The first tremor was innocuous, akin to shivering from the cold. It seemed odd, but J. Lowe Barton, a law enforcement professional who was working on restoring a classic vehicle, didn’t pay too much attention at the time. The tremors became harder to ignore, though, as they increased in regularity over the next few weeks.

Six weeks later, the tremors were occurring every four to five minutes and resembling seizures. If Barton was unlucky enough to be holding a soda can when one hit, his muscles would involuntarily contract and cause him to squeeze the can, spilling liquid over himself and anyone else nearby. Sleeping became next to impossible, and he would wake with blood on his face where he had scratched himself with his ring at night during an episode. He and his wife, Kathy, sought answers from doctors in southern Utah, where they live, but the clinicians weren’t able to provide any answers. Barton was otherwise in good health, and his magnetic resonance imaging (MRI) scans and infectious disease workups were unremarkable.

At the behest of his concerned daughter, Barton and his wife eventually made their way to the University of Utah’s Autoimmune Neurology Clinic, established by Stacey Clardy, MD, PhD, FAAN. By this time, Barton was also exhibiting faciobrachial dystonic seizures and short-term memory loss, both clinical manifestations of autoimmune encephalitis (AE).

Early recognition and treatment of AE are crucial for patients like Barton, but diagnosis can be challenging and time consuming. Fortunately, the synergistic relationship between ARUP Laboratories and the U enables clinicians to stay abreast of rapidly changing diagnostic approaches and work closely with ARUP medical directors to understand test results, ultimately improving patients’ lives.

AE comprises a group of noninfectious, immune-mediated inflammatory disorders of the brain. Some onconeural antibodies, such as antibodies that target antineuronal nuclear antibody (ANNA)-1 (also known as anti-Hu), have been implicated in AE for years and are classically associated with tumors. In recent years, though, antibodies such as N-methyl-D-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) antibodies, which target the neuronal surface or synaptic antigens, have been identified and may develop with or without a cancer association.

Although antibody testing alone cannot provide a definitive diagnosis of AE, paraneoplastic syndromes, or any related autoimmune neurologic conditions, the detection of autoantibodies in the appropriate clinical setting can help distinguish between similar disorders and inform further testing or medical management, said Lisa Peterson, PhD, D(ABMLI), medical director of Immunology at ARUP and assistant professor at the University of Utah School of Medicine.

Because the field is expanding so rapidly, general clinicians—often the first-line providers a patient like Barton might see—can’t be expected to stay abreast of developments in laboratory testing, Peterson said. “There are new antibodies described every few months. It’s impractical to expect general clinicians to stay up to speed on these.”

To assist clinicians in identifying the autoantibody testing that is most likely to yield positive results in their patients, Peterson and her team at ARUP developed a multitude of testing options, ranging from comprehensive panels, to cost-effective, disease-directed panels, to single autoantibody tests that can be used for monitoring treatment and disease course.

Peterson routinely consults with clinical pathologists about this topic but felt that it was equally important that ARUP bring on board an autoimmune neurologist who could serve as a clinical consultant. She envisioned this person as having an understanding of how the tests are performed and their limitations, as well as the ability to help clients interpret the tests and guide them toward next steps.

That’s where Tammy Smith, MD, PhD, comes into the picture. Smith joined ARUP in April 2022 as a clinically trained, board-certified neurologist. During Smith’s time at the U’s Autoimmune Neurology Clinic, where Barton was treated, she appreciated the unique relationship shared by ARUP and the U. “As physicians, we really relied on our relationship with ARUP and Dr. Peterson to help us better understand the testing options that were available to us and to discuss clinical testing in challenging cases,” Smith said.

During her time as an autoimmune neurology fellow at the Mayo Clinic, Clardy experienced firsthand the benefit of having a neurology clinic closely associated with a clinical reference laboratory. “Simply put, when I started the U’s clinic, not many neurology departments had the vision to understand how [this relationship] could be successful, but the U did,” said Clardy. “Having a close partnership with ARUP allows us to diagnose our patients much faster and more efficiently than most any other location in the country.”

While Smith was an autoimmune neurology fellow in Clardy’s program, she rotated with Peterson at ARUP. “Many physicians don’t have the opportunity to see how clinical laboratory testing is done,” explained Smith. “Because of my PhD in microbiology and immunology, I was familiar with a lot of the techniques, but I was just very interested in seeing how clinical laboratory testing happens.”

