Autoimmune neurology testing has evolved beyond limited paraneoplastic evaluations to phenotype-specific panels that identify clinically relevant antibodies. This phenotype-specific approach significantly improves diagnostic accuracy, reduces false positives, and helps guide faster, more personalized treatment for complex neurological diseases.
Neurological paraneoplastic syndrome is a cluster of symptoms (e.g., double vision, memory loss, confusion, seizures, and movement disorders) that develop when a person’s malignant tumor causes their immune system to release antibodies to destroy the tumor. In the process, these antibodies or associated white blood cells (lymphocytes) also damage cells and healthy tissue in the central nervous system -- brain, spinal cord, and nerves. These symptoms can be the first sign of the underlying malignancy. Traditional evaluations that screen for these autoimmune neurological disorders are often limited and can be prone to false-positive results or an overlooked diagnosis. This is because these evaluations are nonspecific and can leave out new, clinically relevant antibodies such as septin-5, septin-7, and PDE10A, discovered by Mayo Clinic.
Mayo Clinic Laboratories transcends traditional testing with cutting-edge autoimmune and paraneoplastic-specific evaluations that use a phenotype-specific approach, pioneered by Mayo Clinic Laboratories, to recognize key phenotypic features of autoimmune CNS disorders. Further, these evaluations have expanded beyond paraneoplastic syndrome disorders.
“These antibodies we test for are comprehensive and include not just paraneoplastic disorders but also disorders that typically have no cancer association such as LGI1 encephalitis, autoimmune GFAP astrocytopathy, and autoimmune ataxias,” says Andrew McKeon, M.B., B.Ch., M.D., neurologist and codirector of Mayo Clinic’s Neuroimmunology Laboratory. “Our testing is based on how the patient presents clinically. For example, a patient with rapid cognitive decline and seizures (autoimmune encephalopathy evaluation) or a patient with rapid onset of slurred speech, incoordination, and falls (autoimmune movement disorders evaluation). The key patient factor is cadence of onset. For autoimmune neurological diseases, these are typically subacute in onset (over days to weeks). Disorders of subacute onset also considered include demyelinating disease (multiple sclerosis) and other inflammatory diseases like sarcoidosis or infectious diseases.”
Testing also spans metabolic disorders that can have a fairly rapid onset and progression, like vitamin B12 deficiency or toxic disorders, or, in some circumstances, patients with underlying psychiatric disease presenting with neurologic symptoms. “A traditional paraneoplastic evaluation really only covers causation,” adds Dr. McKeon. “It doesn't typically tell you anything about the neurological presentation of the patient and only covers patients where we have an antibody with a suspected cancer association.”
A testing approach grounded to the patient’s bedside
This comprehensive evaluation of a patient’s condition starts at the bedside to ensure all antibodies relevant to a patient’s phenotype are included. To avoid false-positive results, antibodies that aren’t clinically significant for a phenotype are not included.
“Over time, our physicians at the bedside have recognized subsets of patients that had similar clinical presentation and responded uniquely to treatment,” says John R. Mills, Ph.D., codirector of the Neuroimmunology Laboratory. “They went on to deeply characterize these patients and correlate their clinical observations with unique staining patterns on our immunofluorescence assays that utilize brain tissue. Once the antigens and antibodies responsible for those unique patterns were identified, these could be grouped into testing panels based on the associated clinical presentation. This helps ensure the right antibodies are being tested for a given patient based on their clinical presentation.”
After determining which antibodies to include in each panel, experts in the Neuroimmunology Laboratory establish a preferred specimen type: serum, cerebrospinal fluid, or both. Some specimen types are more sensitive for certain antibodies but, often, the recommendation is to send both, which maximizes diagnostic yield.
“Then this will lead to a profile of autoantibodies that are tested by optimized technology for each of those antibodies,” says Dr. McKeon. “And, along with test results, we offer a nuanced interpretative report based on the single or multiple autoantibody findings.”
Discovery and translational science at work
The whole process of identifying similar patient presentations, identifying the correlating antibodies, and designing an evaluation with a suite of these antibodies takes an extremely high level of expertise.
“To get to this point, it took a tremendous amount of discovery and translational science that happens behind the scenes,” says Dr. Mills. “It’s driven by our clinicians and our lab staff who take those observations, make a discovery, translate that discovery into a clinical test, and ensure that test performs at the highest level before offering that antibody test to patients.”
As it has over the last 30 years, the lab continues to identify new antibodies and make connections between patterns on tissue immunosuppressants, a disease presentation, and treatment response. And there are few labs, if any, that do it better.
Dr. Mills continues, “When you look at all the labs in the U.S. that do this kind of testing, of the clinically relevant antibodies currently available to patients, in many cases the Mayo Clinic Neuroimmunology Laboratory has been the one to discover that antibody, or has played a major role in establishing the clinical utility of an antibody test.”
