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In the Clinic-Autoimmune Encephalitis
Persistent Cognitive, Neuropsychological Deficits After Anti-NMDAR Encephalitis Require Therapy, Study Suggests


Researchers found that children and adolescents had persistent neuropsychological and behavioral problems even after recovery from pediatric anti-NMDAR encephalitis, which should be monitored and treated.

Children and adolescents presenting with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, one of the most common types of autoimmune encephalitis, often have significant cognitive problems, fatigue, and neuropsychological sequelae that persist well after apparent recovery and affect academic performance and quality of life, according to a study published in the April 27 online edition of Neurology.

Initially described in 2007, anti-NMDAR encephalitis has to date been diagnosed in more than 1,000 patients, 35 percent of whom are children. The disease course is typically severe, with 75 percent of patients admitted to the intensive care unit, the investigators said.

“Nevertheless, if treated with adequate immunotherapy, outcome is considered favorable in 85 percent of children,” the investigators noted. “However, there are signals that actual recovery might be less positive than initially reported. Small studies in both adults and children describe substantial deficits in multiple cognitive domains and also behavioral problems.”

The outcomes of anti-NMDAR encephalitis have typically been assessed using measures such as the modified Rankin scale (mRS). The Dutch investigators sought more robust insight into long-term cognitive and neuropsychological recovery. They used a battery of tests and questionnaires designed to assess skills in six domains: attention, memory, language, executive functioning, quality of life, and fatigue.

“Anti-NMDAR encephalitis is a treatable disease,” co-author Maarten Titulaer, MD, PhD, assistant professor of neurology at Erasmus Medical Center in the Netherlands, told Neurology Today. “Given the severity of the disease, patients recover very well. However, we should not be satisfied too soon and aim for better recovery, not only with immunotherapy and other treatments, but also with better rehab programs aimed at disabilities in real life. Many children have behavioral dysfunction. We should not only aim to inhibit strange behavior or increased impulsiveness, but also be aware of apathy and passivity in children recovering from anti-NMDAR encephalitis. Our study shows that this apathy is too often neglected and can lead to school dropout.”


DR. MAARTEN TITULAER: “Given the severity of the disease, patients recover very well. However, we should not be satisfied too soon and aim for better recovery, not only with immunotherapy and other treatments, but also with better rehab programs aimed at disabilities in real life.”


Of 28 children selected for the study, with a median age of 14 years, only 18 (64 percent) returned to their previous school level. Among 22 patients who participated in the follow-up study, completing questionnaires about work or school performance, the most common problems were word finding difficulties (25 percent); attention and concentration deficits, anxiety, and impulsiveness (all 18 percent); and dyslexia and indecisiveness (both 12 percent).


DR. SEAN PITTOCK: “What is novel here is the identification of these subtle cognitive issues and fatigue that warrants further investigation, especially because were dealing with a younger age group of patients. They do get better, but we may have underestimated the burden on them.”

Among the 16 who completed the full neuropsychological assessment, scores were consistently lower than average on measures of sustained attention (-2.10, p<0.0001) and long-term verbal memory (-0.68, p=0.031). Patients also reported more fatigue (-0.96, p= 0.008), and tended to have lower quality of life (-0.87, p=0.032).

“Overall, our findings highlight the importance to be aware of persisting neuropsychological deficits and excessive fatigue following pediatric anti-NMDAR encephalitis. With a considerable median follow-up time (almost three years) our results clearly indicate that neuropsychological deficits can be prolonged,” the authors wrote. “Currently, disease outcome is assessed with parameters measuring impairment and disabilities (mRS, PCPC), and treatment decisions are based on these parameters. Our results show that neuropsychological parameters measuring participation and QoL [quality of life] are also important and should also be taken into account when assessing outcome, as these factors can substantially affect participation and wellbeing.”


