HYPERTHERMIA AND THE IMPROVEMENT OF ASD SYMPTOMS

ABSTRACT Background The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors. The febrile hypothesis of ASD stems from this observation, and could be due to [1] the direct effect of temperature; [2] a resulting change in the immune inflammatory system function associated with the infection of fever; and/or [3] an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system. Methods We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102 °F) and control condition (98 °F) in a HydroWorx aquatic therapy pool. Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility. Safety measures and Social Responsiveness Scale (SRS) were collected. Ten patients with ASD and history of fever response were enrolled and received both treatment conditions. Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool. Parents completed the SRS and RBS-R. Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. Results Five control subjects without a history of fever completed the hyperthermia condition at 102 °F, and demonstrated the safety and feasibility of the study. Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102 °F) and control condition (98 °F) at the aquatic therapy pool. Improvement in social cognition and repetitive/restrictive behaviors were observed at the hyperthermia condition (102 °F) on parent (SRS, RBS-R) and rater (CGI-I) assessments. Pupillometry biomarker and gene expression can be correlated with clinical improvement. Side effects were minimal, and were the same as those observed in a hot tub/sauna (redness, nausea). Discussion We demonstrated improvement of socialization and repetitive and restricted behaviors at the hyperthermia condition (102 °F), and that we could reliably and safely increase children’s temperatures into the fever range (mean max temperature of 101.7 °F). This temperature increase was observed to cause significant and convergent improvement on clinician ratings (CGI-I) and parent ratings (SRS, RBS-R), both of which were kept blinded to the temperature of the pool. Interestingly, each child’s fever response history was correlated with the improvements observed at the elevated temperature. Those with a history of marked fever response had the most observable behavior changes. Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. Although multiple rationales have been posited, this is the first study looking at the direct effect of temperature on ASD symptomatology. This study explores the direct effects of temperature on ASD symptoms and offers a window into understanding mechanisms involved in the improvement of ASD symptoms during febrile episodes. Future analyses will help to determine the genetic pathways involved in fever response, the role of the LC-NA system, and other immune-inflammatory pathways in mediating ASD symptoms.