Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients

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1 Brain (2000), 123, 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. Posner 1,3 and Josep Dalmau 1,3, ** 1 Department of Neurology and the Cotzias Laboratory of Correspondence to: Josep Dalmau, MD, Department of Neuro-Oncology and 2 Department of Pathology, Memorial Neurology, University of Arkansas for Medical Sciences, Sloan-Kettering Cancer Center, 3 Department of Neurology 4301 W. Markham, Slot 500, Little Rock, AR 72205, USA and Neuroscience and 4 Division of Neurosurgery, Weill dalmaujosep@exchange.uams.edu Medical College of Cornell University, New York, USA *Present address: Neurologische Klinik, Klinikum Grosshadern, D München, Germany **Present address: Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Summary Paraneoplastic limbic encephalitis (PLE) is a rare disorder neoplasms were of the lung (50%), testis (20%) and characterized by personality changes, irritability, breast (8%). Neurological symptoms preceded the cancer depression, seizures, memory loss and sometimes diagnosis in 60% of patients (by a median of 3.5 months). dementia. The diagnosis is difficult because clinical Twenty-five of 44 (57%) patients with MRI studies had markers are often lacking, and symptoms usually precede signal abnormalities in the limbic system. Thirty (60%) the diagnosis of cancer or mimic other complications. patients had antineuronal antibodies (18 anti-hu, 10 anti- The frequency of antineuronal antibodies in patients Ta, 2 anti-ma), and 20 were antibody-negative or had with PLE has not been investigated. We examined the uncharacterized antibodies (n 4). The combination of neurological symptoms and the causal tumours in 50 symptoms, MRI findings and paraneoplastic antibodies patients with PLE to determine the utility of established the diagnosis of PLE in 78% of the patients. paraneoplastic antibodies and other tests. The diagnosis Patients with anti-hu antibodies usually had small-cell of PLE required neuropathological examination or the lung cancer (94%), multifocal neurological symptoms presence of the four following criteria: (i) a compatible (78%) and a poor neurological outcome. Patients with clinical picture; (ii) an interval of <4 years between anti-ta (also called anti-ma2) antibodies were young men the development of neurological symptoms and tumour with testicular tumours (100%), frequent hypothalamic diagnosis; (iii) exclusion of other neuro-oncological involvement (70%) and a poor neurological outcome. In complications; and (iv) at least one of the following: CSF the group of patients without anti-hu or anti-ta with inflammatory changes but negative cytology; MRI antibodies, the tumour distribution was diverse, with demonstrating temporal lobe abnormalities; EEG cancer of the lung the most common (36%); 57% had showing epileptic activity in the temporal lobes. Of 1047 positive MRI. Fifteen of 34 (44%) patients with a median patients with neurological symptoms, whose sera or CSF follow-up of 8 months showed neurological improvement. were examined for paraneoplastic antibodies, 79 had the Treatment of the tumour appeared to have more effect presumptive diagnosis of limbic encephalitis, dementia, on the neurological outcome than the use of immune cognitive dysfunction, or confusion. Fifty of these patients modulation. Improvement was observed in 38% of anti- fulfilled our criteria for PLE. Pathological confirmation Hu patients, 30% of anti-ta patients and 64% of patients was obtained in 12 patients. The commonly associated without these antibodies. Keywords: paraneoplastic; limbic; encephalitis; SCLC Abbreviations: PLE paraneoplastic limbic encephalitis; SCLC small-cell lung cancer Oxford University Press 2000

2 1482 S. Humayun Gultekin et al. Introduction Based upon prior case reports and their own series, Corsellis report the spectrum of neurological symptoms and tumours and colleagues first described paraneoplastic limbic in 50 patients with PLE and analyse the utility of the detection encephalitis (PLE) as a clinicopathological entity 30 years of paraneoplastic antibodies and other diagnostic tests for ago (Corsellis et al., 1968). To date, 137 patients with PLE this disorder. 