the vagus nerve—a common route for epilepsy therapies?
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Reflection & Reaction
Neurology Vol 3 September 2004 http://neurology.thelancet.com
The vagus nerve—a common route for epilepsy therapies?One mechanism not covered in therecent review by Eric Kossoff 1 is thatthe ketogenic diet (and othertreatments for epilepsy) may actindirectly on the brain via thesubabdominal left cervical-brain-stem–vagus-nerve route. Informationabout physiological factors (eg,appetite) travels along this nervebetween the brain and visceral organs,such as the liver and intestines. Externalelectrical stimulation of the left cervicalvagus nerve is an established treatmentfor epilepsy;2 antiepileptic drugs ordietary therapies may therefore exerttheir effect via internal stimulation ofthis route.
Diets rich in fatty acids and thosethat mimic fasting, such as theketogenic diet and the Atkin’s diet, haveappetite-suppressing effects. Recentstudies have shown that the fatty-acid-like molecule oleoylethanolamidesuppresses appetite through amechanism that is dependent on anintact vagus nerve.3 This effect ofoleoylethanolamide is also dependenton the presence of functionalperoxisome proliferator activatedreceptor alpha (PPAR�), probablylocated in the liver or the intestine incells adjacent to vagus-nerve afferents.3
PPAR� has been implicated in themetabolic effects of ketogenic diet orfasting on processes in the liver and thebrain,4 and, indeed, oleoylethanolamideis a ligand for PPAR�. Thus, it isproposed that the appetite suppressingeffects of oleoylethanolamide aremediated via activation of hepatic andintestinal PPAR�; these effects causechanges in cell state that stimulate the
neighbouring vagus-nerve afferents.Interpretation of such vagus-nervesignals in the hypothalamus results inappetite suppression via behaviouralmodifications.
In addition to oleoylethanolamide,PPAR� has an unusually broad range ofligands, including many fatty acids5
abundant in the ketogenic diet.Moreover, fatty-acid-like drugs, such asvalproic acid and several valproic-acidanalogues, activate PPAR�.6 There isalso a relation between potency ofPPAR� activation and antiseizureefficacy.5 This finding is particularlyintriguing because other antiepilepticdrugs may already be exploiting theinternal route of vagus-nervestimulation. Despite poor access to thebrain, the hormone epinephrine mayexert an antiseizure effect viastimulation of the peripheral vagusnerve6 because vagotomy abolishes theantiseizure effects of the drug.
It is tempting to speculate that theketogenic diet and certain antiepilepticdrugs may owe part of their action tothe PPAR�–vagus-nerve–brain route.Given that the mechanism of many ofthe antiepileptic drugs developedthroughout the past century remainseither unknown or contested, it isimperative that procedures such asvagotomy become part of screeningmethods (eg, the pentylenetetrazol test)to determine the contributions of theperipheral and CNS to the actions ofantiepileptic treatments.Tim Cullingford
National Heart and Lung Institute, ImperialCollege London, UK. Email [email protected]
more research is needed, especially in making telemedicine consumer-friendly and acceptable to staff. Stephen W Brown
Peninsula Medical School DevelopmentalDisabilities Research and EducationGroup, Unit 10 Bodmin Business Centre,Harleigh Road, Bodmin, Cornwall PL31 1AH, UK. Email [email protected]
Conflict of interestSWB currently has a grant from the NHSModernisation Agency ‘Action On Neurology’
Conflict of interestI have no conflicts of interest.
References1 Kossoff EH. More fat and fewer seizures: dietary
therapies for epilepsy. Lancet Neurol 2004;3: 415–20.
2 Theodore WH, Fisher RS. Brain stimulation forepilepsy. Lancet Neurol 2004; 3: 111–18.
3 Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamideregulates feeding and body weight through activationof the nuclear receptor PPAR-alpha. Nature 2003;425: 90–93.
4 Cullingford TE. Eagles DA, Sato H. The ketogenicdiet upregulates expression of the gene encoding thekey ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in ratbrain. Epilepsy Res 2002; 49: 99–107.
5 Cullingford TE, The ketogenic diet; fatty acids, fattyacid-activated receptors and neurological disorders.Prostaglandins Leukot Essent Fatty Acids 2004;70: 253–64.
6 Krahl SE, Senanayake SS, Handforth A. Seizure suppression by systemic epinephrine ismediated by the vagus nerve. Epilepsy Res 2000;38: 171–75.
Author’s replyThis is certainly an interesting theory;there is much about the mechanisms of action of the ketogenic diet—andantiepileptic drugs for that matter—that remains unknown. However, theredoes not seem to be any effect ofantiepileptic therapy, other than vagus-nerve stimulation, directly on the vagusnerve, and I suspect the ketogenic diet is unlikely to affect the CNS viathis mechanism. Most of the childrenon the diet only have modest appetitesuppression. In addition, ketosis,rather than calorie restriction, seemsto be the predominant mechanism by which efficacy occurs. However, aclinical trial of oleoylethanolamideand other fatty acids to suppressseizures would certainly be of interest.Eric Kossoff
The Johns Hopkins Medical Institution,Baltimore, Maryland, USA. Email [email protected]
programme to develop telemedicine forepilepsy and dementia services in Cornwall.
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