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.
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
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). In some
disorders, eg, Lambert-Eaton myasthenic syndrome associated with small-cell lung
cancer (SCLC), or myasthenia gravis associated with thymoma, 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]
Most frequently associated with SCLC, subacute sensory
neuronopathy-encephalomyeloneuritis (SSN-EMN) may affect multiple sites within
the central and peripheral nervous system. 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. 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, and the
association with localized SCLC suggests that anti-Hu antibodies are a marker
for systemic immune suppression of tumor progression.
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. The disorder
progresses relentlessly over days to weeks, and sensory nerve action potentials
are lost. 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. At postmortem examination, inflammatory changes in other
regions of the nervous system have been seen in approximately half of the SSN
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.
Immunosuppressive therapy is usually ineffective, although spontaneous
remission may occur. Treatment of the underlying SCLC may ameliorate the
neurologic dysfunction, and treatment of Hodgkin’s disease with
chemotherapy resulted in improvement in one patient.
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. 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.
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. In a series of 13 testicular cancer patients
with limbic encephalitis, 10 harbored antibodies against a novel onconeural
antigen named Ma2a 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.
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.
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, 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.
Brain-stem encephalitis and myelitis usually occur together and
in association with limbic encephalitis. 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.
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