Autoimmune Encephalitis (AIE) in Children: A Q&A with Drs. Catherine Otten and Stephen Wong

Catherine Otten, MD, and Stephen Chee-Yung Wong, MD, lead the Inflammatory Brain Disorders Clinic at Seattle Children’s. With increasing evidence that children with severe problems related to thinking, learning and mental health have inflammatory brain disorders, Seattle Children’s created the clinic in 2021 to bring the latest advances in this fast-growing field to children in our region. The most common condition Drs. Otten and Wong see in patients is autoimmune encephalitis (AIE).

Q: Can you give us a quick reminder of what AIE is?

Autoimmune encephalitis is an inflammatory brain disease associated with antibodies that bind to cells in the brain. It is a type of noninfectious encephalitis. Patients can experience a wide range of neurologic and psychiatric symptoms, including seizures, abnormal movements, behavior changes, psychosis, autonomic dysfunction, cognitive symptoms, or altered level of consciousness. Different types of AIE can affect children and adults at different rates and with different symptoms. Often, patients may present with acutely to subacutely altered mental status, behavioral changes and seizures. Clinicians may be considering different types of encephalitis, including infectious and autoimmune encephalitis, in their differential diagnosis. Symptoms can progress, and a good portion will need critical care, and nearly all will be hospitalized acutely for treatment and management. Long-term, children typically continue to need treatment to manage relapses, refractory disease or sequelae from their AIE.

Q: How common is autoimmune encephalitis?

It is likely more common than we recognize! For instance, the California Encephalitis Project tracked the causes of encephalitis, and autoimmune causes of encephalitis were more common than any infectious agent. The most common type is anti-N-methyl-D-aspartate receptor encephalitis, or NMDARE, which affects women and children in higher proportion. AIE is not expected in very young infants under 6 months of age, but affects all ages otherwise.

Q: Can you tell us more about the different types of autoimmune encephalitis?

NMDARE is the most common form, and it presents with different symptoms depending on age. Prior to the development of neuropsychiatric symptoms, children may have prodromal “viral illness–like” symptoms including fever and headaches. In prepubertal children, it can present with seizures, behavioral and language regression and abnormal movements. Adolescents and adults can present with psychiatric symptoms like psychosis. Both groups are at risk for movement disorders, autonomic dysfunction and sleep disruption.

Other forms of autoimmune encephalitis can include limbic encephalitis. Inflammation affects the limbic system, including the hypothalamus, amygdala and hippocampus. This is associated with multiple different antibodies, including leucine-rich glioma inactivated protein (LGI1) antibodies, anti–glutamic acid decarboxylase (GAD) antibodies and anti-Hu antibodies. It can present with seizures, memory impairment and behavioral disturbances.

There are also several other antibodies that have been identified and associated with autoimmune encephalitis, including anti–gamma aminobutyric acid (GABA) antibodies, contactin-associated protein-like 2 receptor (CASPR2) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies. These bind to different targets in the brain. Most often, a specific antibody is not identified, but this does not rule out the diagnosis of AIE. There are likely many other antibodies that have not yet been identified that can cause autoimmune encephalitis.

Q: How is autoimmune encephalitis diagnosed?

Autoimmune encephalitis is diagnosed based on the clinical symptoms in combination with brain MRI, blood tests and lumbar puncture. Labs are done to test for different antibodies associated with AIE. Sometimes an EEG is also used to look for seizures and to examine background brain activity. Brain MRI is used to look for inflammation in the brain, brainstem and spinal cord. Lumbar punctures can show increased white blood cell count or oligoclonal banding suggestive of inflammation. Infectious testing is done but is typically normal. Antibodies are sent off spinal fluid and/or blood. Other tests may be done to rule out other inflammatory conditions, including infectious encephalitis and systemic rheumatologic disease, since the presenting symptoms are often nonspecific. There is no single test for AIE, since some of these may not be positive. Ultimately, the diagnosis is made based on the clinical presentation and testing together.

Q: Are there any symptoms that occur more commonly with autoimmune encephalitis that should increase suspicion for this diagnosis? 

