Elevating understanding with a phenotype-specific approach

Frequently asked questions

In this video, Dr. Pittock answers several questions related to the phenotype-specific approach to autoimmune neurology testing during a live webinar. Below are the most popular questions asked during a series of Q&A discussions with Mayo Clinic neuroimmunology experts.

1. Is it important to send both serum and CSF samples or, in some circumstances, is it OK to send one or the other?

It can be very challenging to identify the specific antibody you are looking for, so it’s important to be comprehensive. Both are strongly recommended for encephalopathy, epilepsy, dementia, and movement disorders because some antibodies are more sensitive in specific specimen types. For example, NMDA is more readily detected in CSF (GFAP and NIF are also better in CSF), and LGI1 & CASPR2 are better in serum. In patients suspected of having CNS demyelinating disease, we generally just offer serum (AQP4 and MOG are great in serum). Also, autoimmune vision loss and our myasthenia gravis test are only offered in serum. Sequential testing could be possible (serum first, then CSF if high suspicion remains), but only in specific phenotypes (FBDS – LGI1).

2. Does the antibody titer matter? 

Generally, antibody titers don’t provide much clinical value in managing patients and treatment. The titer levels that are specific to neurological disease are very large. The higher the titer, the more specific the result, but we’ve designed assays so that any positivity provides useful clinical information. The exception is probably antibodies that are tested via radioimmunoprecipitation assays (RIAs) such as GAD65, AChR-Ganglionic, VGCC P/Q, VGKC, etc. Low titers in these antibodies are very nonspecific (8% of healthy people have GAD65), and this method can generate false positives, so here we pay attention to titer levels. MOG antibodies have also been found to be problematic at low titer levels. But, in large part, we’ve designed testing so that any positive result will provide physicians with actionable, clinical information.

3. There appears to be a lot of overlap in the phenotype-specific panels. Why?

We want all of our panels to include all relevant antibodies. In our attempt to be comprehensive, you will notice the overlap. But there are intentional, panel-specific differences (myelopathy, peds, movement disorder, etc.) that help us maintain high specificity in our panels. We’ve published on all of these antibodies, so there is relevant, up-to-date data that drives our decisions on which should or shouldn’t be included in each phenotype-specific evaluation. The goal of the physician should be to pick the BEST panel for that patient.

4. How do you decide when to remove some antibody markers from your evaluations?

It depends on knowledge, science, and data. We are always doing research to ensure we have the most up-to-date information. We’ve learned that these “legacy” antibodies (VGCC N-type, striations, etc.) were really just added to panels based on early assumptions of cancer associations. However, now we know that the specificity of these antibodies in some clinical contexts is very low. We’re continually updating our evaluations based on data for antibodies that are very specific and clinically actionable. We only want to include antibodies that are going to help physicians provide better care for patients. Some could be added back in, but as part of an algorithmic reflex that makes the value of that antibody more specific (clinically actionable).

5. Will MOG be offered in the encephalopathy panel?

MOG patients have a very specific phenotype (ADEM, etc.), so we’ve only included it in tests related to that demyelinating phenotype. A lot of our encephalopathy samples are more broad than just ADEM, and we’ve learned that MOG antibodies in low titers are not very specific. This could lead to confusing results in encephalopathy patients. Ordering physicians need to ensure that they have MRI findings that point to a demyelinating disease first, then order one of the demyelinating evaluations. We want to make sure that a positive antibody result leads to meaningful clinical action by the physician, so at this point, you need to order separately. However, MOG is found often in pediatric patients, so it is included in the tailored peds eval (PCDES/PCDEC).

6. Will Mayo Clinic continue to offer paraneoplastic testing or will only phenotype-specific evaluations be available?

There’s been a lot of advancement in the field since traditional paraneoplastic testing was launched. New antibodies have been discovered and better methods of detection have been identified that we’re not able to put into the “legacy” paraneoplastic testing. That means the PAVAL/PAC1 testing is giving physicians a false sense of security, because it’s not comprehensive. Additionally, we now know that these disorders can be paraneoplastic, but not all neuronal antibodies are associated with cancer, so “paraneoplastic” is no longer the appropriate terminology for this testing. The presentation-specific evaluations are the way the field is going and will be what Mayo Clinic focuses on.

