Autoimmune Neurologic Diseases - Antineural Antibody Testing

Last Literature Review: May 2023 Last Update:

Medical Experts



Tammy Smith, MD, PhD
Assistant Professor of Neurology, University of Utah
Clinical Consultant, Autoimmune Neurology, ARUP Laboratories
GRECC Investigator, George E. Wahlen Department of Veterans Affairs Medical Center

Autoimmune neurologic diseases are a broad category of rare conditions, including autoimmune encephalitis, paraneoplastic neurologic syndromes (associated with cancer), and related disorders. Autoimmune neurologic disease arises when a patient’s dysregulated immune system targets “self-antigens” within the nervous system. This immune dysregulation may lead to diverse neurologic phenotypes, depending on the associated antibody and individual patient, including dementia, demyelination, encephalopathy, epilepsy, movement disorders, myelopathy, neuromuscular junction disorders, neuropathy, vision loss, and others.

Symptoms generally develop subacutely (over weeks to a few months) and progress rapidly. In patients with paraneoplastic syndromes, neurologic symptoms may precede the identification of a malignancy and aid in the subsequent diagnosis of cancer.  In other cases, immune-mediated neurologic syndromes may develop after certain kinds of infections.  Often, no cause for the development of autoimmune neurologic disease is identified.

Antibodies serve as markers of autoimmune neurologic diseases and in some cases have been shown to be directly pathogenic. Evaluating patient serum or cerebrospinal fluid (CSF) for these antibodies has become an increasingly common part of clinical care. However, antineural antibody testing is an evolving field. Clinical laboratories routinely add new antibodies to their panels and remove antibodies based on new research, which makes test selection challenging.

Quick Answers for Clinicians

When should I consider testing for antineural antibodies?

Antineural antibody testing should be considered in the evaluation of patients with subacute (over weeks to several months) onset of new neurologic symptoms such as abnormal movements, memory problems, psychiatric symptoms, seizures, or sleep changes. A known history of cancer, recent viral prodrome, or a personal or family history of autoimmunity increases the likelihood of an underlying autoimmune process. Brain magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) studies suggestive of an inflammatory process can support the decision to pursue testing for antineural antibodies. Importantly, other causes of neurologic symptoms, including drug or toxin exposure, genetic disorders, infections, metabolic or endocrine derangements, nutritional deficiencies, primary psychiatric disease, or vascular disorders should not be overlooked or underestimated; these diagnoses warrant different treatment from that used for autoimmune neurologic conditions.

Does antibody testing for autoimmune neurologic diseases provide clinically actionable information?

Yes. Although antibody testing alone cannot provide a definitive diagnosis of autoimmune neurologic disease, the detection of relevant antibodies in the appropriate clinical context can help establish a clear diagnosis, inform additional testing, and support treatment decisions. For example, certain well-characterized antineural antibodies (eg, Hu, Ri, and Yo) are strongly associated with cancer and provide valuable information about malignancies for which a patient might need to be screened.  The detection of some antibodies can also guide treatment decisions or facilitate enrollment in clinical trials. Although some antibodies are very rare and currently of uncertain clinical significance, their identification plays an important role in the characterization of previously undescribed syndromes and the development of future treatments.

Should I order a comprehensive panel or a targeted panel for a patient with suspected autoimmune neurologic disease?

In general, the best strategy for antineural antibody testing is to choose the most targeted panel that fits the patient’s clinical phenotype, rather than a comprehensive panel. Comprehensive panels have been used for many years to broadly assess patients for the presence of antineural antibodies. However, as these comprehensive panels have expanded to include newly identified antibodies in addition to the previously recognized antibodies, turnaround time and cost have increased. Furthermore, including antibodies that are not associated with the patient’s phenotype increases the risk of false-positive results, which can cloud the diagnostic picture. Finally, relying on comprehensive panels rather than clinical judgment can contribute to a false sense that autoimmune neurologic disease has been effectively ruled out.

Refer to Antibody Test Selection for additional details.

Should serum or cerebrospinal fluid be used for antineural antibody testing?

Although serum is much easier to obtain than cerebrospinal fluid (CSF), it is generally recommended that both serum and CSF be tested when autoimmune neurologic disease is suspected because the antibody profiles may differ between specimen types.   For example, tests for antibodies to leucine-rich, glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) may be positive in serum but negative in CSF; if only CSF testing is ordered, the presence of these antibodies could be missed.  Tests for other antibodies, such as N-methyl-D-aspartate receptor (NMDAR) and glutamic acid decarboxylase 65-kd isoform (GAD65), have greater specificity when performed on CSF than when performed on serum.  Refer to Specimens for Antibody Testing for additional details.

Should I order the same tests for suspected autoimmune neurologic disease in adult and pediatric patients?

The autoantibodies associated with autoimmune neurologic disease differ between adult and pediatric patients.  For example, paraneoplastic antibodies such as ANNA-2, ANNA-3, PCA-1, and PCA-2 are very rare in adults, but even less common in children.  Including these antibodies in pediatric panels leads to extremely low yields, so they are excluded. Similarly, myelin oligodendrocyte glycoprotein (MOG) antibody is included in pediatric but not adult encephalopathy panels because the clinical phenotype associated with this antibody in pediatric patients is much more likely to include encephalopathy, whereas MOG antibody in adults is more often associated with optic neuritis or transverse myelitis.  Thus, test selection should be based on the patient’s clinical phenotype, with additional consideration given to pediatric-specific panels in individuals younger than 18 years.

Why are multiple methods used for antibody testing in autoimmune neurologic disease?

All methods used to test for antineural antibodies have associated complexities. Whenever possible, two complementary methods are generally used for antineural antibody testing. Screening methods allow for identification of patterns of antibody binding to tissue, and confirmatory methods identify specific antigenic targets. For more detailed information on antibody testing methods, refer to the ARUP Institute for Learning video lecture entitled, Updates in Autoimmune Neurology: Phenotype-Specific Testing and Avoiding Misdiagnosis. If there are questions or concerns about testing methods, consultation with your clinical reference laboratory is advised.

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


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:

ARUP Laboratory Tests

For a detailed list of ARUP antineural antibody panel components, please refer to the ARUP Autoimmune Neurologic Disease Serum and CSF Antibody Panel tables.

Phenotype-Specific Targeted Antibody Panels


Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)


Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)


Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)/Quantitative Radioimmunoassay (RIA)


Semi-Quantitative Cell-Based Indirect Fluorescent Antibody/Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)

Pediatric Panels

Comprehensive Antibody Panels

Paraneoplastic Panels