Autoimmune Neurologic Diseases - Antineural Antibody Testing

Indications for Testing

Antineural antibody testing is used in the evaluation of individuals with symptoms of autoimmune neurologic disease. Testing in these individuals may be appropriate in cases of:

• New subacute-onset (over weeks to a few months) neurologic symptoms (eg, confusion, dementia, epilepsy, movement disorders, psychiatric symptoms)
• Rapid progression of neurologic symptoms
• CSF findings characteristic of inflammation (eg, elevated protein and/or white blood cells [WBCs])
• A personal or family history of autoimmunity
• A history of cancer or immune checkpoint inhibitor exposure, or elevated cancer risk factors 
• Neuroimaging findings suggestive of inflammation

Antineural antibody testing may also be considered to:

• Detect early evidence of cancer recurrence in previously seropositive patients 
• Determine the presence of antineural antibodies in patients with cancer before initiating immune checkpoint inhibitor therapy if there is any concern regarding neurologic symptoms 
• Differentiate autoimmune neuropathies from the neurotoxic effects of chemotherapy

Diagnosis

The diagnosis of autoimmune neurologic disease relies on a thorough clinical history, complete neurologic exam, and supporting imaging and laboratory studies. Testing for antineural antibodies should not supersede a thorough clinical assessment. In addition, empiric treatment of suspected autoimmune neurologic disease should not be withheld while awaiting the results of antineural antibody testing if the clinical assessment is consistent with autoimmunity and other etiologies have been adequately excluded. 

Antineural antibody testing should be reserved for patients who meet well-established diagnostic criteria. Symptoms of autoimmune neurologic disease generally develop in a subacute fashion (with the notable exception of conditions associated with contactin-associated protein 2 [CASPR2], leucine-rich, glioma-inactivated 1 [LGI1], and immunoglobulin-like cell adhesion molecule 5 [IgLON5], which have been linked to more insidious symptom onset).  This subacute development can help distinguish autoimmune neurologic diseases from syndromes caused by infections or cerebrovascular disease (generally acute) or neurodegenerative, functional, or psychiatric causes (more often insidious in onset). 

For certain syndromes, clinical diagnostic criteria and scoring systems have been established. The application of these may improve the diagnostic yield of antineural antibody testing and can reduce the risk that false-positive or low-positive results will cloud the clinical picture.    ^,  These diagnostic criteria continue to evolve, but may include clinical scoring systems such as:

• The APE² and RITE² scores to predict autoantibody presence in epilepsy and encephalopathy and response to immunotherapy
• The PNS-Care score to stratify paraneoplastic neurologic syndromes into definite, probable, and possible 

Laboratory Testing

Antineural antibody testing for autoimmune neurologic disease is complex and evolving. New antibodies of uncertain clinical relevance continue to be discovered, which complicates test selection and the interpretation of antineural antibody test results. Involvement of neurologists and laboratorians in the process of test selection should be considered.

Initial Workup

Laboratory tests used in the initial clinical evaluation of suspected autoimmune neurologic disease (along with a robust timeline, clinical history, thorough neurologic exam, and imaging) include routine blood and CSF studies.   Specific tests to rule out other potential causes of symptoms (eg, infectious diseases, toxins, nutritional deficiencies, genetic anomalies) may also be appropriate. 

Antibody Test Selection

Different labs offer panels with different antibodies; it is important to research specific panels of interest and consult with the performing laboratory to guide panel selection. Regardless of the antibody test(s) selected, a negative result does not rule out autoimmune neurologic disease.

Test Selection Based on Patient’s Phenotype

Many antineural antibodies are extremely rare, and most have low positivity rates.  Conversely, some antibodies may be detected in the general population, which makes it difficult to interpret positive results.   Ordering comprehensive panels that are not appropriate for the patient’s phenotype can lead to false-positive results, which can cloud the clinical picture.  Overinterpretation of false-positive and low-positive results may lead to adverse outcomes, including delays in appropriate diagnosis and treatment, inappropriate immunosuppressive treatment (along with associated side effects), or failure to make an accurate diagnosis.

Targeted panels focus on antibodies relevant for specific patients (eg, based on age and clinical symptoms), thereby improving the diagnostic yield of these tests. A variety of these targeted, phenotype-specific panels are available from clinical reference laboratories. Many antibodies in these panels overlap, and clinicians should choose the single panel that represents the predominant clinical phenotype in their patient. For example, some patients with NMDAR encephalitis may initially present with encephalopathy, whereas others may have orofacial dyskinesias, and still others will have new-onset seizures. There is no need to order an encephalopathy panel, a movement disorders panel, and an epilepsy panel, as each of these panels will test for anti-NMDAR antibodies. Choosing the panel that best represents a patient’s predominant clinical phenotype will capture not only the anti-NMDAR antibodies associated with all three presentations, but also other antibodies associated with that phenotype.

In some cases, a patient may present with a clinical phenotype that seems pathognomonic for a specific antibody. For example, in a patient with frequent faciobrachial dystonic seizures, testing for LGI1 alone will yield a result more quickly than will a targeted movement disorders panel. In these cases, it may be reasonable to order testing for that single antibody to speed turnaround time. However, it should be noted that many antibodies are associated with overlapping clinical syndromes; phenotype-specific panels may prove more expeditious if the test for the initially suspected antibody is negative. In addition, patients may be positive for multiple antibodies, which may have implications for cancer screening and treatment responsiveness. Due to these considerations, panel testing is usually recommended.

Resource Considerations

Most patients who are found to have autoimmune neurologic disease are positive for only a single autoantibody. As additional antibodies are discovered, comprehensive panels will include antibodies that are likely irrelevant to any specific patient; these panels are more time-consuming to perform and potentially, more expensive.

Targeted panels or single antibody tests generally yield results more quickly than do comprehensive panels and may thus more quickly inform ongoing treatment decisions. However, testing for antibodies one at a time can delay diagnosis and treatment.

Single antibody tests may also be used to monitor a previously identified antibody over time. This strategy is likely to be more time- and cost-effective than ordering a panel with unnecessary components.

Specimens for Antibody Testing

Both CSF testing and serum testing are available for many antineural antibodies. Although antibodies are often present at higher titers in serum, some antibodies are produced intrathecally and are more likely to be detected in CSF.  In addition, antibodies such as glutamic acid decarboxylase 65-kd isoform (GAD65) are present in many patients without autoimmune neurologic disease; the presence of these antibodies in the CSF is more consistent with neurologic disease.  When available, both serum and CSF tests for given autoantibodies should be ordered simultaneously to maximize diagnostic yield.  

Laboratory Testing for Specific Autoimmune Neurologic Diseases

Please visit the following ARUP Consult resources for more information about the laboratory testing strategies for specific autoimmune neurologic conditions:

• Autoimmune Neuropathies topic
• Multiple Sclerosis topic
• Myasthenia Gravis topic
• Neuromyelitis Optica Spectrum Disorders topic