PARANEOPLASTIC DISORDERS OF THE NERVOUS SYSTEM

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CHAPTER 101 PARANEOPLASTIC DISORDERS OF THE NERVOUS SYSTEM

Paraneoplastic neurological disorders (PNDs) are an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are mostly immune mediated (Table 101-1).1 PNDs are more frequent than previously considered, with an incidence that varies with each type of tumor. The tumors most frequently involved are small cell lung cancer (SCLC) (∼3% of patients develop PND), thymoma (15%), and plasma cell dyscrasias associated with malignant monoclonal gammopathies (∼5% to 15%). With other solid tumors, the incidence of PND is less than 1%.2

TABLE 101-1 Classification of Immune-Mediated Paraneoplastic Neurological Disorders

Area Involved Classical Syndromes Nonclassical Syndromes
Central nervous system Encephalomyelitis Brainstem encephalitis
Limbic encephalitis Stiff-person syndrome
Cerebellar degeneration Necrotizing myelopathy
Opsoclonus-myoclonus Motor neuron disease
Dorsal root ganglia or peripheral nerves Subacute sensory neuronopathy Acute sensorimotor neuropathy (Guillain-Barré syndrome, plexitis)
Gastrointestinal paresis or pseudoobstruction Subacute and chronic sensorimotor neuropathies
Neuropathy of plasma cell dyscrasias and lymphoma
Vasculitis of the nerve and muscle
Pure autonomic neuropathy
Muscle Dermatomyositis Acute necrotizing myopathy
Polymyositis
Neuromuscular junction Lambert-Eaton myasthenic syndrome Myasthenia gravis
Acquired neuromyotonia
Eye and retina Cancer-associated retinopathy Optic neuritis
Melanoma-associated retinopathy

In 60% of patients with PND, symptoms develop before the presence of a tumor is known; the majority of these patients are seen by neurologists, who should be aware that prompt diagnosis and treatment of the tumor along with immunotherapy may stabilize or improve the PND. In 40% of patients, symptoms of PND develop after the tumor diagnosis or at tumor recurrence. In this group of patients, the differential diagnosis is extensive because PND may mimic many other neurological complications of cancer or its treatment. The diagnosis of PND has been facilitated by serological tests that are based on the detection of antineuronal antibodies in the patients’ serum or cerebrospinal fluid (CSF), but in at least 40% of patients, no antibodies are detected, and in some instances, the antibodies can be detected in patients who have cancer but not PND.3 Therefore, although testing for these antibodies is useful, it does not replace the importance of a comprehensive clinical assessment that should always rule out other complications of cancer. In addition to the immune-mediated PNDs, patients with cancer may develop neurological symptoms from a large and heterogeneous group of mechanisms unrelated to metastasis; these are not further discussed but are listed in Table 101-2.

TABLE 101-2 Nonmetastatic Neurological Complications of Cancer Different from Immune-Mediated Paraneoplastic Neurological Disorders

Syndrome Proposed Mechanism
Cerebrovascular disease Coagulopathy
Wernicke-Korsakoff syndrome Thiamine deficiency
Myelopathy, sensory neuropathy Cobalamin deficiency
Pellagra-like syndrome Niacin deficiency in carcinoid tumors
Diffuse metabolic encephalopathy Hypoxia, organ failure, electrolyte imbalance, endocrine disorders
Opportunistic CNS infections Cancer- or treatment-related immunodeficiency
POEMS neuropathy Cytokines (IL-6, IL-1β, TNF-α), MMP, VEGF
Carcinoid myopathy Increased serotonin secretion by carcinoid tumors
Cachectic myopathy Proteolytic tumor-derived “toxohormone”-like peptides, cytokines (TNF-α, IFN γ, IL-6, IL-1β)

CNS, central nervous system; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinases; POEMS, syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

