Incidence

Several studies have addressed the frequency of paraneoplastic syndromes. Wide-ranging estimates from these studies are due to: (1) varied definitions; (2) the rigor used to exclude other causes of neurologic dysfunction; (3) the care with which the neurologic evaluation was performed; and (4) biases introduced by referral patterns. For example, the Lambert–Eaton myasthenic syndrome (LEMS) occurs in 3 percent or less of patients with small cell lung cancer (SCLC), but about 50 percent of SCLC patients have either subjective or objective muscle weakness. While in one study only 7 percent of 1,476 cancer patients had a “neuromyopathy” on physical examination, in another, abnormalities of peripheral nerve function were found by quantitative sensory testing in 44 percent. Myopathic changes are found on muscle biopsy in 33 percent of patients with lung cancer. These neurologic symptoms can predate the detection of cancer; in one study of 51 patients with peripheral sensory neuropathy of unknown cause, 18 patients (35%) were found who developed cancer within 6 years.

True incidence figures for paraneoplastic syndromes are rare. Population-based data are available for myasthenia gravis, LEMS, and dermatomyositis. A study from the Netherlands identified the age-corrected point prevalence of myasthenia gravis as 106.1 per million persons, with an annual incidence of 6.48 per million. A total of 5 percent of these patients had a paraneoplastic form of myasthenia gravis. In another study, the annual incidence of LEMS was 0.4 per million persons, equally divided between those with SCLC and those with non–small cell lung cancer (NSCLC) with a prevalence of 2.5 per million persons.

For dermatomyositis, a population-based study from Olmsted County, Minnesota, identified the overall age- and sex-adjusted incidence as 9.63 per million persons; 20 percent had cancer. The overall prevalence was 21.42 per 100,000 persons, and 21 percent suffered from the amyopathic subtype (rash but no muscle weakness).

Other studies have addressed the percentage of patients with a given tumor likely to have a paraneoplastic syndrome. Myasthenia gravis occurs in 10 to 15 percent of patients with thymoma. LEMS has been found in about 3 percent of patients with lung cancer. Paraneoplastic peripheral neuropathy occurs in 10 percent of malignant monoclonal gammopathies, and in 50 percent of patients with osteosclerotic myeloma. Most known paraneoplastic syndromes are so uncommon that exact incidence figures cannot be established, but they probably occur in less than 0.01 percent of cancer patients.

A higher yield is found when patients whose symptoms suggest the possibility of a paraneoplastic syndrome have serum sent for examination for paraneoplastic antibodies. Dalmau and Rosenfeld found that 163 of 649 (25%) consecutive patients examined over 23 months had well-defined anti-neuronal autoantibodies.

Pathogenesis

Although the exact pathogenesis of most paraneoplastic syndromes has not been established, the consensus is that most, or perhaps all, neurologic paraneoplastic syndromes are immune-mediated. Evidence for this hypothesis includes the presence of antibodies that recognize antigens present in both the cancer and the normal nervous system. Some of these so-called paraneoplastic or onconeural antigens are also expressed in normal testes, an organ that, like the brain, is an immunologically privileged site. If the antigen cannot be identified in a cancer with a known serum paraneoplastic antibody, it must be suspected that either the patient does not have a paraneoplastic syndrome or that some other cancer is present and caused the disorder. Examination of the cerebrospinal fluid (CSF) of patients with paraneoplastic syndromes involving the central nervous system (e.g., limbic encephalitis) usually reveals a pleocytosis, at least early in the course of the disease, with a persistently slightly elevated protein level, an increased IgG Index, and oligoclonal bands. Some of these oligoclonal bands in the CSF have been identified as paraneoplastic antibodies. The relative specific activity of the paraneoplastic antibody in CSF (expressed as a concentration of antibody against total IgG) is substantially higher than that in the serum, indicating that the antibody was synthesized within the central nervous system (CNS) rather than simply diffusing across the blood–brain barrier. Serial plasma exchanges, although effective in substantially lowering antibody titer in the serum, have no effect on CSF antibody titers. The tumors of patients with paraneoplastic syndromes, although identical in histologic type to tumors of patients without paraneoplastic syndromes, are more likely to be heavily infiltrated with inflammatory cells including T cells, B cells, and plasma cells. The nervous system is usually also infiltrated by inflammatory cells, and some paraneoplastic syndromes respond to treatment with immunosuppression.

