibodies to a subpopulation of glial cells and a 66 kDa
developmental protein in patients with paraneoplastic neurological
syndromes. J Neurol Neurosurg Psychiatry 1996; 61: 270–8.
Horoupian DS, Kim Y. Encephalomyeloneuropathy with ganglionitis
of the myenteric plexuses in the absence of cancer. Ann Neurol 1982;
11: 628–32.
Hosaka T, Aoki T. Depression among cancer patients. Psychiatry Clin
Neurosci 1996; 50: 309–12.
Ingenito GG, Berger JR, David NJ, Norenberg MD. Limbic
encephalitis associated with thymoma. Neurology 1990; 40: 382.
Janati A, Gray RP, Souheaver GT. A mental syndrome associated with
colonic carcinoma: limbic encephalitis? Psychosomatics 1987; 28:
48–50.
Kalkman PH, Allan S, Birchall IW. Magnetic resonance imaging of
limbic encephalitis. Can Assoc Radiol J 1993; 44: 121–4.
Kaluza J, Slowinski J, Bujny T, Grochala M. Paraneoplastic syndrome
simulating encephalitis in the course of testicular seminoma. Folia
Neuropathol 1997; 35: 24–8.
Kaniecki R, Morris JC. Reversible paraneoplastic limbic encephalitis.
Neurology 1993; 43: 2418–9.
Kaplan AM, Itabashi HH. Encephalitis associated with carcinoma.
Central hypoventilation syndrome and cytoplasmic inclusion bodies.
J Neurol Neurosurg Psychiatry 1974; 37: 1166–76.
Kapur N, Barker S, Burrows EH, Ellison D, Brice J, Illis LS, et al.
Herpes simplex encephalitis: long term magnetic resonance imaging
and neuropsychological profile. J Neurol Neurosurg Psychiatry 1994;
57: 1334–42.
Kawaguchi K, Kishida S, Okeda R, Funata N, Koike M.
Encephalomyeloneuritis with mediastinal germ cell tumor. A
paraneoplastic condition? Acta Pathol Jpn 1988; 38: 351–9.
Kepes JJ, Bridge JA, Flasschoen J. Penetration of neuronal perikarya
by capillaries in chronic limbic encephalitis. J Neuropathol Exp
Neurol 1990; 49: 64–70.
Kodama T, Numaguchi Y, Gellad FE, Dwyer BA, Kristt DA. Magnetic
resonance imaging of limbic encephalitis. [Review]. Neuroradiology
1991; 33: 520–3.
Kohler J, Hufschmidt A, Hermle L, Volk B, Lucking CH. Limbic
encephalitis: two cases. J Neuroimmunol 1988; 20: 177–8.
Lacomis D, Khoshbin S, Schich RM. MR imaging of paraneoplastic
limbic encephalitis. J Comput Assist Tomogr 1990; 14: 115–7.
Langston JW, Dorfman LJ, Forno LS. ‘Encephalomyeloneuritis’ in
the absence of cancer. Neurology 1975; 25: 633–7.
Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and
oncologic profiles of patients seropositive for type 1 antineuronal
nuclear autoantibodies. Neurology 1998; 50: 652–7.
Markham M, Abeloff MD. Small-cell lung cancer and limbic
encephalitis [letter]. Ann Intern Med 1982; 96: 785.
Martin RC, Haut MW, Goeta-Kreisler K, Blumenthal D.
Neuropsychological functioning in a patient with paraneoplastic
limbic encephalitis. J Int Neuropsychol Soc 1996; 2: 460–6.
1494 S. Humayun Gultekin et al.
McArdle JP, Millingen KS. Limbic encephalitis associated with
malignant thymoma. Pathology 1988; 20: 292–5.
Meyer JJ, Bulteau C, Adamsbaum C, Kalifa G. Paraneoplastic
encephalomyelitis in a child with neuroblastoma. Pediatr Radiol 1995;
25: 99–101.
Neumann H, Cavalie A, Jenne DE, Wekerle H. Induction of MHC
class I genes in neurons. Science 1995; 269: 549–52.
Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H. Major
histocompatibility complex (MHC) class I gene expression in single
neurons of the central nervous system: differential regulation by
interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J
Exp Med 1997; 185: 305–16.
Newman NJ, Bell IR, McKee AC. Paraneoplastic limbic encephalitis:
neuropsychiatric presentation. [Review]. Biol Psychiatry 1990; 27:
529–42.
Newsom-Davis J, Mills KR. Immunological associations of acquired
neuromyotonia (Isaac’s syndrome). Report of five cases and literature
review. Brain 1993; 116: 453–69.
Nokura K, Yamamoto H, Okawara Y, Koga H, Osawa H, Sakai K.
Reversible limbic encephalitis caused by ovarian teratoma. Acta
Neurol Scand 1997; 95: 367–73.
Okamura H, Oomori N, Uchitomi Y. An acutely confused 15-year-
old girl. Lancet 1997; 350: 488.
Panegyres PK, Reading MC, Esiri MM. The inflammatory reaction
of paraneoplastic ganglionitis and encephalitis: an immunohisto-
chemical study. J Neurol 1993; 240: 93–7.
Perentes E, Herbort C. Herpes simplex virus encephalitis: a case with
Korsakoff’s syndrome and an immunoperoxidase study of 12 cases.
