Paraneoplastic Neurological Syndromes And Onconeural Antibodies: Clinical And Immunological Aspects
Introduction
Cancer patients often develop symptoms from organs remote from the primary tumor. The symptoms are usually caused by metastasis or toxic effects of therapy and less often by such secondary factors as nutritional deficiency, metabolic disturbances, opportunistic infections, and effects of critical illness. Other systemic diseases such as diabetes or amyloid may become manifest or aggravated during the course of the cancer disease and cause symptoms from remote organs. Paraneoplastic neurological syndromes (PNS) are a rare cause of remote symptoms [1]. The PNS affect less than 1% of all cancer patients [2]. Even in small cell lung cancer (SCLC), the tumor type most commonly associated with PNS, these disorders occur in less than 5% of the patients [[3], [4]].
The PNS are interesting as excellent examples of naturally occurring tumor immunity [[5], [6]]. In PNS, the relevant tumor antigens belong to the group of antigens normally expressed in immunoprivileged sites only, such as the nervous system, and trigger both cellular and humoral responses [7]. These immune responses may limit tumor growth [8] and improve the response to oncological therapy [[9], [10]]. PNS are sometimes even associated with tumor eradication [11]. However, the immune response also targets normal neurons expressing the same antigens, thereby causing autoimmune neuronal damage.
The clinical characteristics, response to therapy, and prognosis of the different PNS are heterogeneous, but some clinical features are common. First, in most patients, the nervous system symptoms appear before cancer is diagnosed. Second, at this stage, the tumor is small and sometimes undetectable. Third, the usual onset of PNS is subacute and the progression rapid, although the opposite case does not exclude a paraneoplastic etiology. Finally, the neurological symptoms are often very serious, and the patient may die from the effects of the PNS and not cancer itself [12].
Some of the PNS affect multiple elements of the nervous system (paraneoplastic encephalomyelitis, PEM), whereas others involve one group of neurons only (Purkinje cells in paraneoplastic cerebellar degeneration, PCD), or one area (hippocampus in limbic encephalitis, LE). PNS and associated tumors overlap considerably, as some tumors are associated with several different PNS and vice versa (Table 1). Many of the disorders are associated with antibodies directed to antigens shared by tumor and nervous tissue (onconeural antigens). The onconeural antigens are normally expressed in immunoprivileged sites only as cells of the nervous system and germ cells [13].
The term “classical PNS” is reserved for the PNS in which the association with cancer is common and includes encephalomyelitis, limbic encephalitis, paraneoplastic cerebellar degeneration, and paraneoplastic opsoclonus–myoclonus (OM), as well as sensory neuronopathy (SN), chronic gastrointestinal pseudo‐obstruction, Lambert–Eaton myasthenic syndrome (LEMS), and dermatomyositis [14]. This chapter does not include dermatomyositis.
Detection of a well‐characterized onconeural antibody (Table 1) in a patient with suspected PNS definitely diagnoses the condition as paraneoplastic [14]. Thus, the antibodies, when present, are highly useful markers of causation. The various antibodies are also valuable as guidance on the most likely site of malignancy (Table 2). However, investigation is complicated by the fact that many PNS are associated with different onconeural antibodies, and patients often harbor several types of onconeural antibodies [15]. Several antibodies are also associated with heterogenous clinical manifestations [16]. This complexity implicates that the antibodies are markers of cancer more than markers of a specific PNS [16].
The scope of this chapter is to present the clinical features of the major PNS and their associated antibodies, diagnostic procedures and updated aspects of the pathogenesis, and treatment of patients with PNS.
Section snippets
Onconeural Antigens
When Posner et al. [[17], [18]] discovered that PNS patients harbor high titres of autoantibodies in the serum and cerebrospinal fluid (CSF) in the 1980s, this represented a new method of identifying PNS. In the following two decades, antibodies from affected patients have been used to screen complementary DNA (cDNA) expression libraries to identify autoimmunity‐related target antigens [19]. This strategy has led to the identification of most of the onconeural antigens associated with PNS.
The
Paraneoplastic Encephalomyelitis
PEM is one of the most frequent cancer‐associated syndromes. This complex disorder usually affects several areas of the CNS. Cerebellar and brain stem disorders, as well as limbic encephalitis, are the most common clinical presentations of PEM [[31], [32]]. Focal involvement of the sensorimotor cortex has been described in a few cases [33], and PEM may manifest as epileptic seizures or epilepsia partialis continua [[33], [34]], or as extrapyramidal symptoms [35]. Two‐thirds of the patients are
Sensory Neuronopathy
The SN often associated with the Hu antibody is characterized by primary damage to the nerve cell body. The patient suffers from progressive, painful sensory disturbances evolving subacutely, usually with a Rankin score of 3 within 12 weeks of the onset of symptoms [14]. Presenting symptoms include paresthesia, hypoestesia, and very often proprioceptive loss in the affected areas; sensory ataxia is common. The upper limbs are often involved [97]. The distribution of the SN is often atypical for
Paraneoplastic Nervous System Syndromes of the Neuromuscular Junction
Myasthenia gravis, LEMS, and neuromyotonia affect the neuromuscular junction. These disorders are not necessarily associated with malignancy but are sometimes associated with tumors and are regarded as PNS in these patients.
Eighty‐five percent of patients with myasthenia gravis have antibodies to the acetylcholine receptor [133], but only 10–15% of patients with myasthenia gravis have a thymoma. LEMS is much more commonly associated with cancer than myasthenia gravis. LEMS affects individuals
Diagnostic Criteria
The diagnostic considerations in PNS are complex and hardly straightforward. Problematic issues include antibody positivity vs negativity, patients with no detectable tumor and the ongoing characterization of new syndromes as well as new antibody specificities. Guidelines of the diagnostic criteria of PNS have been established by an international network of neurologists, in an effort to clarify and outline the nomenclature and criteria for PNS [14]. According to these guidelines, nervous system
Tumors
With the exception of the Tr antigen, onconeural antigens are invariably expressed in the tumors of patients with antibody‐verified PNS, and failure to find the relevant antigen expressed in a tumor from such patients should prompt investigation for a second tumor [14]. However, onconeural antigens are also expressed in tumors from patients without onconeural antibodies and with no signs of nervous system disease. In particular, tumors derived from neuroendocrine cells express the Hu antigen.
Therapy for Paraneoplastic Nervous System Syndromes
There are two approaches to treating PNS: eradicating the source of the antigen, that is, the tumor, through surgery, radiotherapy, or chemotherapy; and modulating the immune response such as by administering corticosteroids, intravenous immunoglobuline or azathioprine, or depleting IgG (plasma exchange) [[219], [220]]. The single most important factor in managing patients with PNS is identifying and treating the associated tumor as early as possible, but even with complete tumor remission, the
Future Aspects
PNS research has progressed considerably during the past 20 years. The classification of separate disease entities and the improved diagnostic possibilities offered by antibody detection have contributed much to the increased clinical awareness of PNS. Progress made in the research of these diseases has not only elucidated the underlying mechanisms but has also brought new insight into tumor immunology in general. Nevertheless, many questions remain unanswered. The pathogenesis of the PNS and
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