Chapter 52G Cancer and the Nervous System
Paraneoplastic Disorders of the Nervous System
Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of disorders caused by cancers located outside the central nervous system. The pathophysiology of PNSs differs from that of metastases or other cancer complications such as metabolic and nutritional deficits, infections, coagulopathy, and side effects of cancer treatment. PNSs may affect any part of the nervous system (Box 52G.1), and their frequency varies according to the type of syndrome and type of cancer. The onset of symptoms of PNSs often begins prior to the diagnosis of systemic cancer; identification of specific antineuronal antibodies may facilitate the diagnosis. The onset of neurological symptoms is often acute or subacute and frequently associated with inflammatory changes in the cerebrospinal fluid (CSF). Once thought to be poorly responsive to treatment, it is now recognized that certain subgroups of PNSs are highly treatment responsive. For all PNSs, treatment of the tumor is the most effective step in controlling or at least stabilizing the neurological disorder (Graus et al., 2001).
Box 52G.1 Paraneoplastic Neurological Syndromes
Syndromes Affecting the Central Nervous System
Limbic and brainstem encephalitis
Motor neuron syndromes† (ALS, subacute motor neuronopathy, upper motor neuron dysfunction)
Syndromes Affecting the Peripheral Nervous System
Pathogenesis
Most PNSs are immune mediated (Darnell and Posner, 2003). It is believed that the expression of neuronal proteins by a tumor provokes an immune response that is misdirected against the nervous system. This hypothesis is supported by the detection in serum and CSF of antineuronal antibodies that react with antigens expressed by the tumor and the nervous system (Dalmau et al., 1999a) (Table 52G.1). Antibodies that target intracellular antigens (e.g., anti-Hu, Ri, Ma) are most commonly associated with PNSs of the central nervous system. The presence of these antibodies is highly predictive of the presence of a cancer. Antibodies that target cell-surface receptors or ion channels may occur in PNSs of the central (e.g., N-methyl-d-aspartate [NMDAR]) or peripheral (e.g., P/Q type voltage-gated calcium channels [VGCC]) nervous system and may be found in patients with or without cancer (Dalmau et al., 2008; Mason et al., 1997).
Table 52G.1 Paraneoplastic Antineuronal Antibodies, Associated Syndromes, and Cancers
| Antibody | Syndrome | Associated Cancers |
|---|---|---|
| Anti-Hu | Focal encephalitis, PEM, PCD, PSN, autonomic dysfunction | SCLC, other |
| Anti-Yo | PCD | Gynecological, breast |
| Anti-Ri | PCD, opsoclonus-myoclonus | Breast, gynecological, SCLC |
| Anti-Tr | PCD | Hodgkin lymphoma |
| Anti-CV2/CRMP5 | PEM, PCD, peripheral neuropathy chorea, uveitis | SCLC, other |
| Anti-Ma proteins* | Limbic, diencephalic, brainstem encephalitis, PCD | Germ cell tumors of testis, other solid tumors |
| Anti-NMDAR | Limbic encephalitis, seizures, psychiatric symptoms | Teratoma |
| Antiamphiphysin | Stiff man syndrome, PEM | Breast |
| Anti-VGCC† | LEMS, PCD | SCLC |
| Anti-AChR† | MG | Thymoma |
| Anti-LGI1 (previously attributed to VGKC)† | Limbic encephalitis | Thymoma, SCLC |
| Anti-CASPR2 (previously attributed to VGKC)† | Morvan syndrome PNH |
Thymoma |
| Anti-AMPAR | Limbic encephalitis, psychiatric symptoms | Lung, breast, thymus |
| Anti-GABA(B)R | Limbic encephalitis, seizures | SCLC, other neuroendocrine tumor of lung |
| Antirecoverin‡ | Retinopathy | SCLC |
| Antibipolar cells of the retina | Retinopathy | Melanoma |
AChR, Acetylcholine receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR, connectin-associated protein 2; GABA(B)R, γ-amino-butyric acid type B receptor; LEMS, Lambert-Eaton myasthenic syndrome; LGI1, leucine-rich glioma inactivated 1; MG, myasthenia gravis; NMDAR, N-methyl-d-aspartate receptor; PCD, paraneoplastic cerebellar degeneration; PEM, paraneoplastic encephalomyelitis; PNH, peripheral nerve hyperexcitability; PSN, paraneoplastic sensory neuronopathy; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channels.