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 Design and methods of the limbic structures, but the majority of patients had The clinical and laboratory data of 79 patients with variable involvement of other areas of the nervous system, presumptive paraneoplastic disorders, including limbic mainly the brainstem (Henson et al., 1954; Bakheit et al., encephalitis, memory problems, dementia, cognitive dys- 1990). The diagnosis of PLE is often difficult because function or confusion, were reviewed. These patients were similar symptoms (seizures, memory problems, irritability, identified from a database of 1047 patients with suspected depression, confusion and dementia) can be caused by many paraneoplastic neurological syndromes, whose sera or CSF other cancer-related complications, including brain were examined for antineuronal antibodies at Memorial metastases, toxic and metabolic encephalopathies, infections Sloan-Kettering Cancer Center. Twelve patients were (especially with herpes simplex encephalitis) and the sideeffects examined by the authors (J.B.P., J.D.). Information on the of cancer therapy (Posner, 1995). In addition, other patients was obtained from their primary physicians. neurological symptoms frequently precede the detection of the The diagnosis of PLE required neuropathological examination tumour, further confounding the diagnosis of the neurological (biopsy or autopsy), or all four of the following criteria: (i) disorder as paraneoplastic in origin. a clinical picture of short-term memory loss, seizures, or Antineuronal antibodies, when present in the serum and psychiatric symptoms suggesting involvement of the limbic CSF, facilitate the diagnosis of PLE and often allow the early system; (ii) an interval of 4 years between the onset detection of the associated tumour (Alamowitch et al., 1997). of neurological symptoms and the cancer diagnosis; (iii) However, the frequency of antineuronal antibodies in patients exclusion of other cancer-related complications (metastasis, with PLE is largely unknown (Dalmau et al., 1999a). We 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., * SCLC No 0/4 Brierley et al., SCLC No Autopsy Verhaart et al., SCLC No Autopsy Yahr et al., SCLC No Autopsy Henson et al., SCLC No 1 Croft et al., SCLC No 1, autopsy Corsellis et al., SCLC, 1 non-sclc No 3, autopsy Kaplan et al., SCLC No Autopsy Markham and Abeloff, SCLC Yes, tumour (chemotherapy) None Carr et al., Hodgkin s disease Yes, tumour (chemotherapy and None radiation therapy) Gritzman et al., Oesophageal cancer No Autopsy Brennan and Craddock, SCLC Yes, tumour (radiation therapy) None Duyckaerts et al., Hodgkin s disease No Autopsy Case records, Bladder cancer No Autopsy Yamada et al., Mixed GCT of the testis No 1 Cornelius et al., SCLC No Autopsy Van Sweden and Van 1 Oesophageal cancer No Autopsy Peteghem, 1986 Camara and Chelune, SCLC No Autopsy Janati et al., Colon cancer No None Kawaguchi et al., Mediastinal GCT with No information Autopsy teratoma elements Tandon et al., SCLC Symptomatic (haloperidol) Autopsy Burton et al., # Non-seminomatous GCT of the testis Yes, tumour (surgery and None (predominant embryonic carcinoma) chemotherapy) McArdle and Millingen, Thymoma No Autopsy Den Hollander et al., SCLC 1, yes, tumour None (chemotherapy) 1, no improvement

3 Paraneoplastic limbic encephalitis 1483 Table 1 Contd Reference No. of Tumour type Neurological improvement with Tissue patients treatment (type) Newman et al., SCLC, renal cancer No Autopsy Bakheit et al., SCLC, 1 non-sclc No 3 Autopsy Dirr et al., SCLC No Biopsy Ingenito et al., Thymoma No Autopsy Veilleux et al., Atypical carcinoid No Autopsy Lacomis et al., Breast cancer No Biopsy Pfliegler et al., Hodgkin s disease Yes, tumour (chemotherapy) None Brashear et al., SCLC No Autopsy Kodama et al., Breast cancer, thymoma No 2, biopsy Amir and Galbraith, SCLC Yes, tumour (chemotherapy None and radiation therapy) Dalmau et al., SCLC 2, yes, tumour (chemotherapy) None Baldwin and Henderson, SCLC No Autopsy Kalkman et al., SCLC Yes, tumour (chemotherapy) None Panegyres et al., SCLC No Autopsy Tsukamoto et al., Colon cancer Yes, tumour (surgery) None Kaniecki and Morris, SCLC Yes, tumour (chemotherapy) None Sutton et al., SCLC No Autopsy Cunningham and Burt, # Thymoma Yes, tumour (surgery and None radiation therapy) Sakai et al., SCLC No information None Ahern et al., # Non-seminomatous GCT No None of the testis (predominant embryonic carcinoma) Cher et al., # Breast cancer Yes, tumour (surgery and None protein A immune absorption) Antoine et al., Thymoma Yes, tumour (surgery) None Meyer et al., Neuroblastoma No None Heidenreich et al., SCLC No Autopsy Honnorat et al., SCLC No information None Martin et al., Non-SCLC Yes, tumour (surgery) None Zacharias et al., SCLC No Autopsy Deodhare et al., Hodgkin