IMMUNOPATHOGENESIS OF PARANEOPLASTIC NEUROLOGICAL DISORDERS AND EFFECTS ON THE TUMOR

Paraneoplastic Neurological Disorders of the Central Nervous System

Many of these disorders occur in association with immune responses against intraneuronal antigens expressed by the underlying cancer (paraneoplastic or onconeuronal antigens). These immune responses are characterized by the presence of antibodies and cytotoxic T cell responses against the onconeuronal antigens. As far as the antibodies are concerned, there have been several attempts to reproduce PND by passive transfer of serum or immunoglobulin G (IgG) to animals or by immunization with recombinant antigens that prime B cell responses.46 These procedures did not result in neurological dysfunction, although immunization did result in high titers of serum antibodies.7 It has been argued that the antibodies cannot reach the intracellular antigens, but data from other immune-mediated disorders suggest that antibodies can enter cells and disrupt the function of the antigen.8 Prior studies may have failed in part because they did not reproduce the continuous intrathecal synthesis of antibodies that occurs in patients with PND.

As far as the T cell response is concerned, a pathogenic role was initially suggested by the neuropathological findings in autopsy studies of patients with PND.9 These studies demonstrated prominent infiltrates of inflammatory cells, later characterized as CD4+ and CD8+ T cells that are usually accompanied by microglial activation and gliosis (Fig. 101-1).10,11 Analysis of the presence of antigen-specific T cells in the peripheral blood and brain infiltrates of patients and studies of antigen presentation by dendritic cells or fibroblasts modified to express the paraneoplastic antigens provide strong evidence of a role of cytotoxic T cells.1215 An attempt to model the disease in animals by priming the T cell response resulted in minimal perivascular inflammatory infiltrates but did not reproduce the disease or result in interstitial T cell infiltrates with neuronophagia that occur in patients.16

Overall, these studies suggest that both antibody and cytotoxic T cell responses are probably necessary to cause neuronal injury. This concept is important not only for modeling the disease but also for the development of treatment strategies for PNDs of the central nervous system (CNS).

GENERAL APPROACH TO THE DIAGNOSIS OF PARANEOPLASTIC NEUROLOGICAL DISORDERS

The diagnosis of PNDs is usually based on (1) the recognition of the neurological syndrome, (2) the demonstration of the associated cancer, and (3) the detection of serum and CSF paraneoplastic antibodies.3

Recognition of the Neurological Syndrome

An extensive group of disorders similar to PNDs may occur in the absence of cancer (Table 101-3). However, some syndromes are associated with cancer much more frequently than others, or the clinical features are characteristic enough that they readily suggest a paraneoplastic etiology. These syndromes are considered “classical PNDs” (see Table 101-1). Other syndromes may result from paraneoplastic mechanisms but occur more frequently in the absence of cancer. These syndromes are considered “nonclassical” and necessitate a more extensive differential diagnosis. For example, a brainstem syndrome, chorea, or the Guillain-Barré syndrome may be paraneoplastic manifestations of cancer but are mostly not cancer related, or their development in a patient with cancer may simply be coincidental.

TABLE 101-3 Differential Diagnosis of Paraneoplastic Neurological Disorders of the Central Nervous System

Paraneoplastic Neurological Disorder Differential Diagnosis Additional Considerations in Patients Known to Have Cancer
Cerebellar degeneration Alcohol-related degeneration Cerebellar metastasis
Vitamin deficiency (B1, E) Chemotherapy toxicity (5-FU, Ara-C)
Toxins (anticonvulsants, other)
Infectious or postinfectious cerebellitis
Miller-Fisher syndrome
GAD-associated ataxia
Gliadin-associated ataxia
Idiopathic degeneration
Limbic encephalitis Viral encephalitis (HSV) Brain metastasis
Nonparaneoplastic (anti-VGKC) encephalitis HHV 6 infection (particularly after bone marrow transplantation)
Temporal lobe tumor
Systemic lupus erythematosus
Doxifluridine toxicity
Toxic-metabolic encephalopathy
Hashimoto’s encephalitis
Sjögren’s syndrome
Idiopathic encephalitis
Sensory neuronopathy Sjögren’s syndrome Chemotherapy (cisplatin, paclitaxel, docetaxel, vincristine)
Toxins (pyridoxine)
Idiopathic neuronopathy
Opsoclonus-myoclonus Infectious, postinfectious encephalitis Brain metastasis
Metabolic encephalopathy
Toxins
Idiopathic encephalitis

Ara-C, cytosine arabinoside; 5-FU, 5-fluorouracil; GAD, glutamic-acid decarboxylase; HHV, human herpesvirus; HSV, herpes simplex virus; VGKC, voltage-gated potassium channel.