* Patients with antibodies to Ma2 are usually men with testicular cancer. Patients with additional antibodies to other Ma proteins are men or women with a variety of solid tumors.
† These antibodies can occur with or without a cancer association.
‡ Other antibodies reported in a few or isolated cases include antibodies to tubby-like protein and the photoreceptor-specific nuclear receptor.
Data suggest that cytotoxic T-cell responses mediate disorders associated with antibodies to intracellular antigens. These data include the presence of prominent infiltrates of CD8+ and CD4+ T cells in the nervous system, as well as in vitro studies showing the cytotoxic effect of the lymphocytes on cells expressing the onconeuronal antigens (Albert et al., 1998; Benyahia et al., 1999; Tanaka et al., 1999). Because the T-cell and humoral immune responses appear directed against the same antigens, it is likely that PNSs result from the cooperation of both arms of the immune response.
In contrast, disorders associated with antibodies to cell-surface antigens are more likely antibody mediated. A pathogenic effect has been demonstrated for antibodies against the acetylcholine receptor (AChR) in myasthenia gravis (Drachman, 1994), P/Q type VGCC in Lambert-Eaton myasthenic syndrome (Fukuda et al., 2003), and ganglionic AChR in autonomic ganglionopathy (Vernino et al., 2000). Similarly, a direct effect of antibodies against the target autoantigen has been demonstrated using in vitro and in vivo models for antibodies to NMDA receptor (anti-NMDA receptor encephalitis) (Hughes et al., 2010) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (limbic encephalitis) (Lai et al., 2009).
The characterization of antibodies against intracellular, cell surface, or synaptic antigens has clinical relevance because in general, those related to antibodies to cell-surface or synaptic antigens are more treatment responsive (Tüzün and Dalmau, 2007).
General Diagnostic Approach
The specificity of paraneoplastic antineuronal antibodies for PNSs or some types of cancer makes them useful diagnostic tools (see Table 52G.2). In some 60% of patients with PNS, the neurological symptoms precede the tumor diagnosis, so in the right clinical context, the detection of a paraneoplastic antibody in the serum or CSF helps diagnose the PNS and focus the search for the neoplasm. Most paraneoplastic antineuronal antibodies are also detectable (usually at low titers) in the serum of some patients with cancer without PNSs. This is a consideration when detecting a paraneoplastic antineuronal antibody in the serum of a patient suspected to have PNSs. Consider other causes for the neurological dysfunction if the detected antibody is not usually associated with the neurological syndrome. Similarly, a second neoplasm should be suspected 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 search for another neoplasm is required if the tumor cells do not express the target antigen of the paraneoplastic antibody (Graus et al., 2001). Clinical experience suggests that finding high titers of paraneoplastic antibodies in the CSF is confirmatory evidence of PNSs of the central nervous system.
A set of diagnostic criteria has been developed that takes into consideration the type of syndrome, detection of a tumor, and presence or absence of paraneoplastic antibodies (Graus et al., 2004). The diagnosis of PNSs is relatively straightforward for patients who develop a well-defined syndrome typically associated with cancer. Patient age is important because symptoms often associated with paraneoplastic mechanisms in adults (e.g., subacute cerebellar dysfunction) are less typical in children. Conversely, the development of opsoclonus in children is often paraneoplastic but is less suggestive of a paraneoplastic cause in adults. In these settings, the detection of an antibody known to be associated with PNSs or cancer is practically confirmatory of paraneoplasia. If cancer is not present, assume the presence of an occult neoplasm unless proven otherwise. Body positron emission tomography (PET) scans may detect tumors that escape detection by other standard imaging methods (McKeon et al., 2010; Rees et al., 2001; Younes-Mhenni et al., 2004). Although almost any neoplasm can cause PNSs, the tumors most commonly involved are small-cell lung cancer (SCLC), cancers of the breast, ovary, thymoma, neuroblastoma, and plasma cell tumors. The development of PNSs frequently heralds tumor recurrence in patients with a history of cancer or those who have recently gone into tumor remission.
