Although 30–50% of patients diagnosed with pediatric systemic lupus erythematosus (pSLE) experience neuropsychiatric manifestations of the disease (NPSLE), a poor understanding of the underlying pathophysiology remains, creating challenges for disease management. Children with NPSLE can experience a range of syndromes, such as cognitive impairment, psychiatric disorders, seizures and strokes, which are often treated with broad immunosuppressive medications. These medications may cause significant side effects, such as growth delay and infections.
“In clinical practice, there are still many unknowns about how lupus affects the brain and how this may affect a child’s developing brain,” says Andrea Knight, MD, MSCE, a rheumatologist who specializes in managing pSLE and other pediatric rheumatic diseases at The Children’s Hospital of Philadelphia in Pennsylvania.
Seeing a Clearer Picture
Dr. Knight believes that combining information provided by different neuroimaging modalities, such as structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI) and functional MRI (fMRI), may allow enhanced characterization of underlying neural mechanisms to better detect the earliest signs of NPSLE.
This research question stems from her previous work using neuroimaging to investigate neurologic structural changes in patients with pSLE. In 2016, Dr. Knight presented the initial findings from her research using sMRI to compare brain volumes in pediatric lupus patients with control patients at the 2016 ACR/ARHP Annual Meeting.1
“Overall, brain volume did not differ. However, gray matter in the regions of the brain known to control cognitive and emotional function was smaller in the lupus patients, suggestive of damage,” she explains. These changes were present early in the disease course, which averaged about a year in the lupus group. Additionally, the initial signs of damage in the same brain regions for a subgroup of pediatric lupus patients without known neuropsychiatric impairment were also present, signifying potential subclinical effects of pSLE on the brain.
By drawing on the expertise from psychiatry and neurology to understand how the brain is affected by inflammatory disorders, Dr. Knight believes combining the unique views of the brain seen through sMRI to study brain structure, fMRI to see brain activity and DTI to see neural tract pathways may uncover a more telling story of how pSLE affects brain regions, their connections and function.
“By combining the data from these modalities, we can get very specific information on brain regions, volume and, if injury has occurred, how the integrity of brain tissue and brain activity between different regions has been affected,” she says.
For this current project, funded by the Rheumatology Research Foundation Investigator Award, her latest study will apply these multimodal imaging techniques to study brain structure, function and development in pSLE patients.2 She will leverage existing normative imaging and cognitive and psychiatric data from typically developing youth in the large Philadelphia Neurodevelopmental Cohort to evaluate structural brain injury, calculate a newly developed measure of brain development and examine structure-function relationships between imaging metrics and clinical features of pSLE. Specifically, her study will:
- Quantify the effect of pSLE on brain integrity and function using multimodal neuroimaging (sMRI, DTI and resting state fMRI) in cross-sectional comparison to age- and sex-matched typically developing youth; and
- Correlate cross-sectional, multimodal imaging metrics in pSLE with longitudinal assessment of cognitive and affective function.
“This multimodal study of brain volume and relation to function is a longitudinal project to expand on my preliminary work, and also incorporate cognitive and psychiatric testing to correlate the imaging to brain function,” Dr. Knight says.
Dr. Knight’s interest in pediatric rheumatic disease activity and treatment was fueled early in her career, when she worked with a pediatric patient with NPSLE during medical school. She says this patient inspired her current focus of research and practice, which is at the intersection of neuroscience, psychiatry and rheumatology to help these young children battling pSLE during the critical years of their neurodevelopment.
Dr. Knight hopes her research will shed light on the potential inflammatory and non-inflammatory mechanisms of neuropsychiatric dysfunction in lupus to inform early detection through advanced imaging and biomarkers, which are less-invasive evaluations for neuropsychiatric disorders in pSLE patients.
She notes, “Knowing these mechanisms would further the development of more targeted and tailored therapies to individual patients with specific neuropsychiatric syndromes.”
Carina Stanton is a freelance science journalist in Denver.
- Knight A, Vickery M, Doshi J, et al. Regional Brain Gray Matter Volume Loss in Children and Adolescents with SLE [abstract]. Arthritis Rheumatol. 2016; 68(suppl 10).
- Rheumatology Research Foundation. 2017 award receipients: Advancing treatment and finding cures. 2017:21.