Overview of Paraneoplastic Disorders of the Nervous System
Paraneoplastic syndromes are nonmetastatic complications of cancer with effects distant from the primary tumor. They are unrelated to neurologic complications secondary to metabolic or nutritional disorders, infection, cerebrovascular incidents, or adverse effects of treatments. They can affect all parts of the nervous system, including the brain, cranial nerves, spinal cord, dorsal root ganglia, peripheral nerves, and the neuromuscular junction. Some are thought to be immunologically mediated through cross-reactivity by immune cells against antigens expressed by tumors and neural tissues (molecular mimicry), whereas others are related to the production of circulating hormones, peptides, or other substances that exert systemic effects.
Paraneoplastic syndromes affecting the CNS are rarely recognized in animals, but lack of awareness may lead to a low detection rate. Sporadic case reports suggest that brain and spinal cord effects can result from various tumor types. An 8-yr-old, male German Shepherd with a history of acute pelvic limb paralysis, progressive loss of motor function, conscious proprioceptive deficits, loss of superficial and deep pain sensation over the trunk and pelvic limbs, and Schiff-Sherrington-like hyperextension in the thoracic limbs was diagnosed with hepatocellular carcinoma with metastasis to the lungs, liver, spleen, and lymph nodes at necropsy. Severe necrotizing myelopathy was present throughout the gray and white matter of the thoracic spinal cord, including spongy degeneration, gliosis, demyelination, axonal swelling and degeneration, and neuronal necrosis. In a second case, a range of neurologic deficits in a 17-mo-old, male Poodle was attributed to hyperviscosity syndrome secondary to macroglobulinemia-associated lymphocytic leukemia. A 3-yr-old Doberman Pinscher developed diencephalic syndrome, associated with a diencephalic tumor (an astrocytoma) that produced growth hormone, resulting in extreme emaciation despite adequate or increased nutritional intake.
Paraneoplastic myasthenia gravis (MG) has been strongly associated with the presence of thymic disease. MG can manifest as systemic weakness, or more focally, especially as megaesophagus. In one review of canine thymoma, 47% of the dogs had MG, 33% had concurrent nonthymic cancer (including pheochromocytoma, mammary adenocarcinoma, or pulmonary adenocarcinoma), and 20% had concurrent signs of polymyositis. Dogs with thymoma-associated MG often have antibodies to nicotinic acetylcholine receptors, which can be used to diagnose and/or monitor treatment response. These dogs may produce autoantibodies to several other neuromuscular antigens, including ryanodine (a skeletal muscle calcium-release channel receptor) and the muscle protein titin. Other tumors that have rarely been reported to cause MG include osteosarcoma, lymphoma, and bile duct carcinoma. MG can improve with immunosuppression or treatment of the underlying tumor but may also be persistent or occur after removal of a thymoma.
An association between myositis (eg, dermatomyositis and polymyositis) and malignant neoplasia in people has been well established. Dogs with malignant tumors such as bronchogenic carcinoma, myeloid leukemia, or tonsillar carcinoma may also have muscular necrosis and low-grade myositis, but the frequency of this potentially paraneoplastic association is unknown. Two dogs with multicentric lymphoma were found to have polymyositis, but the presence of lymphocyte infiltration within the muscle makes differentiating between primary and paraneoplastic disease difficult.
Peripheral neuropathy is commonly associated with neoplasia in people, and is likely so in animals, as well, although less recognized clinically. A large survey on dogs with various malignancies revealed multiple histopathologic changes in the nerve fibers, including paranodal-segmental demyelination, remyelination, axonal degeneration, and myelin globules. Associated tumor types included insulinoma, multiple myeloma, lymphoma, bronchogenic carcinoma, mammary adenocarcinoma, malignant melanoma, thyroid adenocarcinoma, leiomyosarcomas, hemangiosarcomas, undifferentiated sarcomas, and mast cell tumor.
Clinical signs may include reduced or absent spinal or cranial reflexes, flaccid weakness, reduced muscle tone, paralysis of limb or head muscles, and, after 1–2 wk, neurogenic muscle atrophy. Dysphonia may also be present.
Dogs and cats with clinical signs of nervous system disease (or with myositis or necrotizing myopathy confirmed by histopathology) that do not respond to therapy or that relapse should be carefully screened for malignancy, because paraneoplastic syndromes may be the first clinical sign related to tumor presence. Blood tests or imaging may be indicated. Such vigilance may detect tumors at a more treatable stage.