The current concept of the pathogenesis of paraneoplastic syndromes is that the tumor ectopically expresses an antigen that normally is expressed exclusively in the nervous system. Onconeural antigens are present in the tumors of all patients with antibody-positive paraneoplastic syndromes. In some tumors, such as SCLC, onconeural antigens are present in all tumors, even in those patients who do not develop paraneoplastic antibodies or a paraneoplastic syndrome. The onconeural antigen in the tumor cell is probably recognized by the immune system when tumor cells spontaneously undergo apoptosis and the apoptotic bodies containing the antigen are phagocytized by dendritic cells. Current evidence suggests that the antigens in the tumor are identical in structure to normal neural antigens but, nevertheless, are seen by the immune system as foreign, leading to development of paraneoplastic antibodies. Others have found that some paraneoplastic antigens are mutated cancers such as SCLC. The body’s immune system attacks structures expressing the paraneoplastic antigen, resulting in two effects. First, the immune attack may control the growth of the tumor and in rare instances obliterate it. Second, the immune response also attacks the nervous system itself; both B and T cells can be found in the CNS of patients with CNS paraneoplastic syndromes. The B cells generally reside in the perivascular spaces and the T cells in both perivascular spaces and in the brain parenchyma. The T cells found in the nervous system are either mono- or oligoclonal and respond only to a specific antigen.

Paraneoplastic antibodies have also been identified within neurons of some patients who died of paraneoplastic encephalomyelitis. This finding is complemented by the finding of antibodies inside neurons of patients with cancer-associated retinopathy and stiff-person syndrome. Furthermore, experimental evidence indicates that infusion of paraneoplastic IgG antibodies into animals can reproduce the neurologic signs of stiff-person syndrome.

Two paraneoplastic syndromes, LEMS and myasthenia gravis, meet formal criteria for an antibody-mediated autoimmune disease. Other paraneoplastic syndromes in which antibodies appear to play a causal a role include stiff-person syndrome, autonomic neuropathy with antibodies to the ganglionic acetylcholine receptor, NMDA receptor antibody–associated limbic encephalopathy, and carcinoma-associated retinopathy. Increasing evidence, particularly concerning paraneoplastic syndromes of the CNS, suggests a major T cell component in addition to the B cell–driven antibody response. Tumors express paraneoplastic antigens relatively commonly, raising the question of why more cancer patients do not develop immune responses to their tumors. Activation of the CD8 ⁺ T cells in lymph nodes relies on the presence of CD4 ⁺ helper cells and the absence of inhibitory factors. Imbalance in these regulatory pathways might underlie the presence or absence of paraneoplastic syndrome antigen–specific CD8 ⁺ T cells in individual cancer patients.

Diagnosis

Recommended criteria for the diagnosis of a neurologic paraneoplastic syndrome are listed in Table 27-4 . Alternative causes that might explain the clinical symptoms must be excluded. “Classic” refers to those neurologic disorders characteristic of a para-neoplastic syndrome as indicated in Table 27-5 . “Onconeural” refers to antibodies that recognize antigens that are restricted to the nervous system (or testes) and to some cancers. Originally, when the antigens were unknown, two separate nomenclatures were devised to designate these antibodies. The nomenclature applied at Memorial Sloan-Kettering Cancer Center (e.g., anti-Yo, anti-Hu) refers to the first two letters of the last name of the index patient while the Mayo Clinic terminology (e.g., anti-PCA-1, anti-ANNA-1) refers to the staining pattern by immunohistochemistry. In Table 27-5 the latter system is identified in parentheses. Once these antigens have been identified, the antigen’s name is used to designate the antibody in question (e.g., anti-VGCC, an antibody against voltage-gated calcium channels). The term “well-characterized” refers to an antibody whose antigen has been identified and whose gene has been cloned and sequenced.