Experts praised the study as an important illumination of an aspect of autoimmune encephalitis that has been little studied. “Few studies of this disease have focused on the subtler issues of cognition, quality of life, and psychiatric/psychological well-being,” said Sean Pittock, MD, director of Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and of Mayo's Neuroimmunology Laboratory in Rochester, MN. “What is novel here is the identification of these subtle cognitive issues and fatigue that warrants further investigation, especially because we're dealing with a younger age group of patients. They do get better, but we may have underestimated the burden on them.”

Dr. Pittock's group reported in the January issue of the Annals of Neurology that, contrary to prior assumptions, autoimmune causes of encephalitis are equally prevalent to infectious causes of the disease.

“With dramatic advances in biomarker discovery for autoimmune encephalitis, we are much better at identifying these forms of the disease. We also know that anti-NMDAR is one of the most common forms of autoimmune encephalitis. This underscores the importance of understanding the long-term consequences of the disease. Parents want to know, and need to be informed, about what things to look out for as their children are recovering. We probably aren't doing a very good job of that right now. Because the presentation of this disease is so dramatic, you can imagine that we're so relieved that they've made such a good recovery that we tend not to place an emphasis on these subtler problems.”

The paper should help to focus rehabilitative efforts on certain cognitive areas early in the disease course, said child neurologist Luca Bartolini, MD, an expert in neuroinflammation who is currently an epilepsy fellow and investigator at the National Institute of Neurological Disorders and Stroke.

“Once patients are out of the ICU and more stable, rehabilitative efforts typically start in the inpatient setting, but these strategies may not necessarily focus on specific domains and areas, such as cognition and neuropsychological impairment, that this paper clearly indicates these patients have,” he said. “While physical and occupational therapy are very important for daily life activities and specific skills, the problem with autoimmune encephalitis is that you don't necessarily have a focal deficit. Several domains may be affected, because it is a global process affecting the central nervous system rather than a hit on one specific area of the brain, as more commonly happens in stroke.”

Rehabilitation should also focus on academic issues and anxiety, Dr. Bartolini added. “While the majority of these children resumed school, which is in line with what we see in the United States, 23 percent began at a lower education level and three of them stopped school prematurely because of academic difficulties and anxiety. The underlying message is that whatever you do from a functional perspective, the brain took a hit. Rehabilitative efforts need to be focused on fatigue mitigation and the neuropsychological outcomes these authors studied and developing strategies for dealing with them.”

He recommended a coordinated therapeutic approach involving a child's family, school, and other partners. “There has to be a comprehensive set of strategies that take into account that once the child is out of the hospital, he or she is back into the world where everything can be chaotic,” he said.

The paper also has some take-home lessons for researchers, said Benjamin M. Greenberg, MD, FAAN, vice chair of translational research and strategic initiatives, Cain Denius Scholar of Mobility Disorders, and Distinguished Teaching Professor in the department of neurology and neurotherapeutics and department of pediatrics at UT Southwestern Medical Center.

“We need to be much more comprehensive in our outcome measures for a condition like this, and design clinical trials that take into account cognitive domains, not just the functional aspects of people's ability to move or be independent,” he said. “Both clinicians and researchers need to consider neuropsychiatric evaluations on all patients affected by this condition, regardless of how well they appear to be doing. We may find some struggling although they appear to be doing well.”

The small size of the study is a limitation, the experts agreed. “The data is also a cross-sectional study of people at different points out from the condition, which potentially biases the data set,” said Dr. Greenberg. “What is needed is a larger longitudinal study of these patients to confirm these findings.”

But even though the cohort is small, Dr. Bartolini said, the findings are strong. “The authors decided to include three children who developed autoimmune encephalitis post-herpes simplex encephalitis, which is a very serious form of viral encephalitis and a major indicator of poor neurocognitive outcomes,” he notes. “Including those three children in a small cohort possibly biases the findings, but they ran their analysis again after excluding those three children and had no change in the results.”


• De Bruijn MAAM, Aarsen FK, van Oosterhout MP, et al; for the CHANCE Study Group. Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis Neurology 2018; Epub 2018 Apr 27.
    • Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis Ann Neurol 2018;83(1):166–177.