ORIGINALRESEARCH Efficacyofmediumchaintriglyceride oildietarysupplementationin reducingseizurefrequencyindogs Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. withidiopathicepilepsywithout clusterseizuresanon-blinded prospectiveclinicaltrial Jenifer Molina, Clementine Jean-Philippe, Lisa Conboy, Sonia Añor , Cristian de la Fuente,  Marcin Adam Wrzosek, Andrea Spycher,  Eva Luchsinger, Bettina Wenger-Riggenbach, Patricia Montoliu, Gualtiero Gandini, Marika Menchetti, João Carlos Ribeiro,, Artur Varejão,, Antonio Ferreira, Brian Zanghi , Holger Andreas Volk, Abstract Background Despite appropriate antiseizure drug (ASD) treatment, around two-thirds of dogs with idiopathic epilepsy (IE) have seizures long-term and –per cent of aected dogs remain poorly controlled. Methods The current study aim is to test in a eld trial the ecacy and tolerability of a commercially available diet enriched with .per cent medium chain triglyceride (MCT) oil in dogs (n=) with at least a tier  Veterinary Record (2020) doi: 10.1136/vr.105410 idiopathic epilepsy diagnosis, without cluster seizures, 1 12 in  veterinary practices across Europe. Each dog’s Technical Communications, Nestlé Department of Veterinary Sciences, quality of life (QoL), ataxia, sedation and frequency and Purina PetCare EMENA, Barcelona, University of Trás-os-Montes e Alto Spain Douro, Vila Real, Portugal severity of seizures were recorded by owners throughout 2 Regulatory and Scientific Affairs, 13 Centre for Animal Sciences and the study. Nestlé Purina, Lausanne, Switzerland Veterinary Studies, University of Results The mean seizure frequency per month, 3 Animal Medicine and Surgery, Trás-os-Montes e Alto Douro, Vila Real, averaged over the entire -day study, signicantly Universitat Autonoma de Barcelona, Portugal (P=.) decreased per cent compared with the Bellaterra, Barcelona, Spain 14 Clinics, Faculty of Veterinary Medicine, 4 Department of Internal Diseases, University of Lisbon, Lisbon, Portugal baseline monthly seizure frequency recorded during the Uniwersytet Przyrodniczy we 15 Global Nutrition and Communications, month immediately before feeding the diet. Similarly, Wroclawiu, Wroclaw, Poland Nestle Purina PetCare, St. Louis, United the seizure days rate (days/month) also declined 5 Tierarztpraxis Bärn West GmbH, Bern, States (P<.) by per cent. QoL was reported as very Switzerland 16 Veterinary Clinical Sciences, Royal good to excellent (>./) in  of the  dogs before 6 Tierarztpraxis DUOVet AG, Säriswil, Veterinary College, Hatfield, UK starting the diet and this remained unchanged during Switzerland 17 University of Veterinary Medicine, 7 Bessy's Kleintierklinik AG, Watt, Hannover, Germany the trial. Switzerland Conclusions This study demonstrates the use of a diet E-mail for correspondence: Dr Brian Neurology, Ars Veterinaria, Barcelona, Zanghi, Nestle Purina PetCare Co, Saint enriched with MCTs as an adjunct to ASD treatment may 8 Barcelona, Spain Louis, MO 63164, USA; have some antiseizure properties for dogs diagnosed 9 Department of Veterinary Medical brian.zanghi@rd.nestle.com with IE, as demonstrated in previous studies. Sciences, University of Bologna, Ozzano Emilia, Italy Provenance and peer review Not 10 Referência Veterinária, Alcabideche, commissioned; externally peer Introduction Portugal reviewed. Epilepsy is a common, chronic neurological disease 11 Faculdade de Medicina Veterinaria da affecting between .per cent and .per cent of dogs Received February 14, 2019 Universidada, Lisboa, Portugal in the general population with a higher prevalence Revised March 31, 2020 Accepted April 24, 2020 in some at- risk breeds.– Epilepsy is defined as two VETRECORD|  or more unprovoked epileptic seizures occurring More recently, a diet based on inclusion of at least  hours apart.  Idiopathic epilepsy (IE) MCTs was evaluated in epileptic dogs. Although is the most common form and can be a serious the exact mechanism of action of MCTs is not fully condition in dogs stemming from underlying genetic known, proposed mechanisms include provision abnormalities especially in specific dog breeds, but of an alternative energy supply to the brain (energy also occurs where the underlying cause could not be metabolism is insucient in epileptic dogs), global identified.–  Unfortunately, IE not only affects the changes in lipid metabolism and eects on cerebral pet’s general health, but also quality of life (QoL).– neurotransmitters.– The randomised, placebo- A recent review paper highlighted that dogs with controlled, double-blinded, crossover study revealed epilepsy are at risk not only for reduced QoL but also that most dogs fed the test diet (containing MCT oil) quantity of life. QoL can be considered diminished for  days showed a reduction in seizure frequency. Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. in some epileptic dogs, as similarly experienced In this study,  per cent of dogs experienced reduced by people, with the development of comorbidities seizure frequency, with  per cent having a ≥ per such as anxiety, hyperactivity disorders, cognitive cent reduction in seizure frequency and  per cent of impairments and antiseizure drug (ASD) side dogs achieving complete seizure freedom. The positive effects.