Many of the individual symptoms of AIE can overlap with other conditions, but often the combination of symptoms may point towards AIE. For example, if an adolescent patient presents with new psychosis but there are also abnormal movements or seizures, this may raise concern for autoimmune encephalitis. In younger patients, acute new neurologic symptoms occurring in a previously healthy patient like developmental regression, seizures and new movement disorder would raise concern. In patients with infectious encephalitis, we do not expect to see movement disorders, so this would be a red flag. And in patients with primarily psychiatric disease, we would not expect an abnormal neurologic exam or seizures, so a complete neurologic exam and screening for cognitive symptoms and regression can be helpful.

Q: Is autoimmune encephalitis paraneoplastic (associated with tumors)?

Yes, it can be. It is very important to screen for tumors and malignancy in patients diagnosed with autoimmune encephalitis. Different forms of AIE are associated with different tumors at different rates depending on the gender and age of the patient. For example, in NMDARE, patients are at risk for ovarian teratomas and testicular tumors. Tumors are more commonly found in adults with AIE than children, but screening tests are necessary for all.

Q: What is the treatment for autoimmune encephalitis?

Most often, patients are hospitalized and will first receive high-dose corticosteroids. They may also receive intravenous immunoglobulins (IVIG) or plasmapheresis (PLEX). Other immunotherapies like rituximab, cyclophosphamide or tocilizumab may be used next if needed. Tumor resection is done if a tumor is identified. It is important to start treatment early if you have high clinical suspicion, as many of the antibody tests take days or weeks to result.

Q: How long are patients treated?

Patients may be on immunotherapy for weeks or years afterwards. AIE can be refractory, and a portion of patients will relapse. Children may need ongoing immunotherapies. These longer-term therapies may include IVIG or other steroid-sparing agents.

Q: How can patients receive their immune therapy treatments?

We first created our clinic to care for children with AIE and other inflammatory brain diseases because we recognized the complexity of their needs. Patients need a neurologist to manage their neurologic symptoms, but also paired with a rheumatologist who is an expert in their immune therapies. Patients may also be receiving care from physical therapists, occupational therapists, speech therapists, neuropsychologists and physiatrists. We created the Inflammatory Brain Disease Clinic to help coordinate their specialty neurology and rheumatology care, and we often partner with their local team to reduce travel and keep them in their community as much as possible. For immune therapies like IVIG that require regular infusions, we work with the family and local team to identify the best local site for them to receive their therapies. We may partner with their local neurologist or care provider to have follow-up tests, therapies or treatments done locally.

Q: What is the outlook for these patients?

Patients may need ongoing care for their inflammatory disease itself but may also experience sequelae from their disease. They can have motor impairments, epilepsy or cognitive symptoms even after treatment. They may receive long-term immunosuppression and be at risk for infection. As part of our clinic’s approach, we make sure these symptoms are addressed because these can significantly impact their life at home and at school.

Q: What is next on the horizon?

More and more research is emerging to help clinicians identify AIE and care for patients who experience it. We hope to have many more disease-specific therapies to offer as we learn more about the specific antibodies associated with AIE. As research has progressed over the past decade, our immune therapy options are advancing rapidly, and options for infusion-based, injectable and oral treatments are becoming available.

Referring to the Brain Inflammation Disorders Clinic

Please refer your patient to Rheumatology. Note “Inflammatory Brain Disorders Clinic” on the referral. If you’d like to discuss your patient first, you are welcome to call the Rheumatology on-call provider at 206-987-7777.

Access

The current wait time for new patient visits is 3 to 6 months. Clinic is held once a month.

Conditions We See

• Autoimmune encephalitis
• Neurosarcoidosis
• Neuro-Behcet’s disease
• MOG antibody–associated diseases
• Neuropsychiatric systemic lupus erythematosus (NP-SLE)
• Genetic inflammatory diseases that affect the nervous system, such as Aicardi-Goutieres syndrome (AGS)

Conditions We Don’t See

We don’t see patients with PANDA (pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections) or PANS (pediatric acute-onset neuropsychiatric syndrome) because treatment also requires psychiatric consultation, which our clinic does not offer at this time.