Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent.

FULL-LENGTH ORIGINAL RESEARCH Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent *Shaun A. Hussain, *Jackie Tsao, †Menglu Li, ‡Madeline D. Schwarz, *Raymond Zhou, *Joyce Y. Wu, §Noriko Salamon, and *¶Raman Sankar Epilepsia, 58(4):674–682, 2017 doi: 10.1111/epi.13712 S UMMARY Dr. Hussain is the Director of the UCLA Infantile Spasms Program, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California. Objective: Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormal- ities on magnetic resonance imaging (MRI) (VABAM), namely reversible—and largely asymptomatic—signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify pre- dictors of these phenomena. Methods: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. Results: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the lim- ited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumula- tive) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). Significance: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy. KEY WORDS: West syndrome, Epileptic spasms, Toxicity, Neuroimaging. Accepted January 25, 2017; Early View publication February 23, 2017. *Division of Pediatric Neurology, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California, U.S.A.; †School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia, U.S.A.; ‡School of Medicine, University of California, San Francisco, San Francisco, California, U.S.A.; Departments of §Radiology, and ¶Neurology, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California, U.S.A. Address correspondence to Shaun A. Hussain, UCLA Pediatric Neurol- ogy, 10833 Le Conte Ave, Room 22-474, Los Angeles, CA 90095-1752, U.S.A. E-mail: shussain@mednet.ucla.edu Wiley Periodicals, Inc. © 2017 International League Against Epilepsy Infantile spasms (also known as epileptic spasms in the most recently proposed International League Against Epi- lepsy (ILAE) classification scheme 1 ) is an often devastating form of epilepsy with onset in the first year of life; is fre- quently attributed to one of many structural, genetic, or metabolic disorders; and is usually accompanied by neu- rodevelopmental arrest or regression. 2 Infantile spasms is characterized by clusters of brief seizures termed spasms and a spectrum of severe electroencephalographic abnormalities including hypsarrhythmia. 3 A lack of prompt and successful treatment is associated with adverse long-term