s disease Yes, tumour (chemotherapy) None Alamowitch et al., SCLC Yes, 5/15 treated; tumour 1, autopsy (chemotherapy) Byrne et al., # SCLC Yes, tumour (chemotherapy) None Nokura et al., Teratoma of the ovary Yes, tumour (surgery) None Okamura et al., Teratoma of the ovary Yes, tumour (surgery) None Kaluza et al., Testicular GCT No Autopsy (seminoma) Riva et al., Colon cancer No information None Provenzale et al., SCLC No information None Wingerchuk et al., Testicular GCT No None (seminoma) Lucchinetti et al., SCLC No information None Bell et al., Renal cell cancer Yes, tumour (surgery) None Rosenbaum et al., Ovarian cancer, 1, yes, ovarian tumour Hodgkin s disease (chemotherapy) 1, no, Hodgkin s disease 1, biopsy Hart et al., SCLC No None Aydiner et al., # Teratoma of the ovary No None Antoine et al., SCLC No information None Bennett et al., # Embryonal carcinoma No None of the testis Voltz et al., # Testis** Yes, 3/5 treated; tumour 4, biopsy (3 published twice) (all 3 had orchiectomy and immune modulation) Stern and Hulette, 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.

4 1484 S. Humayun Gultekin et al. Table 2 Tumours associated with paraneoplastic limbic encephalitis Type of tumour Current series English literature (50 patients) (72 patients) Table 3 Clinical features Symptom 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 on T 2 -weighted images or atrophy on T 1 -weighted images; *Some patients had more than one symptom. and EEG showing slow- or sharp-wave activity in one or both temporal lobes. Patients with PLE No. of patients 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 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

5 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: 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 T 2 -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, loss (22 patients), seizures (25 patients) or both (20 patients). 1 generalized tonic-clonic), hypothalamic dysfunction (6 Among the 25 patients with seizures, 10 had temporal lobe patients; 3 hypersomnia, 2 hyperthermia, 1 panhypo- or psychomotor seizures, 6 generalized seizures, and 9 a pituitarism), psychiatric abnormalities (6 patients; 5 combination of seizure types. Only 3 patients did not have depression, 1 hallucinations), and symptoms of involvement seizures or short-term memory loss: two developed a of other areas of the nervous system (7 patients; 3 sensory confusional state without epileptic activity on EEG and the neuronopathy, 2 cerebellar ataxia, 1 dizziness, 1 diplopia). other developed hypothalamic dysfunction characterized by For 1 patient, information about presenting symptoms was diabetes insipidus, loss of libido and hypothyroidism. In not available. these three patients the MRI showed mesial temporal changes Table 3 shows the main symptoms during the course of compatible with PLE. the disease and the total number of patients having each Forty-nine patients had neuroimaging studies (44 MRI and symptom. Overall, 47 patients developed short-term memory 5 CT) (Table 4). The most frequent MRI abnormalities were

6 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 T 2 -weighted images and involved the mesial selective diffuse reactivity with the neuropil, but was negative aspect of one (10 patients) or both (15 patients) temporal in immunoblot studies; and the serum of a patient with non- lobes (Fig. 1). In 5 patients, the mesial-temporal MRI SCLC showed faint labelling of the neuronal cytoplasm abnormalities enhanced after contrast administration. A with negative immunoblot findings. Sixteen patients had no biopsy from the enhancing area obtained in 4 patients showed antineuronal antibodies. None of the sera contained anti-cv2 inflammatory infiltrates and neuronal loss (Fig. 2). In addition antibodies. to the temporal lobe findings, 8 patients had MRI Overall, 39 (78%) patients had temporal lobe abnormalities abnormalities in other areas: 4 in the brainstem, 4 in the on MRI studies and/or positive paraneoplastic antibodies in hypothalamus, 1 in the thalamus, 1 in the cingulate gyrus their serum. When the abnormal findings in one or both of and 1 in the basal frontal lobe; none of these abnormalities, these tests were combined with the detection of abnormal except 1 in the hypothalamus, enhanced with contrast CSF, the number of patients with at least two abnormal tests material. Three patients without temporal limbic MRI was 49. The remaining patient, with Hodgkin s disease, had findings had abnormalities involving other areas of the brain