A safe way to study fever’s dramatic relief of autistic behavior?

I first met Peter a couple of years ago at an Autism Research Institute Think Tank. At the Think Tank Peter impressed everybody with his knowledge, specially about biochemical pathways. He was my lunch buddy for that couple of days and ever since we have kept in touch. I invited him to write a contribution to my blog and he obliged.Before going to the blog, I asked Peter to write a few lines about himself.

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Many people with an illness or disorder read the medical literature looking for clues or treatments. I didn’t realize I was autistic till I began studying it. After 30 years reading (and writing) about multiple sclerosis – with no degrees or formal education in the medical sciences – I noticed similarities between MS and autism. As I began my study (got to save the Lost Boys!) I was fortunate to encounter three cordial advisers early on. Without their guidance I might easily have lost my way in a forest of evidence and citations: Martha Herbert (Massachusetts General Hospital) told me of fever’s phenomenal benefit; Eugene Kiyatkin (National Institutes of Health) clarified fever’s nature and uniqueness; and Jon Pangborn (Autism Research Institute) told me of high blood ammonia in these children.

A safe way to study fever’s dramatic relief of autistic behavior?

Although dramatic relief of autistic behavior by infectious fever is common knowledge among parents and pediatricians [1-4] no one has yet investigated its physiology or biochemistry. Researchers hesitate to subject feverish children to the heat of a brain scan, and expose others to contagion. One approach may be to scan children whose relief by fever persists days or weeks after fever subsides.[3] Not only would this minimize the risks of fever, it should distinguish brain metabolites that vary with behavior from metabolites that vary with temperature.

Personal accounts by parents and pediatricians of fever’s dramatic benefit were first published by Ruth Christ Sullivan in 1980, in her column “Parents Speak” in the Journal of Autism and Developmental Disorders.[1] An outbreak of respiratory infection in a Bellevue Hospital nursery provoked the phenomenon in a group of autistic children. Other physicians noted that the stress of blood drawing could also induce brief dramatic improvements. Sullivan: “Though there is practically no mention of the high fever/improved behavior phenomenon in the entire autism literature, every knowledgeable person – both parent and professional – I approached for information knew of it.”[1] Psychologist Gary Brown reported his personal observations: “[T]he changes that occur in these autistic children are . . . dramatic, more like a metamorphosis in which the autistic child suddenly becomes almost normal.”[5] Pediatric neurologist Andrew Zimmerman and colleagues confirmed fever’s benefit in 30 children with autistic disorders (ASD) – parents observed less irritability, hyperactivity, repetitive acts, and inappropriate speech.[2] Martha Herbert, director of the TRANSCEND brain imaging program at Massachusetts General Hospital, is convinced fever’s benefit reveals autism is a “chronic dynamic encephalopathy” – a reversible brain disorder, not a permanent structural one.[6]

Evidence of fever’s benefit was presented at an Autism Research Institute (ARI) ‘think tank’ in April 2013. During the discussion one participant raised the question why fever’s benefit in some children persists days after temperature returns to normal, yet in other children improvements last only as long as fever lasts. “Are there two mechanisms here?” she suggested. I thought some children just produced more of whatever induced the benefit, so theirs lasted longer. But her question lingered . . .

Improvements during fever might simply be due to high temperature, accelerated brain metabolism, and/or more brain blood flow, to judge from intestinal bacteria [7], and low brain metabolism [8] and blood flow [6,9,10] in children with ASD. Yet a sauna or hot bath rarely improves autistic behavior, although several instances were reported.[11] Eugene Kiyatkin (NIH) explained that fever increases brain temperature much more than ambient heat or stress, especially in children.[12]

How might improvements persist after fever subsides? Microbes killed or weakened by heat may take days to renew or recover; blood flow may provide lasting nutrients and carry away accumulated wastes. Improvements may also persist via lingering effects of metabolic shifts that raise the temperature set point in the hypothalamus, or accelerate metabolism. But they can’t depend on the shifts themselves; when they persist, fever persists. Raising the set point, for example, apparently requires that sodium ions move from cerebrospinal fluid (CSF) into the brain, displacing calcium ions.[13,14] This exchange could be decisive in these children, in light of their frequent salt cravings [15], the benefit of fluid/salt diets [16], and evidence of brain calcium accumulation [17]. But can this sodium/calcium exchange persist after the set point returns to normal?

The heat of fever itself accelerates metabolism (∼10% for each °C) – heat generated by shivering, conserved by peripheral vasoconstriction, and probably induced by internal agents (interleukins, prostaglandins) that heat peripheral tissues directly in response to infection.[18] But the primary agent that accelerates metabolism during fever is epinephrine (adrenaline) from the adrenal medulla, which mobilizes metabolic fuels (fatty acids, glucose from glycogen); epinephrine accelerates metabolism 5-10x more than norepinephrine.[19] Epinephrine preferentially stimulates sympathetic nervous system beta-receptors throughout the body. Under stress, stimulation of β-receptors shifts taurine and calcium into cells, e.g. heart muscle – calcium to strengthen contractions, taurine to distribute calcium in intracellular structures (to regulate active concentration in cytosol).[20] Intense β-stimulation, however, reverses this taurine shift. Durlach and Durlach: “[I]ntense β-stimulation produces reverse effects on cell [taurine] influx: instead of an increase, a decrease is observed.” [21] Because calcium moves with taurine under β-stimulation, does the intense β-stimulation of fever flush calcium from the brain? Can this shift persist without high epinephrine?

