April 26, 2019
Charles L. Howe, Ph.D., director of the Translational Neuroimmunology Laboratory at Mayo Clinic in Rochester, Minnesota, and Eric T. Payne, M.D., M.P.H., a pediatric epileptologist at Mayo's campus in Minnesota, answer questions about pediatric epileptic encephalopathies caused by neuroinflammation in the absence of antibodies. These autoinflammatory epilepsies can present with signs and symptoms similar to those of autoimmune epilepsy.
How does autoinflammatory disease differ from autoimmune-mediated seizures?
Both conditions present as refractory epilepsy with no clear etiology. But in autoimmune-mediated seizures, an antibody targets a brain protein, leading to dysregulation of the neurocircuit. In autoinflammatory disease, something — generally an infection outside the brain — triggers systemic inflammation. In certain individuals, that inflammatory event can become a self-propagating inflammatory syndrome, causing dysregulation of the neurocircuit and seizures. The number of these inflammatory seizure disorders that exist in children and aren't mediated by antibodies has been underappreciated.
How is autoinflammatory disease diagnosed?
Mayo's Translational Neuroimmunology Laboratory can perform ex vivo testing of patients' blood samples to measure levels of cytokines associated with autoinflammatory disease, such as IL-1 beta, TNF and IL-6. We are working to develop higher throughput testing panels similar to those that Mayo offers for autoimmune neurology.
What should physicians look for when considering autoinflammatory disease testing?
Our investigations into these conditions are just starting, so it's going to be a moving target. But often these children are previously well and cognitively normal, and present with an explosive onset of seizures that don't respond to anti-seizure medications. Investigative tests and standard neuroimaging fail to identify an underlying cause or detect the neuroinflammation that is continuing to drive seizures and affect cognition.
Autoinflammation has been identified in children with febrile infection-related epilepsy syndrome (FIRES), a devastating epileptic encephalopathy that requires a prior febrile infection occurring between two weeks and 24 hours before the onset of refractory status epilepticus — with or without fever at the onset of seizures. A child might get a cold and a bit of a fever, and then a day or two later, the unrelenting seizures start.
Autoinflammation has also been identified in kids with electrographic status epilepticus in sleep, in children with febrile status epilepticus who later developed mesial temporal sclerosis and even in a teenager with presumed new-onset juvenile myoclonic epilepsy — a relatively common generalized epilepsy.
How are autoinflammatory-mediated seizure disorders treated?
Typically, a steroid — such as methylprednisolone, which blocks inflammation broadly — is trialed first. Sometimes patients may respond to this temporarily, and other times it does not work at all. But if we can identify a specific inflammatory target that is driving the inflammatory process, we can use more-precise immunomodulatory treatments to block that specific cytokine pathway. Many of these precision immunomodulatory treatments have already been approved by the Food and Drug Administration for use in children and have good longitudinal safety profiles. Our rheumatology colleagues have treated patients with these medications regularly for many years.
A few years ago, Mayo Clinic was the first to successfully treat a 2-year-old girl with FIRES using anakinra, a drug that blocks the effects of IL-1 beta. Since then, we have learned that although anakinra isn't always effective in children with FIRES, a substantial number do indeed respond robustly. FIRES is a multifactorial condition that likely varies with a child's genetics, and the cause isn't fully elucidated. But autoinflammation seems to play a key role in the disease pathology for some patients.
We do know that, in general, the earlier we can intervene, the sooner the seizure resolution and the outcome. Our index patient has evidence on imaging of some damage to the brain, and we started treating her six days after seizure onset. But we also have examples of patients who began treatment 30 days after seizure onset and still benefit from therapy. A one- or two-week trial should be sufficient to know if the therapy is helping; sometimes the benefits are apparent within a few days.
We have seen enough of these patients to know how the condition is likely to progress. It's important to understand that the potential benefits of starting treatment far outweigh any risk.
What has Mayo Clinic learned about biomarkers and treatments?
Our lab analysis showed that our patient with FIRES who responded to anakinra has mutations in her IL-1 receptor that are associated with ulcerative colitis and rheumatoid arthritis, as well as some novel IL-1 receptor mutations. We also found that she was making more IL-1 isoform, especially in her cerebrospinal fluid, than other individuals — but the isoform was defective. Our current hypothesis for why this child responded so robustly to anakinra is that she has a functional deficiency in IL-1 receptor antagonist function that anakinra replaced. That suggests that other children with autoinflammatory disease might be screened for a functional IL-1 deficit to help determine if anakinra would be an effective treatment.
In addition to analyzing patient samples, we are using animal models to study the cytokines associated with seizures. That work focuses primarily on TNF because we have a lot of lab-based evidence of how TNF can alter neurocircuitry.
What role do you foresee autoinflammatory disease playing in future diagnosis and treatment of people with refractory epilepsy?
Currently, about 30 percent of all patients with epilepsy do not respond completely to anti-seizure medications. Many of these children and adults will have anti-inflammatory therapy to treat their seizure disorders — and not just people with rare disorders such as FIRES. We know that increased seizure burden can potentiate inflammation in and of itself.
Our research has given us some evidence of a commonality in the changes that occur in the inflammatory profiles of people before they experience seizures. Something may cause the release of the factors that can recruit the innate immune cells into the brain and cause the seizure. In our animal models, we have successfully intervened to block these factors and prevent seizures.
Currently, we use anti-seizure medications like a hammer, to knock the seizures down. Cytokine analysis can result in precision therapy that targets a specific pathway and addresses ongoing inflammation. Our ultimate hope is that, even if someone has had epilepsy for 40 years, we can find an inflammatory component and successfully target it. The goal of Mayo Clinic's lab research is to impact human health.