7. Any tools that can help guide a physician’s laboratory approach?

The main thing to remember is that these autoimmune patients can present with many different neurological symptoms, so they are very complex. You need to pick the predominant patient presentation and order that evaluation in BOTH serum and CSF. Never order more than one type of PSE. The APE2 and RITE scores are great scores because they put together the clinical knowledge we have to help decide who to test and who not to test. You just need to remember that the APE2 only applied directly to encephalopathy and epilepsy phenotypes, but many of the questions can still be used as a guide for other phenotypes. One of the most important criteria is the subacute onset of the neurological problem. If the problems are slowly progressing, it’s not autoimmune encephalitis. Here are some additional resources:

• Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis
• Mayo Clinic Laboratories – Autoimmune Neurology
• Autoimmune Neurology Evolution

8. How do you determine the predominant patient presentation?

It’s not unusual to have multifocal presentation for paraneoplastic neurological disease. You just pick the one that is slightly more pronounced. Our tests are built in a way that there is redundancy. You will not miss the relevant antibody as long as you go with the more predominant presentation. Think about it like cognitive predominant or movement predominant, and then demyelinating separate from that. Sending in both serum and CSF is critical.

9. What is your advice regarding utilization of this testing to avoid misuse?

Under- and overutilization are common themes. It’s a challenging area because there’s not really a screening test. Need to evaluate acuity of onset, clinical context, risk factors (smokers, family history of AI disease). Additionally, MRI, EEG, WBC, OCBs should all be evaluated. It is recommended that more experienced Consultants be involved in ordering these evaluations. Feel free to call our lab anytime for advice.

10. Can you comment on age cutoff or other red flags when ordering these expensive paraneoplastic panels?

Age is a challenging criterion for appropriate usage of this testing. In our experience, the key factor is acuity of onset: subacute (days to weeks) rather than age.

11. What if physicians are specifically interested in some antibodies that aren’t offered in our phenotype-specific evaluations?

There is currently no role for VGKC antibodies clinically. 85% of VGKC antibodies are NEGATIVE for LGI1 and CASPR2, which are the clinically actionable components of that complex. Many other antibodies are very relevant, but only to specific diseases (Gang, VGCC P/Q, etc.). Many of these are RIAs, so the low positive results might not be clinically relevant. For example, in dysautonomia, AChR-Ganglionic is relevant, but in encephalopathy, it’s not relevant. They aren’t included in many evaluations because those test results wouldn’t add clinical value. (Also see answer for #4)

12. Is there a time when PAVAL would be appropriate?

No. We’re covering all the relevant abs and more in the preferred evaluations.

13. Do you think re-testing will add any value to the follow-up of patient with a low positive antibody finding? If so, what is the timeframe to do so? What about repeating negative test results?

No. I would not recommend that. If the antibody value doesn’t fit initially, it won’t be valuable to repeat it later. There are a few exceptions. You need to consider the methodology the lab used to test the sample. If you are still highly suspicious of autoimmune cause and are unsure on methodology, we recommend sending to a more experienced lab. Also, if you sent the sample after IVIg or PLEX, then you could re-test after pausing therapy for a month or so. However, you need to remember that these are very rare disorders, and the most appropriate next step is probably to re-evaluate the clinical presentation (subacute onset, pleocytosis, MRI findings, etc.). In some phenotypes where you have an unexpected seronegative result (MG, NMOSD, LEMS), repeating testing within 6 months could be of some value. A trial of immunotherapy could be appropriate as well. In our lab, we have found that up to 50% of AE patients are seronegative. If you sent the sample to our lab, maybe you could contact us directly to see if there might be an unclassified antibody that we weren’t able to report.

14. For autoimmune testing, would you recommend tissue-based assays (w/hippocampus) as a first-line test, and if positive reflex to CBA, or should CBA be the first-line test?

It depends on the antibody. Some are optimally detected w/TIFA (classic paraneoplastic Abs – ANNA-1, PCA-1, etc.). Others have a role for screening w/CBA (NMDA). But I think for most of these, using both is preferred. Evaluating some antibodies by TIFA alone (especially on serum) can sacrifice sensitivity, so using both methods (and both specimen types) is preferred. MCL has designed testing algorithms to leverage both methods and optimize sensitivity/specificity.

15. Regarding antibody testing, are there approaches to ordering antibody testing that will identify various types at one given time as opposed to limiting testing to individual types of antibodies?

We try to avoid single antibody tests because it’s very difficult to say with certainty which antibody causes the clinical presentation. The panel-based approach that includes both autoimmune and paraneoplastic antibodies is much preferred. Our panels include all the relevant antibodies for a predominant phenotype.

Learn more about how to order these evaluations at your institution.

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