Paraneoplastic neurologic syndromes are characterized by an immune response targeting the central or peripheral nervous system in the presence of an underlying malignancy. This autoimmune response is usually associated with an antibody targeting antigens shared by both the tumor and the nervous system. These antibodies are divided into two categories: (1) directly pathogenic antibodies that target neuronal cell surface or synaptic proteins, and (2) nonpathogenic antibodies that are directed against intracellular neuronal proteins and thus are a surrogate marker for a T-cell-mediated immune response against the nervous system. Diagnostic evaluation of the patient with a suspected paraneoplastic syndrome varies based on the presenting symptoms, but may include lumbar puncture, testing for serum or cerebrospinal fluid (CSF) paraneoplastic autoantibodies, magnetic resonance imaging (MRI) of brain and/or spine with contrast, and nerve conduction studies and electromyography (when peripheral nervous system involvement is suspected). Importantly, patients with cancer often have detectable nonpathogenic paraneoplastic antibodies without clinical manifestations of a paraneoplastic syndrome, and thus results of antibody testing must be interpreted with caution. However, as a paraneoplastic syndrome may precede the diagnosis of cancer, at times by several years, a thorough evaluation to identify occult malignancy is required in any patient with a positive paraneoplastic antibody regardless of clinical manifestations. Treatment of the underlying malignancy (when identified) to remove the antigen source should be undertaken, and immunosuppression (e.g., high-dose steroids, intravenous immunoglobulin, plasma exchange, and in some cases rituximab and cyclophosphamide) may be used. Paraneoplastic syndromes due to directly pathogenic antibodies are more likely to respond to these therapies, whereas those with antibodies targeting intracellular antigens often respond minimally.
Patients with anti-Hu sensory neuronopathy often present with painful paresthesias and subacute distal and proximal sensory loss across all modalities. They may exhibit pseudoathetosis in their hands secondary to severe loss of proprioception. Nerve conduction studies typically show reduced or absent sensory amplitudes with normal motor nerve conduction studies. Spine MRI may show dorsal root or posterior column T2 hyperintensity or contrast enhancement.
Lambert-Eaton myasthenic syndrome (LEMS) is associated with antibodies against the voltage-gated calcium channel. About 65% of patients with LEMS have a paraneoplastic syndrome associated with small cell lung cancer. These patients are more likely to be older and male (see Chapter 91 ).
Thymic tumors are present in up to 15% of patients with anti-AChR antibody-positive myasthenia gravis (MG), and occasionally in patients with seronegative MG. Patients with anti-MuSK antibody–positive MG are not at increased risk of thymoma (see Chapter 97 ).
A demyelinating polyneuropathy can occur in paraprotein-related diseases associated with an underlying hematologic malignancy, and should be considered in any patient not responding to treatment for chronic inflammatory demyelinating polyneuropathy (see Chapter 97 ).
Inflammatory myopathies are associated with various cancers, most commonly adenocarcinoma but also squamous cell carcinoma and hematologic malignancies. Patients with an inflammatory myopathy associated with cancer are older and progress more rapidly. About 50% of patients with a paraneoplastic inflammatory myopathy will have an antibody directed against transcriptional factor 1 gamma; these patients almost exclusively have dermatomyositis (see Chapter 99 ).
Paraneoplastic myelopathy should be considered in patients with symmetric and longitudinally extensive tract-specific T2 hyperintensity on MRI. In addition, anti-Hu antibodies have also been associated with gray-matter T2 hyperintensity. The majority of patients do not respond to treatment.
Both stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are characterized by progressive muscle rigidity, stimulus-induced muscle spasm (hyperekplexia), myoclonus, and autonomic dysfunction. PERM is distinguished from SPS by additional brainstem or other neurologic deficits and is usually more severe and progressive than SPS. SPS is classically an autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD). The paraneoplastic variant of this disorder is extremely rare (< 2% of cases), but should be considered in a patient suspected of having SPS who is negative for GAD antibodies. PERM is also classically an autoimmune disorder associated with antibodies against GAD or the glycine receptor. The paraneoplastic variant of PERM with glycine receptor antibodies is rare but has been associated with thymoma or lymphoma.
Isolated chorea can rarely represent a paraneoplastic syndrome. Bilateral symmetric choreoathetosis of neck and limbs similar to Huntington chorea, unilateral chorea, or orobuccal dystonia have been described. These patients do not typically have basal ganglia abnormalities on MRI at presentation.
Multiple well-characterized paraneoplastic antibodies (e.g., Hu, Ri, Ma2, Cv2) are associated with limbic encephalitis with brainstem or other nervous system involvement. The presence of retinitis and encephalitis is strongly suggestive of antibodies targeting Cv2 (CRMP5). Symptoms are often poorly responsive to immunosuppressive therapy. Patients with isolated limbic encephalitis and seizures are more likely to have an autoimmune etiology in which there is not an associated malignancy (see Chapter 115 ).
Paraneoplastic cerebellar degeneration (PCD) is associated with a wide range of antibodies and cancers, though only anti-Yo, anti-Tr, and anti-mGluR1 predominantly associate with isolated cerebellar dysfunction/ataxia without involvement of other areas of the nervous system. Patients with PCD initially present with dizziness, nausea, and vomiting and later develop gait instability, appendicular and truncal ataxia, and diplopia among other cerebellar signs. PCD is often refractory to immunosuppressive therapy, especially in cases associated with anti-Yo and anti-Hu antibodies.
Opsoclonus-myoclonus syndrome is characterized by rapid vertical and horizontal saccadic eye movements (“dancing eyes”), rapid involuntary movements, and sleep disturbance. In pediatric patients, it is frequently associated with neuroblastoma. In adult patients, it may be a paraneoplastic syndrome but can also be an immune-mediated process without an associated underlying malignancy.