– QoL of owners of epileptic dogs can also be eect of an MCT-enriched diet was also highlighted in a reduced due to worries about their dog’s health and recent study comparing an MCT oil dietary supplement limitations in lifestyle to accommodate their epileptic to a control oil (olive oil) in  dogs with IE being treated pet. with standard ASD(s). Overall seizure and seizure-day The disease in many cases has an early onset (with frequency were signicantly lower in dogs that had the most dogs having their rst seizure between one and MCT oil dietary supplement added to their routine diet three years of age) and is generally lifelong, typically compared to dogs that had the control oil added to their requiring long-term use of ASDs,– with the aim of food. Similar to the study by Law and others, , reducing seizure frequency and severity. Unfortunately,  per cent of dogs improved, and  per cent had –per cent of patients do not respond adequately to more than  per cent reduction in seizure frequency, medical management, which can impact QoL. From a although only  per cent became seizure free. medical perspective, a reduction in seizure frequency of Over recent years, it has become apparent that at least per cent is commonly considered a successful the mechanism of action of the traditional ketogenic treatment. For these reasons, there is great interest in diets, as well as diets containing MCTs, goes beyond nding alternative and/or adjunct treatments for canine ketone production. Medium chain fatty acids are IE. ecient in crossing the blood-brain barrier, unlike Dietary support has long been used in seizure long chain fatty acids, and can be directly oxidised management in people and a recent review describes in the brain. In rats ketogenic diets may increase how metabolic dysregulation appears to increase the mitochondrial function and brain energy reserves. In probability of sporadic seizure activity. As early as the addition, an MCT diet has been shown to dramatically s, it was noted that epileptic children experienced a increase mitochondrial function in dogs, and also reduction in seizure frequency when they were fasted. to increase metabolic synthesis of polyunsaturated In order to mimic the metabolic changes associated with fatty acids (PUFA) and their uptake in the canine brain fasting, ketogenic diets have been used with some success tissue. Interestingly, MCTs and their downstream in epileptic people. One study showed that children with metabolites are thought to have multiple aects in the epilepsy put on a traditional ketogenic diet (high fat, brain.  Recent studies have revealed that decanoic low carbohydrate, low protein—starting at a : ratio— acids (C) can act as a non-competitive AMPA receptor fat:protein and carbohydrate—and gradually increasing antagonist resulting in direct inhibition of excitatory to a : or : ratio over – weeks, as tolerated) had neurotransmission, and thus exerts an anticonvulsant signicant seizure reduction compared with children eect. Furthermore, C on its own might be able to on a control diet. The  per cent of children had > modulate mitochondrial proliferation via peroxisome per cent seizure reduction and  per cent children had proliferator-activated receptor gamma receptor. more than  per cent reduction in seizures (compared Cluster seizures are known to be a risk factor for drug- with  per cent and  per cent, respectively of children resistant epilepsy.  The two aforementioned canine fed the control diet). Dietary change is highly relevant clinical studies  had a high proportion of dogs with to owners of epileptic dogs with a very recent survey cluster seizures. Thus, in the current investigation containing  valid responses, two-thirds of owners it was determined that including a high proportion (. per cent) reported changed their dog’s diet aer of dogs with cluster seizures could potential bias the receiving an IE diagnosis. Nearly half of the owners results regarding the diet eect. No study had formerly (. per cent) reported giving dietary supplements, looked at the eect of MCTs on a population of dogs the most common being coconut oil or derived medium without cluster seizures. Hence, the eect was assessed chain triglyceride (MCT) oil (. per cent). in this subpopulation of patients. The objective of this  | VETRECORD Table  Nutrient composition of the diet (as fed basis) conditions or had surgery in the month before inclusion Nutrient Value (or if surgery was planned during the study period). Moisture (%) . Pregnant or lactating females and dogs over  kg were Crude fat (%) . also excluded from the study. Crude protein (%) . The breed, gender, age, diet and lifestyle of each dog Carbohydrates (%) . were recorded during the inclusion appointment. A full Crude fibre (%) . history was taken including seizure frequency during Crude ash (%) . the past  days to establish baseline monthly seizure Chloride (%) . rate, concomitant disease and treatments given. Dogs Vitamin E (IU/kg)  Arginine (%) . accepted into the trial had an initial clinical examination including body condition score (BCS) assessed using Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. Selenium (mg/kg) . EPA+DHA (%) . a -point scale, BW, rectal temperature and general MCT oil (%)* . health status evaluation. Owner evaluations were Energy value (kcal/g) . made of the dog’s QoL, ataxia, sedation and frequency *MCT oil .