NEUROLOGICAL REVIEW Paraneoplastic Syndromes Josep O. Dalmau, MD, PhD; Jerome B. Posner, MD he fact that a small cancer hidden in the chest, abdomen, or pelvis could destroy or damage portions of the nervous system, such as cerebellar Purkinje cells or choliner- gic synapses, has intrigued neurologists since paraneoplastic syndromes were first de- scribed. In 1965, when little was known about their pathogenesis, a full issue of the Tjournal Brain and an international symposium were devoted to paraneoplastic disorders. In this decade, the discovery of several paraneoplastic antibodies that react with both the nervous system and the causal cancer has rekindled interest in these syndromes (Table). Several other factors make these rare syndromes of clinical and scientific interest. A recent review by Dalmau and Posner1 contains a more comprehensive bibliography of paraneoplastic syndromes. These disorders challenge the diagnostic both patients, cancer of the breast was skills of the neurologist. The patient’s can- subsequently discovered. The anti-Ta an- cer has usually not yet been discovered tibody seems to be specific for testicular and, because other inflammatory disor- cancer. ders of the nervous system can mimic para- Paraneoplastic syndromes are a thera- neoplastic syndromes, the diagnosis is of- peutic challenge for the neurologist. With ten difficult. However, paraneoplastic the exception of myasthenia gravis, the antibodies, in most (but not all) in- Lambert-Eaton myasthenic syndrome, neu- stances, unequivocally establish that the romyotonia, dermatomyositis, and cer- disorder is paraneoplastic. tain peripheral neuropathies associated with The disorders challenge the diagnos- myeloma, treatment of paraneoplastic syn- tic skills of the oncologist. The underly- dromes is generally unsatisfactory. ing cancer may be so small as to be unde- Paraneoplastic syndromes are a thera- tectable by even the most sophisticated peutic challenge for the oncologist. Sub- imaging techniques. Fortunately, many stantial evidence suggests that in patients paraneoplastic antibodies also point to the with paraneoplastic antibody-positive se- most likely underlying tumor. For ex- rology, the neoplasms grow more indo- ample, the anti-Hu antibody indicates the lently and are less likely to metastasize than presence of a small cell lung cancer and in patients with the same cancer who are the anti-Yo antibody, the presence of an not antibody positive or who do not have ovarian or breast cancer. So strong is the paraneoplastic symptoms.2 Recent animal association of the anti-Yo antibody with data support these conclusions.3 If the neu- gynecologic cancers that we and others rec- rologist chooses to treat the neurologic ommend hysterectomy and salpingo- symptoms with immune suppression, it is oophorectomy in anti-Yo–positive post- possible that the oncologist will be faced menopausal patients with normal with a more rapidly growing tumor. mammograms, even in the absence of posi- Paraneoplastic antibodies react with tive imaging studies of the pelvis. In only both the cancer and the nervous system. 2 patients of whom we are aware has a can- These antibodies identify antigens, pres- cer not been found at pelvic surgery. In ent normally only in the nervous system (usually in neurons), but for uncertain rea- From the Department of Neurology, Memorial Sloan-Kettering Cancer Center, New sons expressed ectopically in certain tu- York, NY. mors. The immune system recognizes the ARCH NEUROL / VOL 56, APR 1999 405 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Antineuronal Antibody–Associated Paraneoplastic Disorders* Onconeuronal Antibody Associated Cancer Syndrome Antigen Antigen Anti-Hu SCLC and neuroblastoma Encephalomyelitis, sensory neuronopathy All neuronal nuclei, 35-40 kd HuD, HuC, and Hel-N1 Anti-Yo Gynecologic and breast Cerebellar degeneration Cytoplasm Purkinje cells, CDR34, CDR62-1, 34 and 62 kd and CDR62-2 Anti-Ri Breast, gynecologic, Cerebellar ataxia, opsoclonus Neuronal nuclei CNS, NOVA1 and NOVA2 and SCLC 55 and 80 kd Antiamphiphysin Breast Stiff-man, encephalomyelitis Synaptic vesicles, 128 kd Amphiphysin Anti-VGCC SCLC Lambert-Eaton myasthenic syndrome Presynaptic VGCC a1-Subunit Anti-MysB SCLC Lambert-Eaton myasthenic syndrome Presynaptic VGCC b-Subunit VGCC Anti-Ma Multiple Cerebellar, brainstem dysfunction Neuronal nuclei and cytoplasm, Ma1 and Ma2 37 and 40 kd Anti-Ta Testicular Limbic encephalitis, brainstem dysfunction Neuronal nuclei and cytoplasm, 40 kd Ma2 Anti-Tr Hodgkin lymphoma Cerebellar degeneration Cytoplasm neurons, Purkinje cells, In progress and spiny dendrites Anti-CAR SCLC and others Photoreceptor degeneration Retinal photoreceptor, 23 kd Recoverin Anti-CV2 SCLC and others Encephalomyelitis, cerebellar degeneration Glia (subset), 66 kd POP66 *Data modified from Dalmau and Posner.1 SCLC indicates small cell lung cancer; CNS, central nervous system; VGCC, voltage-gated calcium channels; and CAR, carcinoma-associated