OBJECTIVE. Clinical case reports have suggested that the behaviors of children with autism spectrum disorders may improve with fever. The purpose of this study was to investigate the effect of illness on behaviors of children with autism spectrum disorders. Understanding the role of fever, if any, may be informative regarding causative mechanisms of and treatment opportunities for autism.
METHODS. We conducted a prospective study of 30 children (aged 2–18 years) with autism spectrum disorders during and after an episode of fever. Parent responses to the Aberrant Behavior Checklist were collected during fever (body temperature ≥ 38.0°C/100.4°F), when fever had abated and the child was asymptomatic, and when the child had been fever-free for 7 days. Data were compared with those collected from parents of 30 age-, gender-, and language skills–matched afebrile children with autism spectrum disorders during similar time intervals.
RESULTS. Fewer aberrant behaviors were recorded for febrile patients on the Aberrant Behavior Checklist subscales of irritability, hyperactivity, stereotypy, and inappropriate speech compared with control subjects. Per expectation, lethargy scores were greater during fevers, and all improvements were transient. Data from patients with fever were stratified on variables related to illness severity. In the majority of these subgroup comparisons, the data suggested that effects from fever persisted in the less sick patients as well as in those with more severe illness.
CONCLUSIONS. We documented behavior change among children with autism spectrum disorders during fever. The data suggest that these changes might not be solely the byproduct of general effects of sickness on behavior; however, more research is needed to prove conclusively fever-specific effects and elucidate their underlying biological mechanisms (possibly involving immunologic and neurobiological pathways, intracellular signaling, and synaptic plasticity).
Comments
Consider NO from iNOS
I find this result extremely interesting, and it fits with my own (unpublished) ideas that many symptoms of the ASDs are consistent with and exacerbated by low basal nitric oxide. An acute stimulation of the immune system (as in a fever) can result in higher levels of NO through expression of iNOS. In extreme cases (septic shock), high NO levels can cause systemic vasodilation and hypotension via activation of sGC.
Many of the potential mechanisms suggested by Zimmerman et. al. are regulated by NO mediated pathways. For example long term potentiation is complexly regulated by NO via sGC (Garthwaite 2006), and NO is involved in regulation of many stress proteins, through Nrf2 (Dhakshinamoorthy 2004). Because each NO "sensor" senses the sum of NO from all NO sources, there is no threshold for a change in the basal NO level to affect pathways mediated by NO. In other words, because the operating point of each NO mediated signaling pathway is already in the "active range", any change in the basal level will add to (or subtract from) the signal level and change the effect level (basal + signal = effect). With the EC50 of sGC ~20 nM/L (~0.6 ppb) (Garthwaite 2003) even small changes in NO would be expected to change the range, onset time, and duration of every NO signal. If basal levels cause systemic hypotension, they are affecting basal sGC activation in the vasculature.
Before everyone rushes out and tries to raise NO levels, NO physiology is quite complex and under intense regulation. There are no generally accepted methods for raising NO levels that have been shown to work long term. Organic nitrates induce "nitrate tolerance", L-arginine induces asymmetric dimethyl arginine and arginase perhaps causing "arginine tolerance" (Cooke 2007).
What this work does show is that some of the symptoms of ASDs are due to acute effects, not neuroanatomy, and that some of these effects can be reversed acutely. That implies a shifted regulatory setpoint, not injury or damage. I see this as an extremely encouraging result.
Hopper RA, Garthwaite J. Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J Neurosci. 2006 Nov 8;26(45):11513- 21.
Dhakshinamoorthy S, Porter AG. Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. J Biol Chem. 2004 May 7;279(19):20096-107.
Gibb BJ, Wykes V, Garthwaite J. Properties of NO-activated guanylyl cyclases expressed in cells. Br J Pharmacol. 2003 Jul;139(5):1032-40.
Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation. 2007 Jul 10;116(2):188-95.
Conflict of Interest:
Financial disclosure: DRW and Nitroceutic LLC are privately funded and working to commercialize the use of topical ammonia oxidizing bacteria to treat and prevent a variety of disorders associated with low basal NO, including ASDs.