Paraneoplastic Neurological Syndromes And Onconeural Antibodies: Clinical And Immunological Aspects

1. Abstract

Paraneoplastic neurological syndromes (PNS) are infrequent disorders that are associated with cancer. The syndromes are highly heterogeneous and often affect several areas of the nervous system. Among the most well‐known syndromes are paraneoplastic encephalomyelitis, cerebellar degeneration, sensory neuronopathy, and Lambert–Eaton myastenic syndrome. There are various associated tumors, in particular small cell lung cancer, cancer of the breast and ovary, and thymoma. The onset of neurological symptoms often precedes the cancer diagnosis, and the recognition of a paraneoplastic syndrome should lead to immediate search for cancer. The etiology of the paraneoplastic syndromes is believed to be autoimmune. Antibodies to onconeural antigens, expressed in the tumor of the affected individual and in normal neurons, are found in many of the patients. These antibodies are useful markers for paraneoplastic etiology. The pathogenesis of the PNS is uncertain, but cellular immune responses are thought to be the main effector mechanism.

The cornerstone of therapy is the identification and treatment of the underlying malignancy. In some of the disorders, immunosuppressive therapy is of additional benefit. The prognosis of the different PNS varies depending on the level of affection and the degree of neuronal death.

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.