Paraneoplastic Disorders of the Nervous System

Pathogenesis

Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of disorders that are immune mediated ( Table 81.1 ). It is postulated that the expression of neuronal proteins (called onconeuronal proteins) by a tumor provokes an immune response that is misdirected against the nervous system. This hypothesis is supported by the detection in the serum and cerebrospinal fluid (CSF) of anti-neuronal antibodies that react with antigens expressed by the tumor and the nervous system ( ). Antibodies that target intracellular antigens (e.g., anti-Hu, Ri, Ma2) are most commonly associated with PNS of the central nervous system (CNS). The detection of one of these antibodies is highly predictive of the presence of a cancer ( Table 81.2 ). The PNSs associated with antibodies to intracellular antigens are likely mediated by cytotoxic T-cell responses that produce irreversible neuronal cell death, explaining why many PNSs are not reversible. Since the T cells appear to be directed against the same antigens as the antibodies, the antibodies and the T cells likely play cooperating roles in the pathogenesis of the PNSs that have yet to be defined ( ). Other antibodies, in particular those that target antigens on the neuronal cell surface (e.g., acetylcholine receptor [AChR] or γ-aminobutyric acid type B receptor [GABAbR]) occur with specific neurological syndromes regardless of the presence or absence of cancer. These antibodies are pathogenic and act by binding to and altering the function of the target antigens ( ). Cytotoxic T-cell mechanisms are not involved and the antibody effects are reversible. Thus these disorders often respond to treatment of the associated cancer (when paraneoplastic) and B-cell or antibody depleting strategies.

General Diagnostic Approach

The specificity of paraneoplastic anti-neuronal antibodies for PNSs or some types of cancer makes them useful diagnostic tools (see Table 81.2 ). In approximately 65% of patients with PNS, the neurological symptoms precede the tumor diagnosis ( ). Therefore in the right clinical context the detection of a paraneoplastic antibody in the serum or CSF helps to diagnose the PNS and focus the search for the neoplasm ( ). Most paraneoplastic neuronal antibodies can also be detected, usually at low titers, in the serum of a variable proportion of patients with cancer but without PNS ( ). Therefore, if the detected antibody does not correspond with the antibody that usually associates with the neurological syndrome, other causes for the neurological dysfunction should be considered. Similarly, if the detected cancer is not the histological type typically found in association with the antibody (e.g., anti-Yo with lung cancer rather than breast or ovarian cancer), a second neoplasm should be suspected. A search for another neoplasm is required if the tumor cells do not express the target antigen of the paraneoplastic antibody ( ). Clinical experience suggests that detection of paraneoplastic antibodies in CSF confirms that the neurological disorder is paraneoplastic.

The diagnosis of PNS can be made to different degrees of certainty by taking into consideration the type of syndrome, detection of a tumor, and presence or absence of paraneoplastic antibodies ( ). The diagnosis of PNS is relatively straightforward for patients who develop symptoms of a well-defined syndrome that is typically associated with cancer. Patient age is important because symptoms that associate with paraneoplastic mechanisms in adults (e.g., subacute cerebellar dysfunction) are less typical of paraneoplasia in children. Conversely, the development of opsoclonus in children is often paraneoplastic, but in adults is less suggestive of a paraneoplastic cause. In these settings, the detection of an antibody known to be associated with PNS or cancer is practically confirmatory of paraneoplasia. If a cancer is not discovered, the presence of an occult neoplasm is assumed unless proven otherwise. Body [ ¹⁸ F] ^- fluorodeoxyglucose-positron emission tomography (FDG-PET) scans can detect tumors that escape detection by other standard imaging methods ( ). Although almost any type of neoplasm can cause PNS, the tumors more frequently involved are small-cell lung cancer (SCLC); cancers of the breast and ovary; thymoma, neuroblastoma, and plasma cell tumors. The development of PNS frequently heralds tumor recurrence in patients with a history of cancer or those who have recently gone into tumor remission.

