PANEL 199

Paraneoplastic Syndrome (IIF and Immunoblot)

Indication  Suspicion of paraneoplastic syndrome. 

Clinical background Paraneoplastic neurological symptoms are immunologically mediated phenomena secondary to a cross reaction between tumor and neuronal antigens. All parts of the central and peripheral nervous system can be involved and give subacute or chronic symptoms, such as encephalopathy, cerebellar degeneration, and polyneuropathy. In most of the paraneoplastic syndromes, the neurological symptoms appear before the cancer has been identified. Identification of paraneoplastic antibodies can direct the search for an underlying cancer and increase the likelihood of making an early diagnosis and removal of the tumor with beneficial effects on the neurological symptoms. 

Small cell lung cancer (SCLC) is the most common underlying cause, followed by breast and ovarian tumors, but many different malignancies may be associated with paraneoplastic syndromes. Symptom onset is usually sub-acute and often precedes the cancer diagnosis with 2-5 years. 

Generally, immunomodulatory drugs used in autoimmunity are not effective in these cases and instead treatment of the underlying cancer is most important. If the cancer can be successfully treated the expression of the intracellular antigen and activity of the immune system decrease. Hereby the neurological symptoms may improve. 

• Antibodies against Amphiphysin occur in patients with paraneoplastic variant Stiff person syndrome but can also be seen in autoimmune encephalitis. Antibodies against Amphiphysin are associated with breast cancer and small cell lung cancer.  
• Antibodies against CV2/CRMP5 is a paraneoplastic marker that is primarily associated with small cell lung cancer, but also occurs with thymoma, and other tumor types. Clinical symptoms may be chorea, sensorimotor neuropathy, limbic encephalitis and cerebellar degeneration 
• Antibodies against Hu are also called ANNA-1 (anti-neuron-specific cell nuclear antibodies) and occur in paraneoplastic subacute sensory neuronopathy and/or paraneoplastic encephalomyelitis.  
• Antibodies against Ma-2 is also referred to as Ta. Occurrence is associated to paraneoplastic cerebellar degeneration, limbic encephalitis, and brain stem encephalitis.  
• Antibodies against Ri are also called Nova 1 or ANNA-2 (anti-neuron-specific cell nuclear antibodies), and occur less often than antibodies against Hu, but can be seen in paraneoplastic sensory neuronopathy, cerebellar ataxia and/or paraneoplastic encephalomyelitis.  
• Antibodies against Yo are also called anti-PCA-1 (Purkinje cell antigen 1) and are strongly associated to subacute cerebral ataxia and ovarian or breast cancer.  
• Antibodies against GAD also occur in 60% of patients with Stiff Person Syndrome and have been observed in both serum and CSF. Anti-GAD antibodies may also be associated with limbic encephalitis, epilepsy, and cerebellar ataxia.  
• Antibodies against Recoverin occurs almost exclusively in small cell lung cancer with paraneoplastic retinopathy. 
• Antibodies against SOX1 (or anti-glial nuclear antibody, AGNA) are unusual but have been reported to occur in paraneoplastic neuropathy, Lambert-Eaton syndrome and in unclear forms of neuropathy and ataxia.  
• Antibodies against Titin can be detected in patients with myasthenia gravis and is associated with thymoma. 
• Antibodies against Tr (Trotter antigen, DNER) can be seen in breast or ovarian cancer, small cell lung cancer, thymoma, Hodgkins lymphoma and are associated to paraneoplastic encephalomyelit or cerebellar degeneration. 
• Antibodies against Zic4 may occur with paraneoplastic neurological disease associated to small cell lung cancer with or without neurological symptoms.  

References
Read "Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes" (open access)
Download our overview of neuronal antibodies