Prospective Evaluation of Neuroinflammation in Children with Infantile Spasms using C-11-PK11195 Positron Emission Tomography and its Response to ACTH Treatment
Abstract number :
2.073
Submission category :
1. Translational Research: 1E. Biomarkers
Year :
2017
Submission ID :
349527
Source :
www.aesnet.org
Presentation date :
12/3/2017 3:07:12 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Ajay Kumar, Wayne State University School of Medicine; Ananyaa Kumar, Wayne State University School of Medicine; and Harry Chugani, Nemours DuPont Hospital for Children/Thomas Jefferson University School of Medicine
Rationale: The effectiveness of ACTH in infantile spasms (IS) raises the possibility of underlying neuroinflammation in its etiopathogenesis, at least in some cases, and may partly explain its selective effectiveness. Indeed, lower levels of both ACTH and cortisol in the cerebrospinal fluid and increased serum levels of proinflammatory cytokines and markers of immune system activation have been described in cryptogenic cases of IS. However, not much is known about the presence of brain inflammation in children with IS and whether the effect of ACTH is indeed mediated through the suppression of neuroinflammation. In-vivo detection of neuroinflammation has only been possible with histopathology, which is invasive or possible only post-mortem. Since neuroinflammation is mediated by activated microglia, which express translocator protein (TSPO), it can now be imaged in vivo using positron emission tomography (PET) and the tracer C-11-PK11195 (PK), which selectively binds to these receptors. In this prospective study, we investigated the presence of neuroinflammation in children with IS using brain PK-PET and its response to ACTH treatment by repeating the PK PET after treatment. We hypothesized that PK-PET will show neuroinflammation in cortical and/or subcortical structures of the brain prior to treatment, which will be abolished or reduced with ACTH treatment. Methods: Eight children with IS (5 males; mean age: 1.8 ± 1.1; 0.9-4.1 years) were prospectively recruited in this study. After a clinical and video-EEG evaluation and a dynamic PK-PET brain imaging, children underwent ACTH treatment for 4 weeks (75 IU/m2 of ACTH twice daily x two weeks, then 30 IU/m2 x 3 days, 15 IU/m2 x 3 days, 10 IU/m2 x 3 days and 10 IU/m2 every other day x 5 days), followed by repeat clinical evaluation / video-EEG 2 weeks after the initiation of ACTH treatment and repeat PK-PET 2 weeks after the completion of treatment. Both visual and quantitative analysis of PK-PET scan was performed by calculating binding potential (BP: measure of receptor-ligand binding) in different brain regions using reference tissue model. Results: Clinical and demographic profile is given in the table below. Focal areas of increased PK-binding were seen in various brain regions in the pre-ACTH treatment PK-PET in 5 children, which either reduced or normalized and was associated with cessation (n=4) or significant reduction (n=1) of spasms and complete disappearance of hypsarrythmia in all children (Table). One child showed increased basal ganglia and thalamus BP despite normalization of cortical BP; these increases were considered to be associated with causes related to his death. Conclusions: Our study revealed neuroinflammatory changes in various brain regions in children with IS, which either reduced or normalized after ACTH treatment and was associated with cessation or significant reduction of spasms and complete disappearance of hypsarrythmia on EEG suggesting an important role of neuroinflammation in etiopathogenesis of IS and mediation of ACTH treatment effect through suppression of neuroinflammation. Funding: Support provided by Mallinckrodt Pharmaceuticals, Hampton, NJ, USA
Translational Research