Table 27-5

Antibody-Associated Neurologic Paraneoplastic Disorders

Antibody	Location	Antigen/Gene(s)	Usual Tumor or Site of Origin	Neurologic Disorder
Antibody Markers of Neurologic Paraneoplastic Syndromes and Tumor, Requiring a Search for Cancer
Anti-Hu (ANNA-1)	Nucleus>cytoplasm (all neurons)	HuD (Elavl4); Elavl2, 3	SCLC, neuroblastoma, prostate	PEM, PSN, autonomic dysfunction
Anti-Yo (PCA-1)	Cytoplasm, Purkinje cells	CDR2, Cdr2L	Ovary, breast, lung	PCD
Anti-Ri (ANNA-2)	Nucleus>cytoplasm (CNS neurons)	Nova 1,2	Breast, gynecologic, lung, bladder	Ataxia/opsoclonus; brainstem encephalitis
Anti-CRMP5 (anti-CV2)	Cytoplasm, oligodendrocytes, neurons	CRMP5	SCLC, thymoma	PEM, PCD, chorea, optic, sensory neuropathy
Anti-Ma2 (ANNA-3)	Neurons (nucleolus)	Ma2	Testis	Limbic, brainstem (diencephalic) encephalitis
Anti-amphiphysin	Presynaptic	Amphiphysin	Breast, SCLC	SPS
Anti-Sox (AGNA-1)	Nucleus of Bergman glia, other neurons	SOX1	SCLC	LEMS
Anti-Tr (PCA-Tr)	Cytoplasm, dendrites of Purkinje cells	DNER	Hodgkin	PCD
Anti-recoverin	Photoreceptor, ganglion cells	Recoverin	SCLC	CAR
Anti-bipolar	Bipolar retinal cells	??	Melanoma	MAR
Anti-Titin	Skeletal muscle	Titin	Thymoma	MG
Anti-AChR	Postsynaptic NMJ (electron immunohistochemistry)	AChR	Thymoma	MG
Anti-Ryanodine receptor	Skeletal muscle	Ryanodine receptor	Thymoma	MG (severe form)
Antibody Markers of Autoimmune Neurologic Dysfunction that Do Not Always Require a Search for Cancer
Anti-VGCC	Presynaptic NMJ	P/Q VGCC	SCLC	LEMS
Anti-NMDAR	Neuronal cell surface, hippocampus, other brain regions	NR1/NR2	Ovarian teratoma	PEM
Anti-AMPAR	Neuronal cell surface	GluR1,2 AMPA receptor	Thymoma, breast, lung	LE
Anti-AChR	Postsynaptic NMJ	AChR	Thymoma	MG
Anti-nAChR	Postsynaptic ganglia	α3 subunit nAChR	SCLC, thymoma	Autonomic neuropathy
Anti-VGKC -anti-LGl1	Neuropile	Antibody binds to potassium channels	Thymoma	LE
Anti-VGKC- anti-CASPR2	Neuropile	Antibody binds to potassium channels		Peripheral nerve hyperexcitability, Morvan Syndrome
Anti-GAD	Purkinje cell cytoplasm, nerve terminals, other neurons	Glutamic acid decarboxylase	Several (renal, Hodgkin, SCLC)	SPS, cerebellar ataxia
Anti-glycine receptor	Brainstem, spinal cord neurons	Glycine receptor	Lung	PERM
Anti-GABA-AR	Neuronal surface	GABA-A receptor associated protein	?	SPS
Anti-GABA-BR	Neuronal surface	GABA-B receptor	SCLC	LE
Anti-MuSK	Muscle	MuSK	Thymoma	MG
Anti-α-enolase	Multiple retinal cells	α-Enolase	SCLC	CAR
Uncommon Antibody Markers of Neurologic Disorders. Some Are Paraneoplastic Single Case Reports or Very Small Series
Anti-PCA-2	Purkinje cytoplasm and other neurons		SCLC	PCD
Anti-Ma	Neurons (subnucleus)	Ma1 and Ma2	Lung, others	PEM, brainstem
ANNA 3	Nuclei, Purkinje cells	?	Lung	Sensory neuronopathy, PEM
Anti-mGluR1, mGluR5	Purkinje cells, olfactory neurons, hippocampus	Metabotropic glutamate receptor	Hodgkin	PCD
Anti-Zic4	Nuclei of cerebellar	Zic4	SCLC	PCD
Anti-PKC-gamma	Purkinje cells	PKCγ	NSCLC	PCD
Anti-gephyrin	Postsynaptic membranes	Gephyrin	Unknown primary	SPS
Anti-synaptotagmin	Presynaptic junction	Vesicle protein	?	LEMS
Anti-synaptophysin	Presynaptic junction	Vesicle protein	SCLC	Neuropathy
Anti-BRKSK2	Neuronal cytoplasm	BRSK2	SCLC	LE
Anti-adenylate kinase	Neuronal cytoplasm	Adenylate kinase 5	No identified cancer	LE
Anti-CARP VIII	Purkinje cells	CARP VIII	Melanoma	PCD
Anti-Homer 3	Neuropile cerebellum	Homer 3	None known	PCD
Anti-Aquaporin4	Glia			Neuromyelitis optica
Anti-GABA-AR	Neuronal surface	GABA-A receptor associated protein	?	SPS

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