biopsy findings supporting the diagnosis of PLE. nervous system (Table 4). On the basis of the presence or absence of anti-hu The CSF was examined in 49 patients, and 40 showed one and anti-ta antibodies, we established three immunological or more of the following abnormalities: 24 of 47 had groups of PLE patients. For practical purposes the two pleocytosis ( 5 cells/mm 3 ; range cells/mm 3, median patients with anti-ma antibodies and the 4 patients with noncharacterized 29); 24 of 27 had elevated proteins ( 45 mg/dl; range 47 antineuronal antibodies were included in the 170, median 74); 10 of 13 had oligoclonal bands; and 15 of group of patients without antibodies (Table 5). In 6 patients 15 had intrathecal synthesis of IgG. Only 7 patients had (3 anti-hu, 3 anti-ta) the detection of these antibodies led increased proteins as an isolated finding. None of 49 patients to the diagnosis of the paraneoplastic syndrome and assisted had malignant cells in the CSF (Table 4). in identifying the underlying tumour. Paraneoplastic antibodies were identified in the serum, Of 18 patients with anti-hu antibodies, 16 had SCLC, CSF, or both, of 30 patients (60%): in 18 patients they were 1 was reported to have adenocarcinoma of the lung (the anti-hu antibodies, in 10 they were anti-ta antibodies (also tumour was not examined by us), and no tumour was identified known as anti-ma2 antibodies) and in 2 they were anti-ma in another patient. All patients with anti-ta antibodies had antibodies (Figs 3 and 4). Four patients had antineuronal testicular germ-cell tumours. In the group of patients without antibodies that have not been characterized: the serum from antibodies or with atypical antibodies, 8 (36%) had cancer a patient with breast cancer reacted with several proteins in the of the lung (4 SCLC), 4 adenocarcinoma of the breast, kda range expressed predominantly in the cytoplasm of 2 immature teratoma, 2 Hodgkin s disease, 1 plasma cell hippocampal pyramidal cells; the serum from a patient with dyscrasia, 1 malignant thymoma, 1 adenocarcinoma of the non-sclc reacted with several proteins in the range of 40 colon, 1 chronic myeloid leukaemia and 1 ovarian cancer 60 kda expressed in the cytoplasm of neurons and Purkinje (Table 5). cells; the serum from a patient with ovarian cancer showed Seventy-eight per cent of patients with PLE and anti-hu

7 Paraneoplastic limbic encephalitis 1487 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 instances, the main findings were perivascular cuffing and the nervous system distant from the limbic system (brainstem, interstitial infiltrates of lymphocytes, microglial proliferation, cerebellum, dorsal root ganglia, cerebral cortex, spinal cord gliosis and neuronal degeneration (Fig. 2). Three autopsy and autonomic nervous system) (Table 5). These areas were studies had results of detailed neuropathological examination less likely to be involved in patients without antibodies or showing chronic encephalitis without viral inclusion bodies with atypical antibodies (41%). that was not restricted to the limbic regions. Compared with the anti-hu patients (median age 61.5 Clinical follow-up was available for 34 patients (median years), the anti-ta patients were younger (median age 34 8 months, range 1 84 months) (Table 6). Treatment of the years) and had more restricted involvement of the limbic tumour appeared to be associated with improvement of the system and brainstem (80%); only 2 patients had other neurological syndrome in 11 of the 15 patients (73%) in whom symptoms (1 with involvement of the basal ganglia and 1 this assessment was possible. Eighteen patients received one with cerebellar dysfunction). As part of the limbic symptoms, or more immune modulatory treatments for the paraneoplastic 70% of these patients had severe hypothalamic dysfunction disorder: 12 corticosteroids ( mg prednisone), 4 (clinical details of these patients have been reported elsewhere cyclophosphamide, 4 intravenous immunoglobulin, 5 plasma (Voltz et al., 1999). Unlike patients with anti-hu antibodies, exchange, and 1 removal of plasma IgG by immunoadsorption the anti-ta patients did not develop signs of dorsal root with a protein-a column. Four of these 18 patients (22%) ganglion involvement or myelitis. had partial neurological improvement closely related to the Pathological examination of the brain was obtained in 12 dates when they were treated with immune modulation, patients: 8 had a brain biopsy and 4 an autopsy. In all although all 4 had simultaneous treatment of the tumour.