retinopathy. proteins expressed by the tumor as foreign and mounts acute sensory neuronopathy associated with lung can- an immune attack that partially controls tumor growth cer had in their serum a low-titer antibody that reacted (in some instances it appears to destroy the tumor so that with the cytoplasm [sic] of neurons in the guinea pig ce- no tumor is found even at autopsy). The immune reac- rebral cortex. No additional information was forthcom- tion also attacks portions of the nervous system that ex- ing until 1985, when Graus and colleagues7 described first press the antigen. The pathogenesis of some syndromes 2 and later 4 patients with subacute sensory neuropathy (myasthenia gravis, Lambert-Eaton myasthenic syn- associated with small cell lung cancer who had in their drome, neuromyotonia) is mediated by antibodies but, serum high titers of a complement-fixing antibody that for the majority of antibody-associated paraneoplastic syn- reacted predominantly with the nuclei of central and pe- dromes of the central nervous system (CNS), the major ripheral nervous system neurons. The Hu antigens cor- pathogenic mechanism appears to be related to cyto- respond to a set of proteins of 35 to 40 kd on Western toxic T-cell responses.4 blot using either neuronal or small cell lung cancer pro- In paraneoplastic syndromes affecting the CNS, in- tein extracts. Subsequently, it has become evident that flammatory infiltrates of T cells and plasma cells are found the anti-Hu antibody is a marker not only of sensory both in the nervous system and in the cancer. Further- neuronopathy but also of encephalomyelitis. more, IgG normally absent from the CNS can be found Subsequent work has identified several proteins be- not only within the neuropil but also within neurons. Elu- longing to the Hu family. All of these have high homol- tion studies indicate that the antibody found in the brain ogy with the Drosophila embryonic lethal abnormal vi- and the tumors of patients with paraneoplastic syn- sual (ELAV) protein, necessary for the development of dromes is the same antibody that reacts with onconeu- the eye and the CNS of the fly. All Hu proteins, includ- ral antigens.5 ing HuD, HuC, Hel-N1, and HuR, contain 2 tandem RNA Because onconeural antigens are normally present recognition motifs (RRM), a basic domain, and a third only in neurons, it is likely that they are important for neu- RRM. The basic domains of HuD, Hel-N1, and HuC are ral development and phenotype maintenance. Accord- alternatively spliced yielding HuDpro, HuDmex, Hel- ingly, we and others have used paraneoplastic antibodies N2, and HuC isoforms. The expression of HuD, HuC, and to probe complementary DNA expression libraries to clone Hel-N1 is restricted to neurons, but HuR is reported to the antigen(s) identified by these antibodies (Table). With be ubiquitously expressed in extraneuronal tissues.8 These respect to those antigens that have been identified so far, proteins bind to AU-rich elements, which are present in the molecular analysis appears to confirm that onconeu- the 39-untranslated region of messenger RNA (mRNA), ral antigens are important to neuronal function. The re- that regulate cell proliferation (ie, c-fos, c-Myc, Gap43, mainder of this article will address the question of the func- and GM-CSF). The exact function of the Hu proteins re- tion of some onconeural antigens. mains unknown, but it has been postulated that they act as transfactors involved in selective mRNA degradation. Hu ANTIGENS The anti-Hu antibodies bind to the first and second RRM of HuD, HuC, and Hel-N1 but not HuR; it is un- The term Hu antigens refers to a family of nuclear pro- known how the binding of anti-Hu antibodies may af- teins normally expressed in all neurons of the central and fect the function of these proteins, but for HuD the first peripheral nervous system but not in other cell types (with and second RRM are essential for RNA binding. the possible exception of the testes). The antigen was prob- Although a study of the developing mouse nervous ably first identified by Wilkinson and Zeromski6 in 1965, system has demonstrated a hierarchy of expression of the when they reported that 4 patients suffering from sub- Hu proteins, in the adult mouse, all Hu proteins appear ARCH NEUROL / VOL 56, APR 1999 406 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 to be expressed in most brain regions.9 The same study cho et al,13 is a 34-kd protein that consists of 34 inexact showed that dorsal root ganglia, which in about 70% of tandem repeats of a hexapeptide. Amino acids 2, 3, 4, and patients with the anti-Hu syndrome is the initial target 6 in this hexapeptide are invariably leucine, glutamate, of the disease, has a robust expression of the 4 mouse aspartate, and aspartate, respectively. Amino acids 1 and Hu homologs. The Hu proteins are an early marker of 5 are more variable—1 being leucine or phenylalanine neuronal development.10 Although not present in neu- and 5 being methionine or valine.