Paraneoplastic Syndromes Of The Nervous System

Paraneoplastic syndromes of the nervous system are rare and affect less than 1 % of cancer patients. These disorders often precede the identification of the underlying neoplasm and have a subacute onset. They can affect all parts of the nervous system usually causing focal neurological dysfunction with neuronal degeneration.

6.1. Pathogenesis

The best current hypothesis that explains the peculiar phenomenon of nervous system degeneration in these syndromes is autoimmunity. Most investigations suggest that antigens normally restricted to the nervous system are aberrantly expressed by the tumor. The immune system recognizes the ectopic "foreign" antigen and responds by antibody production thus damaging all neurons expressing this "onconeural" antigen [24], The histopathological picture of these syndromes differs according to the individual syndrome and although sometimes no pathological lesion can be identified in light microscopy, the usual picture is that of neuronal degeneration and inflammatory infiltrates [25],

6.2. Autoantibodies

A number of well documented autoantibodies have been identified in patients with neurological paraneoplastic syndromes which are usually associated with specific syndromes. Although some of these antibodies are quite specific to a specific type of tumor, their sensitivity is less prominent. A summary of the well characterized autoantibodies is given in Table 3.

The presence of these antibodies has been associated with small cell lung cancer (SCLC) in about 90% of patients with this type of neoplasm. Nevertheless, 1520% of patients harbor these antibodies without having paraneoplastic syndromes. The onconeural antigen termed Hu antigen refers to a family of predominantly nuclear proteins expressed in all neurons of the central and peripheral nervous system. The Hu antigen corresponds to a set of proteins with a molecular weight of 35-40 kD expressed both in neurons and SCLC cells [26], The Hu proteins constitute a family of RNA-binding proteins (HuD, HuC, Hel-Nl. and Hel-N2) characterized by an RNA recognition motif of about 80 amino acids. All Hu proteins are thought to have a role in the development and maintenance of the nervous system because of their restricted expression in neurons and their homology to the drasophila protein elav [27], The anti-Hu antibodies have shown specific binding capacity to neurons in both the central and peripheral nervous system.

The main clinical symptoms associated with this antibody are encephalomyelitis, sensory neuropathy, cerebellar degeneration and gastrointestinal dysmotil-ities, although various other neurological symptoms have been reported [28]. The presence of low titers of this antibody in SCLC patients is usually associated with a limited cancer stage, good response to chemotherapy and a longer survival of patients.

The presence of these antibodies has been associated with breast or gynecologic cancer in more than 90% of patients. The onconeural antigen termed Yo protein refers to a family of proteins highly expressed in the cytoplasm of cerebellar Purkinje cells and in the corresponding neoplasms.

The Yo antigen corresponds to two sets of proteins with a molecular weight of 62 and 34 kD, respectively, expressed on Purkinje cells. There are at least three types of Yo proteins, cdr 34, cdr 62-1 and cdr 62-2, whose genes have been cloned and sequenced [29]. Recent work has shown that the mRNA for 62 kD Yo protein is widely distributed in the body but the protein is not expressed outside Purkinje cells. Furthermore, the 62 kD Yo protein binds to c-myc, pulls it out of the nucleus into the cytoplasm, thus inhibiting the activity of the c-myc gene. The clinical symptoms associated with the presence of this antibody are those of cerebellar degeneration. The pathogenic role of these antibodies is suggested by the fact that in paraneoplastic cerebellar degeneration, high titers of this antibody reacting and causing selective loss of Purkinje cells have been demonstrated.

The presence of these antibodies has been associated with a variety of neoplasms including breast, gynecological and SCLC. The onconeural antigen refers to a set of proteins with a molecular weight of 55 and 80 kD. The Ri proteins are neuron specific RNA nuclear proteins and are found in the tumors of the causal cancers but not outside the central nervous system.

The clinical symptoms associated with the presence of these antibodies are opsoclonus/myoclonus and also cerebellar degeneration. Two Ri proteins NOVA (neuronal, onconeural, ventral nervous system antigen)-! and NOVA-2 have been sequenced and cloned and the inhibition of NOVA-1 by anti-Ri antibodies might suggest their pathogenic role in the paraneoplastic disorders [30],

The presence of these antibodies has recently been shown to be specific for paraneoplastic cerebellar degeneration associated with Hodgkin's disease [31]. The exact onconeural antigen has not been identified yet. Nevertheless, it has been shown that the antibodies label the cytoplasm of human and rat Purkinje cells and the molecular layer has a characteristic dotted pattern suggesting immunoreactivity of the dendritic spines of Purkinje cells.

