Hyperthermia and the Improvement of ASD Symptoms
Background: Current literature in autism spectrum disorders (ASD) supports a link between central nervous system (CNS) dysfunction,neuroinflammation and a dysregulated immune response.
Our group has been interested in the association between ASD and immune dysfunction, as the involvement of inflammatory mechanisms suggests that immunomodulatory intervention may be an experimental therapeutic option for individuals with ASD.
In particular, the observation that some ASD patients manifest clinical improvement in response to fever suggests that ASD symptoms may be modulated by immune-inflammatory factors.
The febrile hypothesis of ASD stems from this observation, and could be due to one of three possible causes
(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.
Although parental reports have demonstrated improved social cognition and language skills and decreased disruptive behaviors during febrile episodes of their child with ASD, little has been done to explore the potential direct effect an increased body temperature may have on autism symptomatology.
Methods: We are completing a double blind crossover study with 15 children with ASD between the ages of 5 and 17 years old. Five children with ASD (confirmed by DSM-IV criteria) without fever response acted as controls prior to the completion of the protocol on those with ASD and history of fever response, to ensure the appropriate parameters were in place. The five control subjects were place in a HydroWorx acquatic therapy pool at the single temperature of 102°F (hyperthermia condition) for one hour and 15 min, on a single day. They were monitored before, during and after the visit by a staff member with medical back up. Safety measures (vital signs, temperature, urine pregnancy test, BMI) were collected in addition to a baseline and endpoint Social Responsiveness Scale (SRS) completed by the parent. Once data was collected on the 5 control subjects, 10 patients with ASD (confirmed by DSM-IV criteria supported by ADOS) and history of fever response were screened and enrolled. At screening patient assessments (IQ test, pupillometry, Social Language Test), parent assessments (ABC, SRS, SCQ, RBS-R) and clinician assessments (CGI-S, CGI-I) were completed in addition to medical history, concomitant medications and vital signs.
Patients with ASD and a history of fever response received both treatment conditions at the Hydroworx aquatic therapy pool, 102°F (hyperthermia condition) and 98°F (control condition). Per information collected from the control subjects, ASD patients with fever response were kept in the pool until their temperature reached approximately 102°F and maintained at that temperature for approximately 30 min. Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.
Parents observed the patients throughout their time in the pool and completed the SRS, ABC and RBS-R once the child was at the higher temperature for approximately 30 min. Clinicians completed the Social Language Test and pupillometry when the child exited the pool, with the temperature still heightened. Additionally, in order to observe potential epigenetic effects of the hyperthermia treatment buccal swabs were collected pre and post pool entry for DNA and RNA extraction.
Results: Five control subjects without a history of fever completed the hyperthermia condition at 102°F, and demonstrated the feasibility of increasing a child’s temperature to 102°F using the Hydroworx aquatic therapy pool; the child’s ability to tolerate spending periods of time at the hyperthermia condition; and the ability to complete needed safety measures and behavioral assessments.
Ten subjects with ASD and a history of fever response were entered into the study and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.
Social and behavioral changes were observed by comparing baseline to endpoint in the hyperthermia and control conditions on parent assessments (SRS, ABC, RBS-R, SCQ), clinical biomarkers (pupillometry, social language test) and genetic biomarkers.
Conclusions: This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a fever response, and preliminary data on the relationship between body temperature and changes in social/behavioral measures, biomarkers and epigenetic expression. This method explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.
Future analyses will help to determine the genetic pathways involved in fever response, the role of the locus coeruleus/noradrenergic system, and other immune-inflammatory pathways in mediating ASD symptoms. Funding provided by the Simons Foundation.
Keywords: autism, fever, immune, inflammation, biomarkers.
Disclosures: C. Ferretti, Nothing to Disclose; B. Taylor, Nothing to Disclose; R. Noone, Nothing to Disclose; E. Racine, Nothing to Disclose; J. Kirsch, Nothing to Disclose; E. Hollander, Part 4: Funding provided by The Simons Foundation.
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