Divyanshu Dubey, M.B.B.S., codirector of the Neuroimmunology Laboratory, is at the forefront of the lab’s neuroimmunology discoveries and translational science.
“To get to this point, it took a tremendous amount of discovery and translational science that happens behind the scenes.”
John R. Mills, Ph.D.
“Like myself, Dr. McKeon, Dr. (Sean) Pittock, and Dr. (Anastasia) Zekeridou, we are all neurologists and we see patients with autoimmune neurological diseases,” he says. “But in addition to being neurologists, we are also laboratorians and lab directors who oversee test development, validation, and implementation. Our ideas for what is most relevant, what can help the patients the best, are very personal to us because we take care of these people. That inspiration or motivation we derive from taking care of challenging cases with paraneoplastic or autoimmune diseases also drives us on our innovation journeys and drives us to try and discover new biomarkers. Because we realize, firsthand, how these biomarkers can transform a patient's journey and give people answers to questions that they haven't gotten, sometimes for many, many years, despite being seen at multiple institutions.”
A Phenotype-Specific Approach
Mayo Clinic Laboratories transcends traditional testing with cutting-edge autoimmune and paraneoplastic-specific evaluations that use a phenotype-specific approach, pioneered by Mayo Clinic Laboratories, to recognize key phenotypic features of autoimmune CNS disorders. Further, these evaluations have expanded beyond paraneoplastic syndrome disorders.
New biomarkers lead to better patient care
When an autoantibody biomarker is discovered, is it often disease specific, and it can give clarity about disease pathogenesis or how the disease is being caused, which can lead to treatment insights.
“In some cases, the treatment journey of a patient involves searching for cancer, like in paraneoplastic syndrome cases,” says Dr. Dubey. “So, as a part of our role as clinicians involved in clinical and translational research, in addition to discovery of autoantibodies as novel biomarkers for various paraneoplastic and autoimmune diseases, many of us are also actively involved in clinical trials to find the best answer in terms of treatment for these patients. So it's like a full-circle journey, bridging the entire bench-to-bedside story.”
Groundbreaking discoveries include Kelch-like protein 11 (KLHL11) IgG, an autoantibody associated with paraneoplastic neurological syndrome. It often presents with a rare form of encephalitis, rhomboencephalitis, and is commonly linked to testicular cancer (in about 70% of cases). KLHL11 was identified by Dr. Dubey and Dr. Pittock in collaboration with scientists at UCSF Health. The antibody is now part of a clinical movement disorders evaluation (Mayo IDs: MDC2, MDS2) offered by Mayo Clinic Laboratories.
“This is a classic paraneoplastic disease, which often occurs in men in their 20s, 30s, or 40s, where a testicular cancer stimulates the immune system to try to get rid of the tumor,” explains Dr. Dubey. “But in the process, some of the proteins that are expressed in the tumor lead to friendly fire towards the brain. And this friendly fire leads to significant brain damage and injury and disability in these young men in the potentially most productive years of their lives.”
The assay does two critical things: first, it offers the patient a definitive answer, and secondly, it allows them to get started on the appropriate treatment to help stabilize the disease and prevent progression.
“We've been able to help hundreds of people, some of them that I've personally seen, but also many people all across the world."
Divyanshu Dubey, M.B.B.S.
Dr. Dubey continues, “We've been able to help hundreds of people, some of them that I've personally seen, but also many people all across the world. Other labs around the world are now trying to get this test up and running to help serve patients with this rare condition. So, discoveries such as KLHL11 have now been widely recognized.”
In the non-paraneoplastic discovery realm, for example, there’s caveolae-associated protein 4 (cavin-4), an autoantibody biomarker associated with immune-mediated rippling muscle disease (iRMD), identified by Dr. Dubey in collaboration with other neuromuscular and Advanced Diagnostic Laboratory colleagues (published in JAMA Neurology). Rippling muscle disease is a rare autoimmune muscle disorder that causes wavelike muscle contractions (rippling), muscle mounding (the muscle “bunches up” on percussion), pain, and weakness. While normally not associated with cancer, there are exceptions.
“There have been cases associated with thymoma, breast cancer, where that can trigger cavin-4 antibody production and rippling muscle disease,” says Dr. Dubey. “This is a treatable disease. I recently had a patient who was treated with appropriate treatment, and now he is disease-free and cavin-4 antibodies have turned up negative.”
Going beyond discovery
In addition to discovering new autoantibody biomarkers and clinically characterizing patients, the Neuroimmunology Laboratory always goes further by studying and trying to better understand these autoimmune and paraneoplastic neurological disorders.
“We've done pathology studies, immunogenetic studies, additional cellular response studies, taking the science forward,” says Dr. Dubey. “Our ultimate goal here at Mayo Clinic Laboratories is to serve patients not only through our labs, but also through our research. So this journey of identifying new biomarkers continues well beyond their discovery, into patient care and new treatments.”
