The Fever Theory

fever3by Linda Ruggiero, Ph.D.

There is currently a great deal of interest in the role of fever in alleviating symptoms typical in children with autism spectrum disorders (ASDs). Until recently the evidence for fever as therapeutic has mostly been anecdotal, however, current research has provided more conclusive data. A working model has been proposed which theorizes that dysregulation within the locus coeruleus (LC), an area of the brain implicated in both fever and attention, may be a site requiring more extensive research.

ASDs are disorders of the brain that diagnostically fall within 3 more specified disorders based on symptomatology. Autism, in which symptoms appear during early childhood development, is characterized by deficient social interactions, repetitive and limited behaviors and impaired language and communication skills. Asperger Syndrome displays the impaired social interactions seen in autism, however differs from autism in that does not always involve impairments in language and cognition. The third, less well-defined of the ASDs is Pervasive Development Disorder Not Otherwise Specified (PDD-NOS). PDD-NOS refers to disorders in which children present problems with communication, but do demonstrate impaired social abilities enough to be considered autistic.  Though a number of theories about the potential causes of ASDs exist, the pathophysiology of the disorders is unclear. While there is no cure for ASDs at present, scientific research is unremittingly working toward discovering ways in which to treat the disorders and alleviate symptoms in these children until a cure is identified.

Over the past few decades, anecdotal accounts have suggested that children with ASDs show improvement in social behaviors and have increased clarity in verbal communication during  febrile episodes, or episodes of fever. These accounts were given little attention until 1980, when a report was published discussing similar observations among children with autism at the Bellevue Psychiatric Hospital in New York. During an outbreak of viral upper respiratory infections, the children with elevated temperatures were reported to exhibit longer attention spans and increased social interactions than was typically observed in their behaviors.  Later evaluations suggested that the improvements, though variable among children, were best observed when temperatures were increased by 1.5 – 2.5 C (2.7 – 4.5 F). The symptom remission occurred at the onset of fever and persisted for 1 – 3 days following when the fever diminished.

Years later in an attempt to more closely examine the changes in symptoms of ASDs in children with fever, Curren et al. conducted a study in which the parents of 30 children with ASDs were asked to report the severity of specific symptoms seen in their children during and after febrile episodes. The observations focused on the degree of irritability, hyperactivity, repetitive behaviors and inappropriate speech displayed by children with fever compared to behaviors during healthy states.  The results were compared among children within the same age and gender categories and among children with a similar severity of the disorder to control for variability within the study. Interestingly, the majority of children showed a diminution of symptoms in at least one of the behaviors, suggesting more conclusively that improvements in symptoms occur during febrile episodes.

The implications of these results pose additional questions and theories about the underlying mechanisms of ASDs, and the potential role of fever in alleviating symptoms suggests interactions between the nervous and immune systems. Fever is the body’s natural immune response to an infection. It is believed that fever enhances immune function because the increase in temperature can speed up processes involved in fighting off an infection. For example, fever may increase the proliferation and migration of immune cells to the site of infection, may increase  the rate of removal of pathogens, and may activate certain proteins that are involved in combatting infection.  Through its effects on immune function, fever may impact gene transcription, cell signaling and overall neural networks.

Researchers at Albert Einstein College of Medicine in New York, Drs. Mark Mehler and Dominick Purpura, suggest a working model involving the LC in order to understand how fever may affect symptoms in children with ASDs. The LC is an area of the brainstem involved in the production and transmission of noradrenaline (NA) in the brain, particularly during the stress response. In addition to its role in the stress response, the LC-NA system is believed to be involved in attention. The NA neurons of the LC project to and terminate in different parts of the brain and form extensive networks, while also receiving diverse inputs from other brain areas.  sue to the extent of the projections, changes in this system can have profound effects including affecting cognitive function. Interestingly it has been shown that fever activates NA terminals, and that loss of function within the LC leads to decreases in febrile episodes. The LC-NA is now of interest in ASDs because it is the only known area of the brain which is implicated in both fever and behavior. It may, researchers believe, be involved in the mechanisms underlying the effects of fever on ASD symptoms.

The work that has been conducted in this area so far has set the stage for future scientific research.  In order to better understand why symptoms of ASDs subside during febrile episodes, the LC-NA system is a place to start. With the hypothetical role of the LC-NA system in ASDs as a working model,  a number of questions may be addresses: Is there dysregulation of the NA-LC system in children with ASDs? Does fever enable restoration of the LC-NA system? Does fever affect the LC-NA pathways involved in attention in children with or without ASDs? What processes in the brain might be activated or inactivated during fever that might affect the LC-NA system?   Do changes within the NA during fever underly the attenuation of symptoms in children with ASDs? These are only a few of the many questions that could be examine in furture studies.. Though there are many unanswered questions, having a working hypothesis is crucial in the search for the effects of fever in ASD patients. With a model in hand, scientists can work more diligently towards understanding the mechanisms by which fever eliminates ASD symptoms.

All of the researchers involved in these studies stress the dangers associated with attempting to induce fevers as therapeutics in children with ASDs.

References

Aston-Jones, G., Raikowski, J., Cohen, J. Role of locus coeruleus in attention and behavioral flexibility. 1999. Biological Psychiatry 46: 1309-1320.

Cotterill, R.M. Fever in autistics. 1985. Nature 313:426.

Craven, R. and Hirnle, C.  2006. Fundamentals of nursing: Human health and function. 2006 4th ed.  Lippincott Williams & Wilkins, Philadelphia, PA. p. 1044

Curran, L.K.,  Newschaffer, C.J, Lee, L., Crawford, S.O., Johnston, M.V.,  Zimmerman, A.W. 2007. Behaviors Associated With Fever in Children With Autism Spectrum Disorders. Pediatrics 120: 1386-1392.

Linthorst, A.C., Flachskamm, C., Holsboer, F., Reul, J.M., 1995. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J. Neurosci. 4: 2920-2934.

Mehler, M.F., Purpura, D.P. 2009. Autism, fever, epigenetics and the locus coeruleus. Brain Res. News 59: 388-392.

Ovadia, H., Abramsky, O., Weidenfeld, J. Evidence for the involvement of the central adrenergic system in the febrile response induced by interleukin-1 in rats. 1989.   J. Neuroimmunol. 25: 109-116.

Sullivan, R.C. Why do autistic children . . . ? 1980. J Autism Dev Disord  2:231-241.

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One Comment

  1. Laura
    Posted August 13, 2009 at 5:53 pm | Permalink

    Fascinating article, thank you.

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