8 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 9M,9F 10M 8M,14F Age range (median) (years) (61.5) (34) (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 before tumour diagnosis Symptoms Limbic alone Limbic brainstem alone Outside limbic brainstem Hypothalamic deficits Psychiatric symptoms 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 Immune modulation only Treatment of the tumour and immune modulation No treatment 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 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 years). Thirteen patients had cancer: neurological symptoms developed before the tumour Fig. 4 Immunoblot analysis of human neuronal proteins with serum from patients with PLE. Lanes correspond to the same sera diagnosis in 5 patients (median 12 months, range 1 month examined by immunohistochemistry in Fig. 3. Lane NHS to 6 years) and after the tumour diagnosis in 8 (median 3.5 corresponds to serum from a normal individual. years, range 1 19 years). Tumours included SCLC in 2 patients, non-sclc tumours in 2 patients, renal cell cancer 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 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

9 Paraneoplastic limbic encephalitis 1489 patients and lung nodules (without biopsy) in 2 patients. No colleagues described a patient with undifferentiated bronchial systemic tumour was identified in the other 16 patients after carcinoma and an encephalitic-like picture in the limbic a median follow-up of 12 months (range 1 month to 8 years). system (Störring et al., 1962). In 1965, Yahr and colleagues CSF was examined in 15 patients: 4 showed inflammatory reported a patient with encephalopathy associated with abnormalities, 6 showed increased proteins only and 5 were carcinoma who had SCLC and limbic system inflammatory normal (Table 4). Three patients harboured atypical antibodies changes (Yahr et al., 1965). In 1967, Ulrich and colleagues that reacted with neurons; none of these antibodies was reported a patient with SCLC and neuronal degeneration similar to any of the 4 atypical antibodies found in the PLE in Ammon s horn and elsewhere with some perivascular patients. The other 26 patients were negative for antibodies. lymphocytic cuffing (Ulrich et al., 1967). MRI was obtained in 22 patients. Temporal lobe The name limbic encephalitis was coined by Corsellis and abnormalities were identified in 5 patients, whose final colleagues (Corsellis et al., 1968) when they reported three diagnoses were: herpes simplex encephalitis in 2 patients additional patients and extensively reviewed the prior (1 associated with glioma); metastasis of renal cell cancer literature, including those patients first reported by Brierley in 1 patient; bilateral temporal lobe abnormalities with and colleagues (Brierley et al., 1960). This description of frontoparietal and periventricular white matter changes in limbic encephalitis generated more reports, and by patient with non-caseating bone marrow granulomatosis of Bakheit and colleagues were able to report three new patients uncertain significance; and bilateral temporal lobe T 2 - with PLE, and reviewed the extant literature, which consisted weighted abnormalities with contrast enhancement in 1 patient of 16 cases that had been verified clinically and pathologically with primary CNS lymphoma, who eventually developed (Bakheit et al., 1990). Once the relationship between cancer involvement of the left basal ganglia and occipital lobe. and the nervous system lesion had been established, three The final diagnoses of the patients without MRI pathogenic hypothesis were advanced: (i) a (not further abnormalities in the temporal lobes included 1 of each of defined) degeneration of the nervous system in which the the following: viral encephalitis; primary CNS lymphoma; inflammatory infiltrates were a secondary reaction to the Creutzfeldt Jakob disease; ischaemic cerebrovascular tissue breakdown (Verhaart, 1961; Ulrich et al., 1967); (ii) disease; psychiatric disorder with pseudodementia; frontal a viral infection (Corsellis et al., 1968); and (iii) an immunemediated lobe metastasis; and intracranial hypertension due to remote response against the nervous system (Russell, 1961). subarachnoidal haemorrhage; and 17 patients had primary The third hypothesis is the currently accepted one. degenerative dementia (either of the Alzheimer type or of Despite the now fairly large number of patients reported, unknown cause). 