Paraneoplastic Syndromes and Nervous System

Paraneoplastic syndrome is a group of autoimmune disorders that occurs in response to tumor. One of the causes of the syndrome is the substance (antigen) secreted by the tumor, which triggers immune response. One of the most devastating forms of the syndrome is paraneoplastic neurologic disorders (PND). Most PND are immune-mediated and can affect any part of the nervous system. Common symptoms include dementia, memory loss, ataxia, loss of muscle tone, difficulty swallowing, sensory loss in the limps. It's neurological symptoms that take a patient to a doctor,

  

PND are rare, affecting 0.01 percent of cancer patients. Although some forms of PND are more common, such as Lambert-Eaton myasthenic syndrome, which affects 3% with small-cell lung cancer, myasthenia gravis that affects 15% thymoma patients. Most of the time, neurological symptoms appear before cancer has been found and sometimes, it takes months or even years to locate it. PET scan is currently the best method to search for cancer.

Examination of CSF revealed elevated protein (50-100mg/dc), IgG, and WBC (30-40 wc/mm^3), 75% of which are T cells and the rest are B cells and natural killer cells. The most important indicator of paraneoplastic syndromes, however, the antibodies, found in the serum and CSF. These antibodies are produced against antigens presented in a tumor. Although there is an overlap, each of these antibodies and antigens associates with specific tumors, which is very helpful in localizing one.

Unfortunately, antibodies are not always found in paraneoplastic patients, which raises a question whether antibody detecting techniques are not accurate or perhaps some paraneoplastic disorders may not be immune-mediated.

Currently, it is believed that most PND are immune-mediated. A tumor expresses an antigen that is identical to neural antigen and for some reason the immune system doesn’t recognize it as its own. Dendritic cell process the antigen and takes it to lymph node where Th and B cells get activated. B cells mature into plasma cells and starts secreting antibodies against tumor antigen. In some cases, B cells and CTL break blood-brain barrier and mount attack on neurons expressing that very same neural antigen as a tumor. That’s when the neurological symptoms begin. The symptoms depend on the  portion of nervous system that will react to the antibodies. For example, a patient with anti-Purkinjie antibody will have paraneoplastic cerebellar degeneration. Also, the antibody level in the CSF will be elevated, meaning the B cells have crossed blood-brain barrier and synthesized within the brain.

There are two treatment options for paraneoplastic syndrome: immunosuppression and removal of an antigen source, which considered to be more effective. It is recommended to combine immunotherapy with cancer treatment. Because the pathogeneses of some paraneoplastic disorders is not fully understood, and yet both humoral and cell-mediated responses believed to be involved, it’s important to target both responses. The prognosis varies for different groups of paraneoplastic syndromes. Lambert – Eaton syndrome responds very well to immunotherapy, opsoclonus – myoclonus may resolve spontaneously after immunosuppressant. PND, on the other hand, respond to treatment poorly, although may stabilize once cancer is treated.

It is not yet knows if antitumor immune response can operate without damaging nervous system. Although, if we could have a better understanding of the mechanism that triggers antitumor response,  in the future it will lead to new approaches in immunotherapy.  


References: 

Robert B. Darnell, M.D., Ph.D., and Jerome B. Posner, M.D. Paraneoplastic Syndromes Involving the Nervous System. N Engl J Med. October 2003

Nath U, Grant R. Neurological paraneoplastic syndromes. J Clin Pathol. Dec 1997