Neurologic diseases are defined as paraneoplastic when they occur with increased frequency in patients with cancer and are not related to a direct effect of the tumor, infection, metabolic abnormalities, or toxicity of therapy.[1,2] Autoantibodies and evidence of cellular autoimmunity directed against neuronal, glial, or muscle cell antigens have been identified in several paraneoplastic neurologic disorders.[3,4] Over the past 4 decades, investigators have identified and reported these disorders using a variety of names. This review follows the nosology employed by Posner.[2]
Paraneoplastic disorders are rare, but accurate diagnosis is important. In patients without a known malignancy, correct diagnosis may lead to the discovery and early treatment of the underlying malignancy. Effective treatment may improve the patient’s neurologic dysfunction and quality of life. In addition, proper diagnosis of a paraneoplastic disorder can spare the patient an extensive and expensive search for alternative etiologies of the neurologic dysfunction.
Paraneoplastic disorders are diagnosed by recognition of stereotypic clinical syndromes and, when appropriate, confirmatory laboratory studies demonstrating evidence of autoimmunity. Autoantibodies against specific neural antigens characterize several neurologic disorders (Figure 1).[3] In some disorders, eg, Lambert-Eaton myasthenic syndrome associated with small-cell lung cancer (SCLC),[5] or myasthenia gravis associated with thymoma,[6] the antibodies are clearly important to the pathogenesis of the disease, and immunosuppression is clearly effective.[7,8] In other disorders, such as encephalomyeloneuritis associated with SCLC, the role of the antibody response in producing neurologic dysfunction is less clear.[8-10]
Subacute Sensory Neuronopathy-Encephalomyeloneuritis
Most frequently associated with SCLC, subacute sensory neuronopathy-encephalomyeloneuritis (SSN-EMN) may affect multiple sites within the central and peripheral nervous system.[11] When SSN-EMN occurs in patients with SCLC, antibodies called anti-Hu are usually present in the serum (Figure 1); high-titer antibodies to the Hu antigen are almost never seen in patients without SCLC.[11] Diagnosis of SSN-EMN and documentation of anti-Hu antibody should lead to a search for SCLC, which is often localized at the time of diagnosis of the neurologic disorder. Low-titer anti-Hu antibodies have been documented in patients with SCLC and no neurologic disease,[12] and the association with localized SCLC suggests that anti-Hu antibodies are a marker for systemic immune suppression of tumor progression.
Various Presentations
The range of presentations and extent of neurologic involvement in patients with paraneoplastic disorders associated with anti-Hu antibodies is quite broad. One presentation is a pure sensory neuropathy.[13] The disorder progresses relentlessly over days to weeks, and sensory nerve action potentials are lost.[14] The cerebrospinal fluid usually demonstrates increased protein concentration and a lymphocytic pleocytosis. In SSN associated with anti-Hu antibody (Figure 2), the dorsal root ganglia show lymphocytic infiltration and loss of neurons.[15] At postmortem examination, inflammatory changes in other regions of the nervous system have been seen in approximately half of the SSN patients studied.
Most cases of SSN are associated with other autoimmune disorders rather than cancer, and anti-Hu antibodies are absent. The association of anti-Hu antibodies with Sjögren’s syndrome is probably spurious.[16] Immunosuppressive therapy is usually ineffective,[17] although spontaneous remission may occur. Treatment of the underlying SCLC may ameliorate the neurologic dysfunction,[18] and treatment of Hodgkin’s disease with chemotherapy resulted in improvement in one patient.[18]
Limbic Encephalitis
The clinical, radiologic, and immunobiologic features of limbic encephalitis have been described in two recent analyses encompassing 250 patients.[19,20] Limbic encephalitis may be mistaken for herpes simplex encephalitis, because its symptoms also include memory disturbance, agitation, and seizures. Magnetic resonance imaging (MRI) scans may show mesial temporal contrast enhancement or T2 signal hyperintensities.[21] The cerebrospinal fluid shows increased protein concentration and a lymphocytic pleocytosis. Patients may exhibit symptoms of SSN, or there may be involvement of the brain stem or spinal cord. Biopsy of the temporal lobe may reveal perivascular lymphocytic infiltrates. In autopsy specimens, neuronal loss and gliosis are most prominent in the limbic and insular cortex.[19]
Molecular characterization of target antigens divides this syndrome into distinguishable diseases. Most cases of limbic encephalitis are associated with SCLC and the presence of anti-Hu antibodies in the serum and cerebrospinal fluid.[19,20] Testicular cancer patients with limbic encephalitis harbor a different antibody.[22] In a series of 13 testicular cancer patients with limbic encephalitis, 10 harbored antibodies against a novel onconeural antigen named Ma2—a 40-kd protein shared by the testis and normal brain that is widely expressed in the normal human central nervous system (CNS) as well as dorsal root ganglia. A related onconeural antigen, Ma1, is associated with cerebellar or brain-stem dysfunction in patients with lung, breast, parotid gland, or colon cancer.[23]
Treatment Options
Limbic encephalitis may be one of the more treatable CNS paraneoplastic disorders.[19,20] Over 40% of patients followed for more than 8 months in a recent series demonstrated some neurologic improvement. Treatment of the underlying tumor appears to be more effective than immunosuppressive therapy. This experience adds to earlier reports of improvement after successful treatment of an underlying lung cancer.[24]
The distinction between anti-Ma2- and anti-Hu-associated limbic encephalitis is important, because patients with anti-Ma2-associated limbic encephalitis have a better prognosis. Orchiectomy and aggressive treatment of residual disease have proven to be most effective as therapy for the anti-Ma2-associated syndrome,[22] whereas immunosuppression has been less successful. One patient, however, did improve after treatment with corticosteroids and intravenous (IV) immunoglobulin (Ig) G.
Patients with limbic encephalitis should be tested for anti-Hu antibodies; male patients should undergo examination of the testes and be tested for anti-Ma2 antibodies. Detection of anti-Hu or anti-Ma antibodies indicates the likely presence of SCLC or testicular cancer, respectively. In rare instances, small-cell cancers of other organs, including poorly differentiated small cell carcinoma of the prostate, have been diagnosed as the only systemic cancer in patients with limbic encephalitis and anti-Hu antibodies.[11]
Brain-stem encephalitis and myelitis usually occur together and in association with limbic encephalitis.[25] MRI scanning must exclude metastatic tumor. Most cases are associated with anti-Hu antibodies, although other autoantibodies may be present. Brain-stem encephalitis and myelitis usually progress relentlessly and rapidly.