The diagnosis of PNS is more difficult in patients who develop less characteristic symptoms (e.g., brainstem dysfunction, myelopathy), especially if no antibodies are found in the serum or CSF. Most PNSs have an acute or subacute onset compared with noninflammatory neurodegenerative disorders that are chronically progressive. If the patient is known to have cancer, the possibility of metastases and nonmetastatic neurological complications of cancer (side effects of treatment, metabolic encephalopathy, infection, or cerebrovascular disorders resulting from coagulopathy) should be considered before the diagnosis of PNS. Novel immunotherapeutic treatment strategies such as chimeric antigen receptor (CAR) T cells and immune checkpoint inhibitors can produce a wide variety of immune-related neurological complications, including CAR T-cell–related encephalopathy caused by cytokine-release syndrome ( ), or immune-related adverse events caused by immune checkpoint blockade. In fact, there is evidence that immune checkpoint blockade can favor the development of PNS, which may be associated with classic paraneoplastic neuronal antibodies targeting intracellular antigens or antibodies against neuronal cell surface antigens ( ).

Neuroimaging, in particular magnetic resonance imaging (MRI), helps to exclude some of these complications. Brain FDG-PET in the early stages of some PNS of the CNS may show hypermetabolism in the involved regions even when MRI is normal, and may be indicative of early inflammatory changes ( ; ). The CSF profile in patients with PNS of the CNS often suggests an inflammatory process: pleocytosis, increased protein concentration, intrathecal synthesis of immunoglobulin (Ig)G, and oligoclonal bands ( ).

Specific Paraneoplastic Neurological Syndromes and Their Treatment

Paraneoplastic Cerebellar Degeneration

Paraneoplastic cerebellar degeneration (PCD) is characterized by the rapid development of severe pancerebellar dysfunction, including truncal and appendicular ataxia, dysarthria, and downbeat nystagmus. Frequently the symptoms of cerebellar dysfunction are preceded by dizziness and vertigo, suggesting peripheral vestibular dysfunction. In adults, the subacute onset of PCD differentiates it from chronic degenerative diseases of the cerebellum. A subset of patients with SCLC develops PCD associated with Lambert-Eaton myasthenic syndrome (LEMS), often before the tumor is diagnosed ( ). In some cases LEMS may be overlooked unless it occurs prior to the onset of PCD. The tumors more frequently associated with PCD are SCLC, breast and ovarian tumors, and Hodgkin lymphoma ( ). Anti-Yo (PCA1) is the most frequent antibody found in PCD and is usually associated with breast or gynecological tumors ( ). Anti-Yo antibodies have been identified in a few male patients with PCD and cancer of the salivary gland, lung, and esophagus. Some patients with predominant truncal ataxia, opsoclonus, and other ocular movement abnormalities may harbor an antibody called anti-Ri. In such cases, the tumor is usually a breast carcinoma or, less frequently, gynecological cancer, bladder cancer, or SCLC ( ). These patients may also develop dementia, peripheral neuropathy, axial rigidity, myoclonus, brainstem encephalitis, and laryngeal spasms ( ).

In patients with SCLC the development of PCD may be the presenting symptom of paraneoplastic encephalomyelitis (PEM) in which case other areas of the nervous system become involved and anti-Hu or anti-CV2/CRMP5 antibodies are usually identified ( Fig. 81.1 ). Patients with symptoms restricted to cerebellar dysfunction and negative anti-Hu antibodies often harbor voltage-gated calcium channel (VGCC) antibodies ( ). Patients with PCD associated with Hodgkin disease develop Tr antibodies ( ); these antibodies are directed against Delta/Notch-like epidermal growth factor-related receptor (DNER). The neurological disorder may develop before or after the diagnosis of the lymphoma, sometimes heralding tumor recurrence. Sox1 antibodies are found in about 50% of patients with PCD and SCLC but are not found when PCD is associated with other cancers ( ).

Antibodies reported in isolated cases or small series of patients with acute to subacute onset ataxia and cancer have been shown to target protein kinase Cγ (PKCγ), carbonic anhydrase related protein 8 (CARPVIII), or tripartite motif-containing (TRIM) protein 9 or TRIM protein 67 ( ). These antibodies should be considered in patients for whom there is a strong suspicion of PCD and who do not have any of the more common PNS-associated antibodies.

Several single case reports describe patients with PCD who improved after treatment of the tumor, plasma exchange, intravenous immunoglobulin (IVIG), rituximab, or immunosuppression with cyclophosphamide or corticosteroids ( ; ). However, due to early, irreversible neuronal loss most patients with PCD do not improve with any of these treatments ( ) (see Fig. 81.1 ).