Most PNDs develop and progress rapidly until stabilization in a few weeks or months, causing severe disability. Patients often become wheelchair bound or bedridden over a short period of time. PNDs that affect the CNS, dorsal root ganglia, or proximal nerve roots are often accompanied by lymphocytic pleocytosis, an elevated IgG index, the presence of oligoclonal bands, or intrathecal synthesis of paraneoplastic antibodies. However, similar CSF abnormalities can be encountered in any inflammatory or immune-mediated disorder of the CNS, and some patients with PNDs may have normal findings on CSF studies. In most instances, CSF studies are necessary to rule out other cancer complications, such as leptomeningeal metastasis.26

All patients with PNDs of the CNS and some peripheral nerve syndromes (e.g., plexopathies) should undergo neuroimaging evaluation of the involved area. Magnetic resonance imaging (MRI) is the best technique for ruling out metastatic lesions or other complications that may suggest a PND. In most PNDs of the CNS, the function of the blood-brain barrier is preserved, and therefore the affected brain regions are rarely enhanced with contrast material. The abnormalities are usually demonstrated with T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences. In syndromes such as limbic encephalitis with predominant hippocampal involvement (short-term memory loss, seizures), the MRI findings are often suggestive of the syndrome, although the etiology could be nonparaneoplastic.27 There is also increasing evidence that brain [F18] fluorodeoxyglucose positron emission tomography (FDG-PET) has diagnostic usefulness in PNDs.28 In the early stages of PNDs, FDG-PET may show hypermetabolism in the abnormal brain regions identified by MRI, but in some patients, the MRI findings are normal.29

Biopsy of an abnormal brain region identified by MRI or FDG-PET may be considered if a neoplastic process is suspected or if the clinical, CSF, and MRI findings are unusual. Abnormalities supporting but not specific to PND include infiltrates of mononuclear cells, neuronophagic nodules, neuronal degeneration, microglial proliferation, and gliosis.30

Demonstration of Associated Cancer

PNDs usually develop at early stages of cancer, and therefore the tumor (or tumor recurrence) may be difficult to demonstrate. Modern imaging techniques are able to demonstrate small tumors that were often missed by techniques used previously. In most instances, the tumor is revealed by computed tomography of the chest, abdomen, and pelvis. The type of syndrome and paraneoplastic antibody may suggest a specific underlying tumor and the need for additional tests, such as mammography or ultrasonography of the pelvis or testes. Whole-body FDG-PET is very useful in demonstrating occult neoplasms or small metastatic lesions that may be more accessible for biopsy than the primary tumor is (Fig. 101-2).31 In addition to imaging studies, serum cancer markers such as carcinoembryonic antigen, CA-125, CA-15.3, or prostate-specific antigen are helpful. All patients with a neuropathy of unclear etiology should be examined for the presence of a monoclonal gammopathy in the serum and urine and, if results are positive, undergo a skeletal survey and bone marrow biopsy; these studies may uncover a malignant plasma cell dyscrasia, amyloidosis, or B cell lymphoma.2

Close oncological surveillance should be undertaken in patients with classical PNDs with or without paraneoplastic antibodies and in patients with nonclassical PND and paraneoplastic antibodies. It is recommended that patients undergo periodic cancer screening for at least 5 years after diagnosis of PNDs; in 90% of patients, the underlying tumor is discovered within the first year of PND symptom manifestation. Patients whose cancer is in remission and who develop PNDs should be examined for tumor recurrence.