Another mechanism that may explain persisting improvements is release of the amino acid glutamine from skeletal muscles as provisional fuel to compensate fever’s loss of appetite. [21,4] Plasma glutamine is low in ASD children, brain glutamine/glutamate also usually low. Children with high brain glutamine from urea cycle disorders rarely show autistic behavior.[4] Another persisting agent may be water brought in with sodium. Are autistic brains dehydrated? Yet if these agents induce improvements that persist days after fever – why don’t they persist in every autistic child?

Conclusions: A brain scan by magnetic resonance spectroscopy (MRS) at 3 Tesla in a child whose dramatic improvement persists days after fever ends should primarily detect metabolites associated with improved behavior, not temperature – as well as minimize overheating and contagion. This scan would measure metabolites that may persist in brain or CSF after fever ends (glutamine, taurine, sodium, calcium, water) and not ones unlikely to persist (e.g. epinephrine). What else should we measure by MRS if we can? Probably glutamine synthetase, ammonia, nitrogen, magnesium, neurotransmitters glutamate, GABA, and serotonin, and arginine/nitric oxide.

Peter Good
Autism Studies
web site: http://www.autismstudies.info

email: autismstudies1@gmail.com

Acknowledgements

I’m grateful to William Ellis of St. John’s Cathedral, Spokane, for generous support of these
studies, friendship, and faith.

References
1. Sullivan RC. Why do autistic children . . . ? J Autism Dev Disord 1980;10: 231-241.
2. Curran LK, Newschaffer CJ, Lee LC, Crawford SO, Johnston MV, Zimmerman AW. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 2007;120:e1386-1392.
3. Herbert MR, Weintraub K. The Autism Revolution: whole-body strategies for making life all it can be. New York: Ballantine Books, Harvard Health; 2012.

4. Good P. Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel? Med Hypotheses 2013;80:1-12.
5. Brown G. The sometimes son. Humanist 1999;59:46-47.
6. Herbert MR. Autism: the centrality of active pathophysiology and the shift from static to
chronic dynamic encephalopathy. In: Chauhan A, Chauhan V, Brown T, editors. Autism: Oxidative Stress, Inflammation and Immune Abnormalities. Boca Raton, FL: Taylor & Francis/ CRC Press; 2009. pp. 343-387.
7. Finegold SM. State of the art; microbiology in health and disease. Intestinal bacterial flora in autism. Anaerobe 2011;17:367-368.
8. Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, et al. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology 2003;60:100-107.
9. Zilbovicius M, Garreau B, Samson Y, Remy P, Barthélémy C, Syrota A, et al. Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry 1995;152:248-252.
10. Gendry Meresse I, Zilbovicius M, Boddaert N, Robel L, Philippe A, Sfaello I, et al. Autism severity and temporal lobe functional abnormalities. Ann Neurol 2005;58:466-469.
11. Zimmerman AW, Connors SW, Curran LK. Fever in autism spectrum disorders (ASDs): Spontaneous reports. Poster presented at the 7th International Meeting For Autism Research (IMFAR), London, May 15-17, 2008.
12. Kiyatkin EA. personal communication 2010.
13. Myers RD, Veale WL. The role of sodium and calcium ions in the hypothalamus in the control of body temperature of the unanaesthetized cat. J Physiol 1971;212:411-430.
14. Frosini M. Changes in CSF composition during heat stress and fever in conscious rabbits. Prog Brain Res 2007;162:451-460.
15. Good P. Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine? Med Hypotheses 2011;77:1015-1021.
16. Herbert MR. SHANK3, the synapse, and autism. N Engl J Med 2011;365:173-175.
17. Ji L, Chauhan A, Brown WT, Chauhan V. Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. Life Sci 2009;85:788-793.
18. Tang JS, Kiyatkin EA. Fluctuations in brain temperature induced by lipopolysaccharides. Central and peripheral contributions. Oxid Med Cell Longev 2010;3:332-341.
19. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia: WB Saunders; 2005.
20. Bkaily G, Jaalouk D, Sader S, Shbaklo H, Pothier P, Jacques D, et al. Taurine indirectly increases [Ca]i by inducing Ca2+ influx through the Na(+)–Ca2+ exchanger. Mol Cell Biochem 1998;188:187-197.
21. Durlach J, Durlach V. Speculations on hormonal controls of magnesium homeostasis: a hypothesis. Magnesium 1984;3:109-131.
22. Wannemacher Jr RW, Pekarek RW, Bartelloni PJ, Vollmer RT, Beisel WR. Changes in individual plasma amino acids following experimentally induced sand fly fever virus infection. Metabolism 1972;21:67-76.

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