Alexander L Cohen1,2,3, Brechtje P F Mulder1,4, Anna K Prohl2, Louis Soussand3, Peter Davis1, Mallory R Kroeck1,2,3, Peter McManus1,2,3, Ali Gholipour2, Benoit Scherrer2, E Martina Bebin5, Joyce Y Wu6, Hope Northrup7, Darcy A Krueger8, Mustafa Sahin1,9, Simon K Warfield2, Michael D Fox3,10,11, Jurriaan M Peters1,2. 1. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA. 2. Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. 3. Laboratory for Brain Network Imaging and Modulation, Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 4. VUmc School of Medical Sciences, VU University Medical Center Amsterdam, Amsterdam, the Netherlands. 5. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL. 6. Division of Pediatric Neurology, UCLA Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA. 7. Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX. 8. Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 9. F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Harvard University, Boston, MA. 10. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA. 11. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
OBJECTIVE: Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms. METHODS: We segmented tubers from 123 children with (n = 74) and without (n = 49) infantile spasms from a prospective observational cohort. We used voxelwise lesion symptom mapping to test for an association between spasms and tuber location. We then used lesion network mapping to test for an association between spasms and connectivity with tuber locations. Finally, we tested the discriminability of identified associations with logistic regression and cross-validation as well as statistical mediation. RESULTS: Tuber locations associated with infantile spasms were heterogenous, and no single location was significantly associated with spasms. However, >95% of tuber locations associated with spasms were functionally connected to the globi pallidi and cerebellar vermis. These connections were specific compared to tubers in patients without spasms. Logistic regression found that globus pallidus connectivity was a stronger predictor of spasms (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10-3.50, p = 0.02) than tuber burden (OR = 1.65, 95% CI = 0.90-3.04, p = 0.11), with a mean receiver operating characteristic area under the curve of 0.73 (±0.1) during repeated cross-validation. INTERPRETATION: Connectivity between tuber locations and the bilateral globi pallidi is associated with infantile spasms. Our findings lend insight into spasm pathophysiology and may identify patients at risk. ANN NEUROL 2021;89:726-739.
OBJECTIVE: Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms. METHODS: We segmented tubers from 123 children with (n = 74) and without (n = 49) infantile spasms from a prospective observational cohort. We used voxelwise lesion symptom mapping to test for an association between spasms and tuber location. We then used lesion network mapping to test for an association between spasms and connectivity with tuber locations. Finally, we tested the discriminability of identified associations with logistic regression and cross-validation as well as statistical mediation. RESULTS: Tuber locations associated with infantile spasms were heterogenous, and no single location was significantly associated with spasms. However, >95% of tuber locations associated with spasms were functionally connected to the globi pallidi and cerebellar vermis. These connections were specific compared to tubers in patients without spasms. Logistic regression found that globus pallidus connectivity was a stronger predictor of spasms (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10-3.50, p = 0.02) than tuber burden (OR = 1.65, 95% CI = 0.90-3.04, p = 0.11), with a mean receiver operating characteristic area under the curve of 0.73 (±0.1) during repeated cross-validation. INTERPRETATION: Connectivity between tuber locations and the bilateral globi pallidi is associated with infantile spasms. Our findings lend insight into spasm pathophysiology and may identify patients at risk. ANN NEUROL 2021;89:726-739.
Authors: Andreas Horn; Martin Reich; Johannes Vorwerk; Ningfei Li; Gregor Wenzel; Qianqian Fang; Tanja Schmitz-Hübsch; Robert Nickl; Andreas Kupsch; Jens Volkmann; Andrea A Kühn; Michael D Fox Journal: Ann Neurol Date: 2017-07 Impact factor: 10.422
Authors: Kiho Im; Banu Ahtam; Daniel Haehn; Jurriaan M Peters; Simon K Warfield; Mustafa Sahin; P Ellen Grant Journal: Cereb Cortex Date: 2015-03-05 Impact factor: 5.357