Neurologic paraneoplastic disorders are caused by indirect damage to central or peripheral nervous system structures from a systemic cancer, resulting in a wide spectrum of neurologic signs and symptoms. The cause is thought to be immune-mediated as opposed to the direct effects of tumor invasion, metastases, toxicity from treatment, malnutrition, or coincidental infection.

Paraneoplastic syndromes are quite rare, affecting less than 0.1% of all patients with malignancy. However, other studies suggest up to 7% of patients with malignancy are afflicted. They are associated with a broad range of symptoms that are typically subacute in onset, evolving over weeks to months. Most patients develop neurologic symptoms before a cancer is identified. After onset of symptoms, the cancer may still be small enough to elude detection and may not be identified for many months or years, sometimes discovered only postmortem.

Any cancer may be associated with a paraneoplastic syndrome but some syndromes are associated with a specific cancer or a particular group of neoplasms. Small cell lung cancer (SCLC) is one of the most common tumors associated with paraneoplastic syndromes. Other tumors that are associated with these syndromes are those that express neuroendocrine proteins, those that affect organs with immunoregulatory functions, or those derived from cells that produce immunoglobulins.

The pathogenesis of paraneoplastic syndromes is thought to be immune-mediated. It is generally accepted that malignancies causing these syndromes express proteins normally restricted to the nervous system. The host mounts an immune attack against those antigens in the tumor but the response is directed against central or peripheral neural antigens, resulting in neurologic deficits. In many paraneoplastic syndromes, the detection of characteristic antibodies has served as a useful diagnostic tool but the pathogenesis of these antibodies is not clearly understood.

In general, antibodies associated with paraneoplastic syndromes are classified based on location of their targeted antigen, either intracellular or on the neuronal surface. This distinction has further implications on the understanding of the pathogenic role of the antibody and the diagnostic value of its detection. Antibodies targeted against intracellular antigens, or onconeural antibodies, may predict with high frequency the presence of an underlying tumor and may be used to establish a neurologic symptom as paraneoplastic. The pathogenic role of these antibodies is not clearly understood and they may be present (often at lower levels) in a patient with an underlying cancer but without neurologic symptoms. There is evidence to suggest that the mechanism for neuronal damage is sometimes mediated by cytotoxic T cells, and these syndromes are typically poorly responsive to immunomodulatory therapy. Conversely, antibodies against surface antigens are thought to be pathogenic—interfering with neuronal cell signaling or synaptic transmission. These antibodies are often associated with well-characterized central nervous system (CNS) syndromes, although their presence does not necessarily denote a malignancy. Some syndromes are responsive to immunomodulatory therapy, often with a correlation between antibody titers and outcome. Notably, there are many cases where a neurologic syndrome exists that is suspected to be paraneoplastic without the detection of any associated antibodies.

Paraneoplastic syndromes encompass a broad range of clinical manifestations. Onset is typically acute (as in paraneoplastic cerebellar degeneration) or subacute. There are some symptoms that are almost always associated with a malignancy (Lambert-Eaton myasthenic syndrome, cerebellar degeneration, and opsoclonus-myoclonus as examples) and others that may occur without malignancy (encephalitides, sensory neuropathies). Discussed in the following text are some of the most well-recognized symptoms of paraneoplastic syndromes (Table 104.1).