Detection of Paraneoplastic Antibodies

Paraneoplastic antibodies are antibodies whose presence serves as a marker of the paraneoplastic origin of a neurological syndrome. Several concepts are important in testing for paraneoplastic antibodies (Table 101-4). First, antibodies are present in approximately 60% of patients with PNDs of the CNS; therefore, the absence of antibodies does not preclude a paraneoplastic syndrome. Second, paraneoplastic antibodies may be identified (usually at low titers) in the serum of a variable proportion of patients with cancer but without PND (i.e., anti-Hu and anti-CV2/CRMP5 in 20% and 10% of patients with SCLC, respectively).32,33 Third, in PNDs of the CNS, the antibodies are found in serum and CSF; detection of CSF antibodies is a strong indicator that the associated neurological syndrome is paraneoplastic. Fourth, most PNDs of the peripheral nerve or muscle are not associated with paraneoplastic antibodies, except for anti-Hu (Fig. 101-3) and anti-CV2/CRMP5 antibodies. Fifth, not all paraneoplastic antibodies have the same sensitivity and specificity; on the basis of their clinical relevance, the paraneoplastic antibodies are classified in two categories: well-characterized paraneoplastic antibodies and partially characterized antibodies (see Table 101-4).3

TABLE 101-4 Paraneoplastic Antibodies

Antibody Associated Syndrome Most Frequent Cancers
Well-Characterized Paraneoplastic Antibodies
Hu (ANNA1) Paraneoplastic encephalomyelitis, PSN, PCD, limbic encephalitis Small cell lung cancer
Yo (PCA1) PCD Ovary, breast cancers
CV2/CRMP5 Several Small cell lung cancer
Ri (ANNA2) Ataxia, opsoclonus-myoclonus, brainstem encephalitis Breast, gynecological, small cell lung cancers
Ma2* Limbic, diencephalic, brainstem encephalitis Testicular, lung cancers
Amphiphysin Stiff-person syndrome, paraneoplastic encephalomyelitis Breast, small cell lung cancers
Partially Characterized Paraneoplastic Antibodies
Tr PCD Hodgkin’s disease
Zic4 PCD Small cell lung cancer
PCA2 Several Small cell lung cancer
ANNA3 Several Small cell lung cancer

PCD, paraneoplastic cerebellar degeneration; PSN, paraneoplastic sensory neuronopathy.

* Some patients harbor Ma1 and Ma2 antibodies; the presence of Ma1 is usually associated with predominant brainstem and cerebellar involvement and with tumors other than testicular neoplasms. The prognosis in patients with tumors other than testicular neoplasms is poorer than that of patients with Ma2 antibodies and testicular neoplasms.

Well-characterized paraneoplastic antibodies include anti-Hu, Yo, Ma2, Ri, CV2/CRMP5, and amphiphysin. These six antibodies and the corresponding antigens have been characterized by different laboratories and reported in large series of patients with PNDs. Detection of any of these antibodies strongly supports the diagnosis of PND even if no tumor is found at initial evaluation. Some antibodies are more syndrome specific than others; for example, anti-Yo antibodies are almost always accompanied by cerebellar degeneration, and anti-Ma2 antibodies are almost always accompanied by limbic or upper brainstem dysfunction, whereas anti-Hu or anti-CV2/CRMP5 antibodies are accompanied by a much wider spectrum of symptoms.

Partially characterized antibodies are those with which clinical experience is limited or for which the target antigens are unknown. Until there is more experience, detection of any of these antibodies is of limited diagnostic value, and the management of affected patients should be similar to that of patients without paraneoplastic antibodies, including extensive clinical, CSF, and neuroimaging evaluations to rule out other, more frequent complications of cancer.

Several antibodies, including P/Q-type voltage-gated calcium channels, voltage-gated potassium channels, and nicotinic or ganglionic AChR antibodies can be detected in both the paraneoplastic and nonparaneoplastic forms of the associated disorder (Table 101-5

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