Smith’s interest in continuing to do basic science research and see patients was intriguing to Peterson, who sees Smith as uniquely situated to bridge the gap between clinical practice and the laboratory. “She brings in the experience of having seen patients, of determining the appropriate tests to order, and of being able to understand and interpret results in a clinical setting,” Peterson said.

Because the majority of autoantibodies are extremely rare, most have low positivity rates. Therefore, reliable autoantibody identification is highly dependent on determining the likelihood that a patient will test positive for any given antibodies. To obtain the most actionable information from autoantibody testing, it makes the most sense to order a targeted panel based on the clinical presentation of the patient, Peterson said. “If you consider how the patient presented, their history, and their clinical and imaging exams, you can start to parse out which tests are most likely to be positive.”

Moreover, if there is a high pretest probability of a known syndrome, Smith said, waiting for the results of antibody testing should not delay treatment. Some antibody-mediated disorders can be severe and even life-threatening, but may be reversible with prompt and appropriate treatment. Even so, the results of antibody testing help support clinical decision-making when it comes time to consider long-term management options and prognosis, explained Smith.

Fortunately, Barton’s condition was one that responded to treatment. Barton was diagnosed with LGI1 antibody encephalitis, a form of AE for which early treatment may prevent long-term cognitive deficits and reduce seizure activity over time.

Kathy Barton recalls the neurologist at the U telling her that they were fortunate to have gotten her husband in when they did. “They told me that if J.’s illness had persisted much longer, he may not have recognized me in a few months’ time,” she said. It took many years of immunosuppressive therapy to treat his illness, but today, Barton has completed his treatment plan and lives a full and happy life with Kathy.

“Dr. Peterson and her team are devoted to this patient population and care deeply. They never fail to bring all of the resources ARUP has available to benefit our patients,” said Clardy. “Our patients benefit despite never knowing what’s required behind the scenes to make it happen.”

Stories like Barton’s keep Peterson and Smith focused on ways they can continue to advance patient care. Importantly, Peterson and Smith will work with Clardy’s autoimmune neurology fellows during their rotation at ARUP in an ongoing effort to share knowledge about the intricacies of neural antibody testing.

“An autoimmune neurologist needs to understand the details of this testing to avoid misdiagnosis and misinterpretation of low-positive results,” said Clardy. “Understanding which test results are relevant in each given clinical context is essential to know when to utilize—and importantly, when not to utilize—available therapies,” said Clardy.

For her part, Peterson said that she is always collecting positive samples for new antibodies and plans to validate several to add to ARUP’s test menu in the coming year.

“ARUP was one of the first laboratories in the country to offer testing for NMDAR antibodies. I want to continue on that path of identifying new antibodies and understanding the pathogenesis behind these diseases because that will ultimately inform and improve therapies for patients,” Peterson said.

Smith plans to continue to conduct basic science research at the VA Salt Lake City Healthcare System to study the mechanisms behind paraneoplastic syndromes and neurologic disease. She and Peterson are also collaborating on a study to determine the value in testing for autoantibodies in both serum and cerebrospinal fluid (CSF).  

“There’s so much room in this field to improve patients’ lives,” Smith said. “We’re still in the infancy of understanding these diseases, how we test for them, and how we treat them. In five years, the story we tell will be different from the one we tell today.”

ARUP’s Medical Experts Assist Clinicians in Selecting Laboratory Tests to Diagnose
Autoimmune Neurologic Disorders

As a child growing up on her family’s vegetable farm, Tammy Smith, MD, PhD, spent a lot of time thinking about the rhythm of an ecosystem.

“You’ve got precipitation, soil, sun, nutrients, invasive species,” she said. “You’ve got all these things interacting, so how do you ensure they work well together?”

Now a neurologist, Smith thinks about the body in much the same way.

“The nervous system, digestive system, heart, lungs, kidneys … these function as discrete organs but have to work together for the organism to survive,” said Smith, whose love of science eventually took her from the farm just north of New York City to medical school. “The human body is like an ecosystem on an individual scale, and the immune system carries information throughout the body to make sure all of the parts communicate with each other.”

Smith’s subspecialty is autoimmune neurology, the study of antibody-associated diseases that affect the nervous system. It’s a perfect pairing of her natural interests in immunology and neurology. She was drawn to neurology by the many unanswered questions in that field and the opportunity to collaborate across medical specialties to provide patient care.