The diagnosis of PNSs 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 PNSs. Neuroimaging, in particular magnetic resonance imaging (MRI), helps exclude some of these complications. The CSF profile in patients with PNSs of the central nervous system often suggests an inflammatory process: pleocytosis, increased protein concentration, intrathecal synthesis of immunoglobulin (Ig)G, and oligoclonal bands (Psimaras et al., 2010). If paraneoplasia remains a consideration, make every attempt to find the associated neoplasm.
Specific Paraneoplastic Syndromes and Their Treatment
Paraneoplastic Cerebellar Degeneration
Clinical Findings
Rapid onset of severe pancerebellar dysfunction characterizes paraneoplastic cerebellar degeneration (PCD). Clinical features include truncal and appendicular ataxia, dysarthria, and downbeat nystagmus. In adults, the subacute onset of PCD differentiates it from chronic degenerative diseases of the cerebellum. A subset of patients with SCLC develop PCD associated with Lambert-Eaton myasthenic syndrome (LEMS), often before the tumor is diagnosed (Mason et al., 1997). In some cases, one misses the diagnosis of LEMS unless it occurs prior to the onset of PCD.
Tumor Association
Small-cell lung cancer, cancer of the breast and ovary, and Hodgkin lymphoma are the tumors most commonly associated with PCD (Shams’ili et al., 2003).
Immune Responses
Anti-Yo is the most frequent and well-characterized antibody associated with PCD; it is usually associated with breast or gynecological tumors (Peterson et al., 1992). The presence of anti-Yo antibodies has been detected 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, a gynecological cancer, bladder cancer, or SCLC (Luque et al., 1991). These patients may also develop dementia, mixed peripheral neuropathy, axial rigidity, and myoclonus.
In patients with SCLC, the development of PCD may be the presenting symptom of a paraneoplastic encephalomyelitis (PEM). In such cases, other areas of the nervous system become involved and anti-Hu or anti-CV2/CRMP5 antibodies are usually present. Patients with symptoms restricted to cerebellar dysfunction and negative anti-Hu antibodies often harbor VGCC antibodies (Graus et al., 2002). Patients with PCD associated with Hodgkin disease develop anti-Tr antibodies (Graus et al., 1997). The neurological disorder may develop before or after the diagnosis of the lymphoma, sometimes heralding tumor recurrence.
Treatment
Several 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 (Blaes et al., 1999; Shams’ili et al., 2006). However, most patients with PCD do not improve with any of these treatments (Vedeler et al., 2006).
Paraneoplastic Encephalomyelitis
Clinical Findings
Patients with PEM may develop clinical features of dysfunction at several different levels of the neuraxis (Dalmau et al., 1992; Graus et al., 2001; Sillevis et al., 2002). Many patients will develop a sensory neuronopathy (see Paraneoplastic Sensory Neuronopathy [PSN]) and cerebellar dysfunction—in particular, gait ataxia. Limbic and/or brainstem encephalopathy (see Limbic and Brainstem Encephalitis) are common and occur in up to one-third of patients with PEM. Lower motor neuron involvement secondary to myelitis occurs in approximately 20%; the presence of symptoms affecting other areas of the neuraxis helps rule out pure motor neuron disorders. Approximately one-fourth of patients with PEM develop autonomic nervous system dysfunction; symptoms include postural hypotension, gastroparesis and intestinal dysmotility, sweating abnormalities, neurogenic bladder, and impotence. Cardiac dysrhythmias and respiratory or autonomic failures are frequent causes of death. Paraneoplastic chorea and uveitis occur more frequently in a subset of patients with PEM and CV2/CRMP5 antibodies (Vernino et al., 2002).
Tumor Association
PEM, with or without PSN, can be associated with almost any tumor, but in most patients, the underlying tumor is lung carcinoma, particularly SCLC (Graus et al., 2001).
Immune Responses
Patients with PEM/PSN and SCLC often have anti-Hu and at a much lower frequency, anti-CV2/CRMP5 antibodies, or both. In these patients, neurological symptoms usually precede the cancer diagnosis. Anti-CV2/CRMP5 antibodies are also associated with thymoma and other cancers (Benyahia et al., 1999).
Limbic and Brainstem Encephalitis
Clinical Findings
Limbic encephalitis is one of the few PNSs in which neuroimaging is often useful (Fig. 52G.1). Typical MRI findings include unilateral or bilateral mesial temporal lobe abnormalities, best seen on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Ances et al., 2005; Gultekin et al., 2000). The temporal-limbic regions may be hypointense on T1-weighted sequences and may enhance with contrast.