6.7. Other autoantibodies

Several other autoantibodies have been identified in the sera of patients with neurological paraneoplastic syndromes. Anti-VGCC (voltage gated calcium channel) antibodies can be detected in patients with Lambert-Eaton myasthenic syndrome (LEMS) which is associated with SCLC. These antibodies react with the active zone of the presynaptic cholinergic-synapses, thus blocking the entry of calcium necessary for the release of acethylcholine. The antigens recognized by these antibodies are contained in the p/a type VGCCs of the presynaptic cholinergic-synapse. Unlike other antibodies such as anti-Hu and Yo and Ri and anti-Tr, this antibody is present in patients with LEMS whether it is associated with cancer or not.

Antiamphiphysin antibodies are normally present in the sera of patients with stiff-man syndrome and less frequently in encephalomyelitis associated with lung, breast or other cancers. The antigen amphiphysin is a 1,28-kD protein on the synaptic terminal that binds the vesicle core protein adaptor AP2 and dynamin, thus causing the antibodies against this protein to prevent the release of the appropriate neurotransmitter.

6.8. Clinical Syndromes

Encephalomyelitis: This type of clinical syndrome is an inflammatory disorder of the nervous system with a variable symptomatology occurring in patients with SCLC. The clinical findings vary from single cell type involvement like Purkinje cells to involvement of the dorsal ganglia, spinal cord, autonomic nervous system, peripheral nerves and muscles [32], The clinical picture has a subacute course and most patients with SCLC and these clinical findings have anti-Hu antibodies.

Lambert-Eaton myasthenic syndrome (LEMS): This disorder is characterized by generalized weakness which worsens on exertion, starting from lower extremity and spreading to the upper limbs. Weakness affects more often proximal muscles and many patients complain of autonomic dysfunction such as dry mouth, blurred vision and impotence [33].

Cranial nerve involvement including diplopia, dysphagia and dysarthria, occurs frequently but the clinical findings are usually mild. About 1-3% of patients with SCLC suffer from LEMS, but in only 2/3 of LEMS patients this disorder is paraneoplastic, while in the others the causal mechanism is unknown.

Peripheral neuropathy: In most cancer patients peripheral neuropathy is not a consequence of paraneoplastic syndrome but rather of other causes, such as chemotherapy, nutritional or metabolic. The peripheral neuropathy which is paraneoplastic occurs in patients with anti-Hu antibodies and SCLC [32]. The polyneuropathy can be motor, sensory, mixed type or autonomic. The motor neuropathies include the Guillan-Barre syndrome which occurs more commonly in patients with Hodgkin's disease and a subacute motor neuropathy affecting the anterior horn cells of patients with lymphomas. The sensory neuropathies can be subacute and affect distal neurons or an acute disease developing rapidly and causing loss of all sensory modalities in all limbs. This type is usually associated with SCLC and high titers of anti-Hu antibodies. The autonomic neuropathy is also associated with SCLC and anti-Hu antibodies and is expressed by abdominal distention, gastroparesis, postural hypotension, urinary retention and impotence.

Neuromyotonia and stiff-man syndrome: Neuromyto-nia is characterized by continuous muscle activity with stiffness and cramps which increase with exercise and have delayed relaxation.

This clinical presentation is often associated with anti-Hu encephalomyelitis. Stiff-man syndrome is also characterized by rigidity and severe spasms of skeletal muscles which can cause even bone fractures. This paraneoplastic syndrome occurs in patients with

SCLC, breast cancer, thymoma and especially in those who have antiamphiphysin antibodies.

Paraneoplastic cerebellar degeneration (PCD): This clinical syndrome has a sudden onset and is expressed by ataxia, dysarthria and dysphagia, causing severe debilitation. In this disorder which is rare and is associated with breast, ovarian and lung carcinoma, anti-Yo and anti-Tr antibodies are usually detected.

Opsoclonus/myoclonus: This disorder has an acute onset and occurs mainly in children with neuroblastoma. The clinical symptoms are those of involuntary arrhythmia, conjugate eye movements in all planes, together with diffuse or focal myoclonus. In adults with this syndrome a variety of cancers have been described and in some, anti-Ri antibodies can be detected.

For most of these paraneoplastic syndromes, no established therapy exists. Only some syndromes respond to treatment of the underlying malignancy or to immunosuppression.

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