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 Discussion or behavioural changes). In 27% of our patients these In 1960, Brierley and colleagues described three patients symptoms were not part of the presentation of the suffering from subacute encephalitis of later adult life mainly paraneoplastic disorder. Usually, patients are not known to affecting the limbic areas (Brierley et al., 1960). At autopsy, have cancer, as occurred in 60% of our patients. Symptoms the first patient had a small leiomyoma of the left kidney but resembling PLE are frequent in cancer patients and may no other evidence of malignancy. The second patient had result from multiple different metastatic and non-metastatic several mediastinal and hilar lymph nodes extensively complications (Clouston et al., 1992; Hosaka and Aoki, 1996; replaced by oat-shaped cells, appearing identical to those Spiegel, 1996; Porta-Etessam, 1999). In fact, a 1956 report seen in anaplastic bronchial carcinoma ; no tumour was of a mental disorder associated with primary lung carcinoma found in the lungs or elsewhere in the body. The third patient described three patients who probably suffered from hepatic had an encapsulated mass at the root of the right lung encephalopathy (Charatan and Brierley, 1956). With the which consisted of fibrotic lymph nodes. Although one of exception of the anti-hu antibody in some patients with the authors had previously reported patients with a mental SCLC and the anti-ta antibody in patients with testicular disorder associated with primary lung carcinoma (Charatan tumours, there are no known serological markers of PLE. In and Brierley, 1956), they believed that it was most unlikely the current study, 60% of the patients had paraneoplastic that this finding [lung cancer in patient 2] is in any way antibodies in their serum (see below). Identification of these related to the encephalitis but its occurrence should be noted. antibodies, when combined with characteristic MRI findings, They also noticed that a lung cancer had been clinically helped establish the diagnosis of PLE in 78% of the patients. suspected in patient 3 but they failed to consider that the Symptoms of involvement of areas of the nervous system fibrotic lymph nodes may have represented a remitting distant from the limbic system (particularly the brainstem tumour. In 1961, Verhaart described two patients with and cerebellum) are frequent in patients with PLE. This inflammatory lesions of the medial temporal lobe and nerve occurred in 60% of our patients and similar findings were 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 recognized by Bakheit and colleagues, who found that only 6 of 19 (32%) patients had isolated limbic encephalitis (Bakheit et al., 1990).

10 1490 S. Humayun Gultekin et al. Typical MRI findings of PLE include unilateral or bilateral be confirmed by PCR (polymerase chain reaction) analysis of mesial temporal lobe abnormalities that are best seen on T 2 - the CSF or brain biopsy (Cinque et al., 1996). weighted images. On T 1 sequences, the temporal limbic Symptoms and pathological findings of limbic encephalitis regions may be hypointense and atrophic, and may sometimes have been reported in the absence of cancer (Brierley et al., enhance with contrast injection. These abnormalities, 1960; Langston et al., 1975; Horoupian and Kim, 1982; although well known (Dirr et al., 1990; Lacomis et al., 1990), Daniel et al., 1985; Kohler et al., 1988; Kepes et al., 1990). had not been examined in a large series of patients. In our We believe that in most cases a cancer was present but not study, 64% of the patients with PLE had abnormal MRI detected. In one of our patients with PLE and life-threatening studies, which in 89% of the cases showed the changes neurological deterioration, the family consented to right indicated above. Patients with herpes simplex encephalitis orchiectomy because of the detection of serum anti-ta may have similar MRI findings in the early stages of the antibodies and ultrasound findings of a mild abnormality in disease. However, these patients usually develop prominent the right epididymis (consistent with epididymitis). The signs of oedema and mass effect involving one or both original pathological evaluation was negative for testicular inferior medial temporal lobes, the inferior frontal lobes and cancer, but detailed review of the slides demonstrated the cingulate gyrus. In addition, gyral enhancement is present microscopic intratubular germ-cell tumour (Dalmau et al., in more than half of the patients and signs of haemorrhage 1999b). are not uncommon (Demaerel et al., 1992; Kapur et al., 1994). We compared the histological types of tumours of our CSF analysis assists in making the diagnosis of PLE in patients with those reported in the English literature, bearing two ways. First, a negative cytological analysis for malignant in mind two considerations. First, 53 of 137 reported patients cells in combination with the absence of meningeal come from three studies of patients selected on the basis enhancement on the MRI helps exclude leptomeningeal of suffering from SCLC or harbouring anti-hu antibodies metastases. Secondly, the detection of inflammatory (Dalmau et al., 1992; Alamowitch et al., 1997; Lucchinetti abnormalities (pleocytosis, intrathecal synthesis of IgG, et al., 1998). Secondly, 12 of our patients have been