Hindawi Publishing Corporation Autism Research and Treatment Volume 2012, Article ID 291601, 7 pages doi:10.1155/2012/291601 Research Article Safety and Observations in a Pilot Study of Lenalidomide for Treatment in Autism Michael Chez,1 Renee Low,1 Carol Parise,2 and Tammy Donnel2 1 Sutter Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104, Sacramento, CA 95816, USA 2 Sutter Institute for Medical Research, 2801 Capitol Avenue, Suite 400, Sacramento, CA 95816, USA Correspondence should be addressed to Michael Chez, chezm2@sutterhealth.org Received 17 February 2012; Revised 18 June 2012; Accepted 6 July 2012 Academic Editor: Will Spooren Copyright © 2012 Michael Chez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autism aﬀects 1 : 88 children in the United States. Familial history of autoimmune disease, autoantibodies in the serum of mothers when there is more than one autistic oﬀspring, and neuroglial response in CSF and brain tissue in autistic patients suggest an immunological variable may be associated with this condition. Lenalidomide has the potential to invoke changes in TNF-α with less toxicity than thalidomide. This pilot study evaluated lenalidomide at reduction of TNF-α and improvement of behavior and language in children with autism with elevated TNF-α. Subjects with elevated TNF-α were given 2.5 mgs lenalidomide daily for 12-weeks. Pharmacodynamics and safety was evaluated. Changes in language and autistic behaviors after six and twelve weeks were measured. Although statistical signiﬁcance was not achieved for most measures, there were trends toward improvement. After 6- weeks, mean receptive language increased: 60.67 ± 12.06 to 65.00 ± 15.10 (P = 0.11) and symptoms of autism decreased (40.75 ± 5.96 versus 38.67 ± 7.90, P = 0.068). After 12-weeks, CSF-TNF-α declined 57%± 25% from 80.5 ± 41.03 to 38.0 ± 31.27 (P = 0.068). Serum TNF-α declined 57% (92.50 ± 68.92 to 40.25 ± 44.53 (P = 0.048). This study suggests that lenalidomide is tolerated as a treatment by children with autism and should be further studied as a potential agent for cytockine inﬂammation. 1. Introduction Autism is currently the leading cause of developmental disability in the United States and most other countries of the world. The condition currently aﬀects 1 in 88 children born in the United States as of 2010 [1]. Autism is best deﬁned as a spectrum of heterogeneous developmental disabilities mainly involving three core aspects of behaviors: (1) speech and communication; (2) social interest and interaction; (3) stereotypic behaviors or mannerisms [2]. Historically, the incidence of autism has increased; however, debate exists as to whether this reﬂects simple population growth, recategorization and increased recognition, or whether there is a true increase in the percent of the population aﬀected [3]. Despite this controversy, most experts and the general population agree that the incidence of autism has greatly increased, especially in states such as California which has shown a massive increase of 600% for autistic children in state educational records over two decades [4–6]. There is currently no agreed upon single genetic or other etiological risk factor that has been shown to cause autism in isolation. Current thinking is that multiple risk factors such as familial, environmental such as extreme prematurity or infection, and immune triggers may need to occur. Patients with autism may have a dysfunctional immune system, especially in the nervous system. There is evi- dence of serum markers for inﬂammation including ele- vation of cytokine, autoantibodies, lower levels of normal immunoglobulins for immune defense, and neuroglial and cytokine activation in cerebral spinal ﬂuid (CSF) or brain tissue [7, 8]. Innate neuroglial immune dysregulation has been shown with elevation of interleukin-6 and other proinﬂammatory markers in the frontal cingulate cortex and CSF, as described by Vargas et al. and others [9–11]. Only one study looking at cytokine levels in CSF and serum in autism has been completed that describes an elevated TNF-α ratio of the cerebrospinal ﬂuid levels to serum levels [7]. Lenalidomide, an analogue of thalidomide, has the potential to invoke more signiﬁcant changes in TNF-α and other immunomodulatory cytokines with less toxicity than thalidomide. Lenalidomide may be clinically viable as an oral agent early in the course of autism subtypes and may