Reply to letter of Peter Good.

Authors Helt, Kelley, Boorstein, Pandey, and Fein, askedauthors Kinsbourne and Herbert to respond to the Goodletter because of their expertise in this area. Following isDr. Herbert's response.The most remarkable thing about fever-associatedtransient improvement of core features of autism (Curranet al. 2007) is the challenge it poses to the conception ofautism as trait, as static encephalopathy (Herbert 2009).What neurobiological mechanisms might underlie autism asdynamic encephalopathy? Others have advanced variousmodels; Good proposes that in the setting of fever the freeamino acid taurine may reduce astrocytic enlargement andcapillary compression, thereby improving brain blood flow,and may account for clinical improvement in this context.He also proposes that ASD individuals who do not respondin this way may be taurine deficient.One problem with pinning an explanation on any onemechanism oragent,suchastaurine,isthe pleiotropicweb ofinfluences of the components involved; shifts in a fewparameters could lead to opposite outcomes. Good arguesthatfeverreducesGABAandelevatestaurine.GABAmaybereduced by fever, but might this not reduce inhibition andcause a net increase in excitation, which if anything couldincrease autistic behaviors? Enlarged astrocytes would alsoleavemoreextracellularglutamatelyingabout,furtherdrivingexcitation. Would transient improvement of blood flowovercome this excitatory vector? Would taurine be uniquelyefficacious in improving the functioning of this system?Ontheotherhand,taurinehasawiderangeofimpacts;itisknown to counteract many physiological problems docu-mented or under study in ASD that could increase brainexcitation, such as antioxidant effects (Oliveira et al. 2010)which counter oxidative stress (Chauhan et al. 2009;Jameset al. 2006), support of calcium homeostasis (Albinana et al.2010; El Idrissi and Trenkner 2003)whichmaybegenetically and/or environmentally compromised (Pessahand Lein 2008), protection against glutamate toxicity(Molchanova et al. 2007) which may be present in ASDagain for genetic and/or environmental reasons (Rubensteinand Merzenich 2003) (Blaylock and Strunecka 2009;Haradaet al. 2010), and toxicity of xenobiotics and heavy metals(Yu et al. 2007; Zhu et al. 2005) and to be protective againstseizures (El Idrissi et al. 2003;Kirchneretal.2003).From a clinical point of view it is not necessary to havecomplete answers regarding the role of every component inone’s model of the neurobiology of transient improvementwith fever in order to test Good’s taurine hypothesis. GoodhasrisentothechallengeposedbyimprovementofASDwithfeverbythinkinginterms ofmeasuresthatcan bedynamical.From there it is a logical step to thinking about mechanismsamenable to intervention. Measuring taurine in children withautism while following their response to fever is one route ofinvestigation. If taurine depletion is associated with a lack ofresponse to fever, might it also be associated with otherfunctional differences even in the absence of fever? Mightthere be other associated clinical correlates? Overall whilethere may be heterogeneity in the routes by which fevermediates improvement, this particular hypothesis is thoughtprovoking and should provoke research and discerningclinical observation as well.