Schweiz Arch Neurol Neurochir Psychiatry 1984; 135: 229–41.
Pfliegler G, Posan E, Glaub D, Telek B, Rak K. Hodgkin’s disease
and memory loss: another case of the Ophelia syndrome. Br J
Haematol 1990; 74: 232.
Porta-Etessam J, Dalmau J. Analisis de las consultas neurologicas en
un hospital oncologico: contribuciones de la neurooncologia.
Neurologı́a 1999; 14: 266–74.
Posner JB, editor. Neurologic complications of cancer. Philadelphia:
F.A. Davis; 1995.
Provenzale JM, Barboriak DP, Coleman RE. Limbic encephalitis:
comparison of FDG PET and MR imaging findings. AJR Am J
Roentgenol 1998; 170: 1659–60.
Riva M, Brioschi AM, Marazzi R, Donato MF, Ferrante E.
Immunological and endocrinological abnormalities in paraneoplastic
disorders with involvement of the autonomic nervous system. Ital J
Neurol Sci 1997; 18: 157–61.
Rosenbaum T, Gartner J, Korholz D, Janssen G, Schneider D,
Engelbrecht V, et al. Paraneoplastic limbic encephalitis in two teenage
girls. Neuropediatrics 1998; 29: 159–62.
Russell DS. Encephalomyelitis and ‘carcinomatous neuropathy’. In:
van Bogaert L, Radermecker J, Hozay J, Lowenthal A, editors.
Encephalitides. Amsterdam: Elsevier: 1961. p. 131–5.
Sakai K, Gofuku M, Kitagawa Y, Ogasawara T, Hirose G,
Yamazaki M, et al. A hippocampal protein associated with
paraneoplastic neurologic syndrome and small cell lung carcinoma.
Biochem Biophys Res Commun 1994; 199: 1200–8.
Spiegel D. Cancer and depression. [Review]. Br J Psychiatry Suppl
1996; 30: 109–16.
Stern RC, Hulette CM. Paraneoplastic limbic encephalitis associated
with small cell carcinoma of the prostate. Mod Pathol 1999; 12: 814–8.
Störring G, Hauss K, Ule G. Zur topischen Diagnostik des
amnestischen Symptomenkomplexes. Psychiat Neurol (Basel) 1962;
143: 161–77.
Stubgen JP. Nervous system lupus mimics limbic encephalitis. Lupus
1998; 7: 557–60.
Sutton RC, Lipper MH, Brashear HR. Limbic encephalitis occurring
in association with Alzheimer’s disease. J Neurol Neurosurg
Psychiatry 1993; 56: 808–11.
Tandon R, Walden M, Falcon S. Catatonia as a manifestation of
paraneoplastic encephalopathy. J Clin Psychiatry 1988; 49: 121–2.
Tsukamoto T, Mochizuki R, Mochizuki H, Noguchi M, Kayama H,
Hiwatashi M, et al. Paraneoplastic cerebellar degeneration and limbic
encephalitis in a patient with adenocarcinoma of the colon. J Neurol
Neurosurg Psychiatry 1993; 56: 713–6.
Ulrich J, Spiess H, Huber R. Neurological syndrome as a remote
effect of a malignant tumor (Ammon’s horn sclerosis in bronchial
carcinoma). [German]. Schweiz Arch Neurol Neurochir Psychiatr
1967; 99: 83–100.
Van Sweden B, Van Peteghem P. Psychopathology in paraneoplastic
encephalopathy: an electroclinical observation. J Clin Psychiatry
1986; 47: 267–8.
Veilleux M, Bernier JP, Lamarche JB. Paraneoplastic encephalo-
myelitis and subacute dysautonomia due to an occult atypical
carcinoid tumour of the lung. Can J Neurol Sci 1990; 17: 324–8.
Verhaart WJC. Grey matter degeneration of the C.N.S. in carcinosis.
Acta Neuropathologica (Berl) 1961; 1: 107–112.
Voltz R, Gultekin SH, Posner JB, Rosenfeld MR, Dalmau J. Sera of
patients with testicular cancer and paraneoplastic limbic/brainstem
encephalitis harbor an antineuronal antibody (anti-Ta) that recognizes
a novel neuronal protein [abstract]. J Neurol 1998; 245: 379.
Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, Posner
JB, et al. A serologic marker of paraneoplastic limbic and brain-stem
encephalitis in patients with testicular cancer. N Engl J Med 1999;
340: 1788–95.
Wingerchuk DM, Noseworthy JH, Kimmel DW. Paraneoplastic
encephalomyelitis and seminoma: importance of testicular
ultrasonography. Neurology 1998; 51: 1504–7.
Yahr MD, Duvoisin RC, Cowen D. Encephalopathy associated with
carcinoma. Trans Am Neurol Assoc 1965; 90: 80–6.
Yamada M, Okeda R, Chen W, Nito H, Hatakeyama S, Tsukagoshi H.
Cortical cerebellar degeneration with testicular neoplasm. Acta
Neuropathol (Berl) 1985; 66: 170–2.
Zacharias AS, Brashear HR, Munoz EL, Alexander B, Gimple LW.
Paraneoplastic encephalomyeloneuritis obscured by coma. Neurology
1996; 46: 1177–9.
Received November 11, 1999. Revised January 29, 2000.
Accepted February 3, 2000