“When you have a chronic neurologic disease, such as multiple sclerosis, a stroke, or Parkinson’s disease, your neurologist becomes an essential member of your healthcare team. I love that neurology provides an opportunity to have an ongoing relationship with my patients.”

Smith completed a fellowship in autoimmune neurology, during which she cared for patients with multiple sclerosis, paraneoplastic neurologic syndromes (PNSs), and autoimmune encephalitis. Her research focuses on the mechanisms that lead to the development of PNSs, a group of conditions that affect the nervous system—brain, spinal cord, nerves, and/or muscles—and are frequently associated with cancer.

She joined ARUP Laboratories in April 2022 as a clinical consultant in autoimmune neurology, becoming part of a team run by Lisa Peterson, PhD, D(ABMLI), medical director of Immunology. The group is working to advance the scientific understanding of immune-mediated neurologic diseases and improve patient testing and treatment outcomes. “I’m really excited to be joining this team and to be working with Dr. Peterson,” Smith said.

Smith has lived in Salt Lake City on and off since 2001, when she first moved to Utah with her husband to enjoy skiing “The Greatest Snow on Earth.” From 2006 to 2015, she attended the University of Utah, earning a combined MD/PhD degree with an emphasis in microbiology and immunology. She spent four years in Chicago at Rush University Medical Center, completing her internal medicine internship and neurology residency. She returned to Salt Lake City, and the “academic powerhouse” of the U, for an autoimmunology fellowship, which included a month-long, laboratory-intensive rotation at ARUP.

That’s where Smith met Peterson, who helped launch and oversee the laboratory portion of the fellowship program. Peterson said she was immediately impressed by Smith and felt a kinship with her.

“We share similar goals in terms of what we want to do to expand tests and what we are trying to do for patients,” said Peterson, who was already hoping to add a neurologist with clinical experience to her team to help with a growing demand for test consultations.

Smith’s desire to pair basic science research with patient care made her a perfect fit, Peterson said.

In an email to ARUP leadership, Peterson made her pitch, saying Smith would be an incredible asset: She could help grow the reference laboratory’s test, educational, and consultative offerings, as well as facilitate research that could lead to the discovery of novel antibodies associated with neuronal diseases.

“I really see the two of us being able to have a great synergism; she can help us here, and we can help identify and provide samples that can then be used in her research lab to really study these diseases,” Peterson wrote. “Her work can also inform how we better perform testing as well as other aspects of patient management.”

Clinicians and patients will see an immediate benefit from Smith’s expertise as they look for answers to important and daunting medical questions.

“I have the experience to speak to ordering clinicians and share my understanding of how the assays are being done, as well as their limitations, sensitivity, specificity, and the pretest probabilities,” Smith said. “My clinical training allows me to help them interpret the tests and hopefully guide them to the next steps for diagnosis and treatment.”

Peterson believes those same insights will be invaluable as she and her team consider how to prioritize next steps in research and test development to advance patient care.

“I have this list of tests that we want to validate,” Peterson said. “And I can look at frequencies in the literature and make assumptions, or I can even do retrospective evaluations of frequencies to help drive those decisions. What Tammy can do is provide perspective about which of these options she finds most clinically valuable.”

Smith also brings her own network of resources and relationships to the table, connections that may expand ARUP’s opportunities for new collaborations, Peterson said.

It is an exciting time to be working on the challenges of immune-mediated neurologic diseases, Smith said. New antibodies targeting the nervous system are identified every year, and these discoveries have allowed researchers to characterize the syndromes these antibodies cause. That’s good news for patients and families who are struggling to understand their symptoms and looking for answers, she said.

One example of such a finding is the identification of antibodies to aquaporin-4, which are associated with a disease called neuromyelitis optica (NMO). Before the discovery, patients were often diagnosed with multiple sclerosis (MS), Smith said, but many treatments for MS can actually worsen NMO. With the discovery of new antibodies and the development of tests specific to them, patients with NMO can be clearly identified and grouped for clinical trials. During the past three years, advancements like these have led the U.S. Food and Drug Administration (FDA) to approve three new medications for the treatment of NMO.

Such advancements promise to provide future patients diagnosed with immune-mediated neurologic disorders with targeted treatments that are more effective and have fewer side effects.

“We are still in the infancy of understanding these diseases—how to appropriately test for antibody-mediated neurologic diseases and how to appropriately treat them,” Smith said. “I am excited to see what we will learn going forward to improve the lives of patients.”