reported oligoclonal bands) supports the diagnosis of an inflammatory previously. Thus, after excluding these 65 patients from Table or immune-mediated neurological disorder; 64% of our 1, the remaining 72 patients were compared with the 50 patients of the current study (Table 2). This comparison patients had one or more of these abnormalities. We did not revealed a preferential association of PLE with certain find any patient with antibodies present only in the CSF; tumours: SCLC, germ-cell tumours of the testis, breast cancer, however, two patients had barely detectable serum anti-ta Hodgkin s lymphoma, immature teratoma and thymoma. titres, while the CSF titres were several orders of magnitude The reason for the preferential association of PLE with higher (data not shown). certain tumours is unknown. SCLC and testicular germ-cell The EEG has limited usefulness in making the diagnosis tumours express a number of proteins (including the Hu and of PLE, but it is useful in assessing whether changes in the Ma proteins) that in normal adult tissues are restricted to level of consciousness or behaviour are related to temporal neurons and germ cells of the testis (Carpentier et al., 1998; lobe seizures. In a review of 19 patients, Bakheit and Dalmau et al., 1999c; Voltz et al., 1999). In addition, these colleagues identified temporal lobe seizures in only one tissues are immunoprivileged by the presence of endothelial patient (Bakheit et al., 1990). In our study, the incidence of barriers and atypical or absent expression of antigen- EEG abnormalities was limited by the fact that only patients presenting molecules (MHC class I) (Haas et al., 1988; in whom seizures were suspected received EEG evaluation. Neumann et al., 1997; Corriveau et al., 1998). These findings Nevertheless, among the 35 patients with EEG studies, 45% suggest a mechanism whereby the tumour expression of had epileptic activity. brain/testis proteins is the trigger of autoimmunity against Symptoms resembling PLE may result from several the nervous system. This hypothesis is supported by our disorders, including systemic lupus erythematosus (Glanz study, in which SCLC and testicular germ-cell tumours et al., 1998; Stubgen et al., 1998), Wernicke Korsakoff were consistently associated with antineuronal antibodies in encephalopathy with or without cancer (De Reuck et al., patients with PLE. Immunological disturbances have also 1981; Engel et al., 1991), toxic effects of doxifluridine (an been identified in patients with PLE and thymoma (Antoine antineoplastic agent) (Heier and Fossa, 1986) and herpes et al., 1995), a tumour frequently related to other autoimmune simplex encephalitis (Aimard et al., 1979; Perentes and neurological disorders, including myasthenia gravis and Herbort, 1984). Two of our patients with PLE were initially neuromyotonia (Newsom-Davis and Mills, 1993; considered to have herpes simplex encephalitis and received Drachman, 1994). treatment with acyclovir without neurological improvement. Thirty of our patients (60%) had positive paraneoplastic However, patients with herpes simplex encephalitis usually antibodies (anti-hu, anti-ta or anti-ma). We took into develop acute or subacute mental confusion and seizures that consideration a possible bias of serum referral to our often lead to stupor or coma. The MRI findings (see above) laboratory for anti-ta antibody testing. However, only 2 of and the presence of red blood cells in the CSF point to the the 10 patients with positive anti-ta antibodies were included diagnosis of herpes simplex encephalitis, which diagnosis can in the study after the discovery of these antibodies (Voltz

11 Paraneoplastic limbic encephalitis 1491 et al., 1998); the other 8 were retrospectively identified from antibodies, and only 2 had MRI abnormalities similar to the 1047 patients in the database. those identified in PLE; one had herpes simplex encephalitis, On the basis of the presence of paraneoplastic antibodies, and the other a primary CNS lymphoma that eventually we established three immunological subsets of PLE (Table showed multifocal areas of enhancement. 5) that differ from each other by the age of the patients, the From this and previous studies (Table 1), it appears likely type of tumour association and some clinical features. The that PLE is an immune-mediated disorder that can be caused most distinctive of these include the presence of symptoms by several types of tumour-induced autoimmunity. When from areas outside the limbic system in most anti-hu patients PLE is suspected, the following tests should be considered: (i) and the frequent hypothalamic and brainstem involvement in MRI of the brain without and with contrast; (ii) paraneoplastic anti-ta patients. In addition, PLE patients with anti-ta antibody testing of serum and CSF; (iii) CSF studies to rule antibodies are more likely to have abnormal MRI findings out the presence of metastatic