Tumor Association
Limbic and brainstem encephalitis occur in both paraneoplastic and non-paraneoplastic settings. The cancers most commonly associated are SCLC, testicular germ-cell tumors, teratoma (usually of the ovary), thymoma, and Hodgkin lymphoma (Gultekin et al., 2000).
Immune Responses
The classification of immune responses in limbic and brainstem encephalitis is according to the location of the target antigen: intracellular or cell surface. The main intracellular antigens are Hu, Ma2, and less commonly, CV2/CRMP5. In patients with Hu antibodies, limbic encephalitis is a fragment of PEM, although the limbic encephalitis may predominate or be the initial presenting symptom (Dalmau et al., 1992). Patients often have signs of pontine dysfunction that progresses downward, with involvement of other areas of the neuraxis becoming more prominent with time. Most of these patients have SCLC.
Men younger than 45 years of age with symptoms of limbic, hypothalamic, and brainstem dysfunction are likely to have antibodies to Ma proteins and an underlying germ-cell tumor of the testis (Dalmau et al., 1999b; Hoffmann et al., 2008; Mathew et al., 2007). Ma antibodies are also encountered in older patients with similar neurological symptoms and other cancers (Dalmau et al., 2004). In contrast to patients with Hu antibodies, patients with Ma antibodies usually have a predominant mesencephalic syndrome with vertical gaze palsies (Saiz et al., 2009).
Antibodies to CV2/CRMP5 are seen in association with encephalomyelitis, sensorimotor neuropathy, cerebellar ataxia, chorea, uveitis and optic neuritis (Honnorat et al., 1997). Neurological findings rarely stay confined to the limbic and brainstem structures, and patients will often have frontostriatal and basal ganglia disturbances such as obsessive-compulsive behavior and cognitive deficits. CV2/CRMP5 antibodies can co-occur with anti-Hu or Zic antibodies, in which case patients often have multifocal deficits or PEM.
Patients with AMPA receptor antibodies usually present with acute limbic dysfunction or, less frequently, with prominent psychiatric symptoms (Graus et al., 2010; Lai et al., 2009). These disorders most commonly affect middle-aged women; about 70% have an underlying tumor in the lung, breast, or thymus.
Patients with antibodies to LGI1 develop memory disturbances, confusion, and seizures. Some patients develop hyponatremia or rapid eye movement (REM) sleep behavior disorders such as dream-enacting behavior and abnormal REM sleep patterns (Iranzo et al., 2006; Vincent et al., 2004). Most patients with limbic encephalitis and LGI1 antibodies do not have an underlying neoplasm. Only 20% of cases are paraneoplastic, and the commonly associated tumors are SCLC and thymoma (Pozo-Rosich et al., 2003). LGI1 is a secreted epilepsy-related protein that interacts with pre- and postsynaptic receptors (ADAM23 and ADAM22) (Lai et al., 2010). Mutations of LGI1 are associated with the syndrome of autosomal dominant lateral temporal lobe epilepsy (Gu et al., 2002; Kalachikov et al., 2002).
The encephalitis associated with GABA-B receptor antibodies is usually a limbic encephalitis and seizures. Approximately half of patients have an SCLC or a neuroendocrine tumor of the lung (Lancaster et al., 2010). These patients have a tendency to autoimmunity and frequently have additional antibodies to glutamic acid decarboxylase (GAD) and several non-neuronal proteins of unclear significance.
Limbic encephalitis with temporal lobe seizures occurs in association with GAD antibodies. The disorder is similar to other autoimmune limbic encephalitis; it is usually not paraneoplastic and is refractory to treatment (Blanc et al., 2009; Malter et al., 2010). Some patients have other more relevant antibodies against cell-surface antigens that may be causing the symptoms (Lancaster et al., 2010).
Treatment
Limbic encephalitis is the most likely PNS to improve with tumor treatment and immunomodulation with steroids and IVIg (Gultekin SH et al., 2000). The likelihood of improvement is higher if the disorder is associated with antibodies to cell-surface receptors or ion channels. Data suggest that in such cases, the antibodies are pathogenic; removal of the antigenic source (tumor) and antibodies with antibody-depleting treatments are often successful (Tüzün and Dalmau, 2007).
