Paraneoplastic neurological disorders (PNDs) are rare syndromes that are caused by, or associated with, an underlying neoplasm. PNDs do not occur by direct tumor involvement in neuroanatomic tissues;¹ it is believed that most are caused by an immune response against onconeural antigens.² These antigens, common to both neoplastic and normal neural tissue, are recognized as foreign and lead to autoantibodies attacking both the tumor as well as portions of the nervous system.³

This autoantibody response leads to progressive neurological damage.² PNDs can affect many parts of the nervous system and, unlike most gradual neurodegenerative disorders, PNDs typically exhibit rapid onset of symptoms: “Patients may develop a severe neurologic syndrome over the course of hours, although more frequently over the course of days to weeks.”⁴

PNDs are diagnostically challenging for two reasons. First, at the onset of the neurological symptoms, an individual’s cancer has usually not been discovered.³ PNDs can precede the detection of a tumor by months or years.⁵ Second, other neurological disorders can mimic paraneoplastic syndromes.³ These symptoms are “relatively common to the neurologist: for example, sensory neuropathy, idiopathic cerebellar dysfunction, obscure visual complaints.”⁴

Despite these challenges, in most instances, the presence of paraneoplastic antibodies establishes that the disorder is paraneoplastic.³ In addition, many autoantibodies are usually associated with specific tumors.² The presence of a specific autoantibody can therefore help indicate the most likely underlying tumor. “The detection of antibodies against onconeuronal antigens points to the diagnosis of a paraneoplastic syndrome and focuses the search for an underlying tumor to a few organs.”⁶

For more information on the most well-known paraneoplastic autoantibodies, the clinical presentations associated with them, and their most commonly associated cancers view our Clinical Presentation Chart.

The importance of testing for paraneoplastic autoantibodies is summarized by the following:

• PND syndromes may be the first sign of an occult cancer⁴
• Identification may lead to earlier treatment and improved outcomes in affected patients⁷
• PNDs may actually be more disabling than the cancer that causes them⁸
• PNDs can mimic other neurological conditions⁴

Currently, PNDs are diagnosed using two different technologies: immunohistochemistry and Western blot with recombinant antigens. These methods differ in ways that can produce very different test results and diagnoses.

• Immunohistochemistry
  This method uses immunofluorescence performed against whole cells, typically whole slices of brain, to detect PND antibodies in test serum. Three issues may arise with this method. First, brain slices contain many neuronal target antigens that may cross-react with the test serum. Second, normal tissues may exhibit endogenous fluorescence, even without test serum being present. Finally, it is often difficult to distinguish, using staining pattern alone, between different PND antibodies.
  
• Western blot using recombinant human antigen
  This method uses single, cloned onconeural antigens to detect specific PND antibodies in test serum. These recombinant antigens are separated on an acrylamidegel andimmobilized on a nitrocellulose filter according to size (kilodalton or kD) by Western blot methodology. After incubation with test serum and careful washing, antibody bound to the recombinant PND antigen is detected with high sensitivity. Because there is only one type of antigen with which the serum may react, this method is highly specific – it can clearly distinguish between different paraneoplastic antibodies.

The following images demonstrate the difference between immunohistochemistry and Western blot with recombinant antigens when differentiating between the RiandHu antibodies.

Patient One	Patient Two
Patient One's specimen was sent to a lab that performs paraneoplastic testing by immunohistochemistry.	Patient Two's specimen was sent to Azthena Diagnostics which performs paraneoplastic testing using recombinant human antigens in Western blot.
Immunohistochemistry cannot distinguish between specific PND antibodies and non-specific antibodies based on their staining pattern. In addition, as demonstrated above, immunohistochemistry cannot differentiate between different anti-neuronal antibodies such as Hu, Ri, Ma and Ta. For these reasons, immunochemistry cannot give a definitive diagnosis of the paraneoplastic disease.	In contrast, Athena uses recombinant human antigens and Western blot methodology for PND testing. The use of recombinant human antigens helps to eliminate non-specific reactivity and reduce the likelihood of false positives. The Western blot methodology enhances the specificity by confirming the identity of proteins based on molecular weight. Therefore, with the method Athena uses, paraneoplastic diseases are easily identified and the search for an underlying malignancy can begin.
No Definitive Diagnosis	Definitive Diagnosis of a SpecificParaneoplastic Disease

Athena Diagnostics is the only commercial lab that performs testing using purified recombinant human antigens. We believe this methodology is importantbecause only recombinant human antigens can indicate where to direct the search for malignancy.^4,6,9 Because of its high specificity, it also can help avoid unnecessary surgical procedures due to false-positive results.^6,9

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