cells and demonstrate the than other PLE patients. presence of inflammatory abnormalities (oligoclonal bands, It is important to note that the group of patients with intrathecal synthesis of IgG, pleocytosis); and (iv) EEG no antibodies or with other antibodies is an ill-defined, studies, particularly in patients with an acute confusional state heterogeneous group that includes patients without of unknown cause. Patients older than 40 years, particularly if antineuronal antibodies, and 6 patients with antibodies other they are smokers, should be examined for serum and CSF than anti-hu and anti-ta (4 non-characterized and 2 anti- anti-hu antibodies; the detection of this antibody confirms Ma). One anti-ma patient was a woman, without a cancer that the limbic syndrome is paraneoplastic and indicates that diagnosis, who developed confusion, lethargy and T 2 MRI the tumour is probably SCLC. In patients older than 40 abnormalities involving the medial temporal lobes, years without paraneoplastic antibodies, the tumours most hypothalamus and upper midbrain; the other was a woman frequently encountered are non-sclc, carcinoma of the with breast cancer, typical symptoms of PLE, and T 2 MRI breast and thymoma; however, the absence of anti-hu abnormalities in the medial temporal lobes. Unlike other antibodies does not rule out the possibility that the underlying anti-ma sera that react similarly with both Ma1 and Ma2 tumour is SCLC. Patients younger than 40 years, particularly proteins (Dalmau et al., 1999c), the sera and CSF of these if they are male, should be studied for serum and CSF antitwo patients showed more reactivity with Ma2 than Ma1 Ta antibodies; the detection of these antibodies indicates that (data not shown). This finding and the data from patients the disorder is paraneoplastic and that the tumour is likely with anti-ta antibodies (which recognize Ma2) (Voltz et al., to be located in testis. In patients younger than 40 years 1999) suggest that Ma2 contains epitopes related to and without paraneoplastic antibodies, the tumours most autoimmunity associated with limbic dysfunction. frequently involved are Hodgkin s lymphoma and immature In contrast to most paraneoplastic syndromes of the CNS, teratoma. Regardless of the antineuronal antibody status, which do not improve with treatment, PLE may respond to MRI studies show T 2 abnormalities in mesial temporal therapy. In our study, 44% of patients with a median follow- regions in 57% of the patients; these findings, although not up of 8 months showed neurological improvement regardless pathognomonic, are highly suggestive of PLE, particularly if of the type of treatment. Treatment of the tumour appeared they are associated with inflammatory changes in the CSF. to have more effect on neurological improvement than the Although we did not find anti-cv2 antibodies, which are not use of immunosuppressive therapies. We found similar results consistently associated with PLE, there are 3 reported patients in the literature review of 137 patients (Table 1). Information (2 with SCLC and 1 with thymoma) in whom detection of about the response to treatment was available for 107 anti-cv2 antibodies helped to establish the paraneoplastic patients; 25 (23%) had neurological improvement, in 24 the origin of a limbic dysfunction (Antoine et al., 1995; Honnorat improvement was attributed to tumour treatment, and in 1 it et al., 1996). was attributed to symptomatic treatment (haloperidol). These From our study and review of the literature, no definitive findings, coupled with the high frequency of limited stage treatment is available for PLE. However, early identification disease (88% of our patients, irrespective of antineuronal and treatment of the tumour is the approach that appears to antibody status), underscore the need for prompt detection and offer the greatest chance for neurological improvement. 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 Acknowledgements the design of the study. To explore this possible bias, we We thank Drs James Miller, Nicolas Miret, Ian Sutton, examined the clinical information of a group of 29 patients Francesc Graus, Antoine Carpentier, Jerome Honnorat, Jeanwith memory loss, cognitive dysfunction or confusion Yves Delattre, Charles F. Bolton, Fred Hochberg, Casilda (considered to be paraneoplastic) whose sera were sent to us Balmaceda, Hakan Gurvit, Joseph Landolfi, Michael Homerfor antineuronal antibody testing. When compared with our Ward, Lisa Rogers, Louisa Thoron, Jeffrey Raizer, Bruce group of 50 patients with PLE, the two main discriminating Cree, Daniel Park, Ronald Kanner, Lawrence Haber, Jon diagnostic tests were the MRI studies and antineuronal Wilson and Nuno Antunes, for providing clinical information antibody testing. None of the 29 patients had paraneoplastic and Dr Victor Reuter for the pathological evaluation of the

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