% added to the recipe (as is). and severity of seizures using a visual analogue scale DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MCT, medium chain triglyceride. as previously described (see online supplementary gure ). Dogs being treated with phenobarbital and/ prospective study was therefore to test the ecacy, or potassium bromide (KBr) had blood collected during palatability and tolerability of a commercially available the inclusion appointment ve hours aer the ASD diet enriched with . per cent MCT oil in dogs administration to monitor serum drug concentrations. diagnosed with IE with single seizures across Europe. Owners who gave permission for their dog to This study will further clarify the role of nutrition in participate in the study, were requested to change their epilepsy management. dog onto the study diet (Purina Pro Plan NC NeuroCare) gradually over a seven-day period so that by day  the Materials and methods dogs were eating  per cent of the recommended A prospective open-label, single-arm food study with amount of the study diet and nothing else other than no placebo was carried out across Europe (France, free-access water to drink. The feeding amount was Italy, Poland, Portugal, Spain and Switzerland) with initially advised as described per the product label  veterinary practices. Study protocol was designed feeding instruction, with daily amounts determined and followed in strict accordance with the guidelines according to metabolic energy requirements calculated established by the Nestlé Purina PetCare Animal Care according to the European Pet Food Industry Federation and Use Advisory Committee. All dogs were privately (FEDIAF) recommended energy equation of  owned and were enrolled only after owner consent was kcal×BW.. Each clinician had the liberty to adjust obtained. The aim of the study was to investigate the daily recommended portion based on individual pet’s efficacy and tolerability of a commercially available home climate conditions, the pet’s physical activity and veterinary prescription-based diet containing . per physical health condition. Depending on the BW and cent of MCT oil (Purina Pro Plan NC NeuroCare, Nestlé animal health status in the rst month visit, the amount Purina, St. Louis Missouri, USA) for the management of was adjusted to ensure the BW and BCS maintenance. dogs diagnosed with IE. Proximate analyses results of Daily feeding frequency (once or multiple meals daily) the diet are listed in table. was at the discretion of the pet owner. Purina Pro Plan Twenty-two dogs diagnosed with IE, which had no NC NeuroCare was recommended to be provided as reported events of cluster seizures, were recruited and treats or snacks. included in the trial based on multiple criteria; aged Follow-up visits were performed at day ,  and between  months (small and medium dogs)/ . At each follow up visit, a clinical examination months (large dogs) and  years old, with a maximum (including BCS, BW, rectal temperature and general bodyweight (BW) of  kg and with a tier  IE diagnosis. health status evaluation) was performed, as well In addition, dogs must have experienced at least three as the ASD dose administered and its possible side seizures in the three months before inclusion and must eects were recorded. The owners also evaluated the have been treated with at least one antiepileptic drug dog’s QoL, ataxia, sedation and diet consumption, as for a minimum of one year before inclusion. Finally, pet well as frequency and severity of seizures along with owners must have been in full agreement to their dogs global evaluation of the diet’s ecacy and tolerance taking part in the study. each month as described previously. Throughout Dogs were not included in the study if they had the study, owners were also asked to record days another identiable cause of their seizures (eg, brain when their dog experienced a seizure and number neoplasm, brain trauma, etc), were experiencing and duration of seizures experienced during that cluster seizures (more than one seizure per day), had day. Similar to day  visit, dogs being treated with concomitant diseases such as liver, kidney or heart phenobarbital and/or KBr had blood collection ve VETRECORD|  Table  Pet-specific demographics, antiepileptic drug treatment, bodyweight, relative test food ingestion and seizure data Number of seizure days/month Seizure frequency/month Day  Average % food Age Medical bodyweight consumed over End of End of Case Breed (years) Sex* treatment† (kg) trial Baseline trial % change Baseline trial % change  Cocker spaniel  F PKBr .   . −.  . −.  Mixed setter  SF PI .   . −.  . −.  Mixed breed . SM P    . −.  . −.  Dachshund  SM PKBr .   . −.  . −.  Dachshund  M PKBr .   . −.  . −.  Beagle  M I .   . −.  . −.  Crossed Griffon  SM I    . −.  . −. Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021].  Mixed breed  M P .   . −.  . −.  Labrador retriever  M PKBr    . −.  . −.  Belgian shepherd . SF P    . −.  . −.  Giant schnauzer  SM PKBr .   . −.  . −.  Poodle  M I .   . −.  . −.  Crossbreed  F I .   . −.  . −.  Labrador retriever  F I .   . −.  . −.  Crossbreed  F PL .   . −.  . −.  Labrador retriever  M PI    . −.  . −.  English setter  SM PL .   . .  . .  Shih Tzu  M PLT    . .  . .  Crossbreed  M P .   . .  . .  Crossbreed  M P    . .  . .  Irish setter  M PLT    . .  . . *Sex and intact status. F, female; I, imepitoin; KBr, potassium bromide; L, levetiracetam; M, male; P, phenobarbital; S, sterile; T, topiramate. hours aer the ASD administration to monitor serum during month two:  per cent of ration during month ). drug concentrations. Of the remaining  dogs, the median age was . years At the end of the study period ( weeks), records old (range: – years) and the gender distribution was were taken on the pet owner’s perception of the  (. per cent) entire females,  (. per cent) spayed palatability and eectiveness of the food and whether or females,  (. per cent) entire males and  (. not they would recommend it for use by other epileptic per cent) neutered males. No significant difference was dogs. The participating veterinarians were asked to also observed for BW (P=.) and BCS (P=.) change record whether or not they would recommend the dog during the trial period (table). to continue on the test diet for long term. Of the  dogs,  dogs continued to only have single seizure events on a given day during the entire Statistical analysis test period, whereas  dogs experienced either  or  Data were analysed using R lme software package. cluster seizures, and  dogs had no seizures observed. All analyses were conducted using R (V..., accessed Acceptance of the food was good (> per cent of ration) September , ). The dog was considered the to excellent ( per cent of ration) in  out of the  experimental unit for all analyses. To compare the BW, dogs in the rst month and throughout the remainder of BCS and seizure frequency between the starting point the test period. and the day  (end of study), a Wilcoxon rank-sum statistical test (non-parametric paired test) was performed. Seizure frequency refers to the number of Table  Effect of the diet in all dogs (n=) and only dogs that experience single seizure events per day (n=) for each of the measurements seizures per month, and seizure day rate refers to the (mean±se) between baseline and the end of the study number of days in a month with seizure occurrence. Wilcoxon A P value <. was considered to be statistically rank-sum significant. statistical Parameter N Baseline End of study test p value BW (kg)  . (±.) . (±.) . Results BCS  . (±.) . (±.) . Data were collected from  dogs (table ) including N° of seizure days/month  . (±.) . (±.) <.  pure breeds (dachshund, Belgian shepherd, English Total n° of seizures/month  . (±.) . (±.) . setter, cocker spaniel, poodle, Labrador retriever, giant BW (kg)  . (±.) . (±.) . schnauzer, beagle, Maltese, Irish setter, Shih Tzu), and BCS  . (±.) . (±.) .  mixed breed dogs table. A single dog (. years old, N° of seizure days/month  . (±.) . (±.) <. Total n° of seizures/month  . (±.) . (±.) <. female Maltese) was removed from the analysis because BCS, body condition score; BW, bodyweight; n°, number. of lack of test food ingestion ( per cent of ration  | VETRECORD As a result of feeding the diet for  days, the mean levetiracetam and topiramate. Serum concentrations seizure day rate signicantly declined (P=.) by of phenobarbital, with or without KBr, were reported  per cent (. seizure days/month; median=.) for  of  dogs. For those dogs, serum concentrations compared with the baseline (. days/month; were unchanged at the end of the study compared with median=.) (table ). At baseline, seizure days/ baseline. month ranged from a minimum of one to a maximum QoL was reported as excellent (/) at the start of of six, whereas aer the diet phase it ranged from  to the study in  of the  dogs. In three dogs, the QoL a maximum of . days/month. Of the  dogs, . was reported as very good, starting with a minimum of per cent ( of  dogs) became seizure free, . per ./. One dog was initially reported as poor (/), cent of dogs ( of  dogs) had ≥ per cent reduction but was reported as / throughout the entire test in seizure days and . per cent ( of  dogs) had < phase, which coincidently was a cluster seizure dog Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. per cent reduction. In addition, three dogs (. per that had a  per cent reduction in seizure rate. The cent) had no change, whereas two dogs (. per cent) majority of dogs (/) maintained the same level of had an increase in seizure days. Overall,  of  dogs QoL during the study. (. per cent) experienced fewer seizure days with the Regarding the ataxia level, three owners reported test diet. mild ataxia (/ or /) at day , two of which For total seizure frequency, feeding the diet resulted improved during the study (ataxia level of / or / in a  per cent decline (P=.) (. seizures/month: at day , respectively). One dog remained unchanged median=.) compared with baseline (. seizures/ over the trial (/). Sedation was reported in  out of month; median=.; table ). Generally similar to  dogs at day . Two dogs had a sedation level of /, seizure day rate, the relative proportion of dogs that four had a level of ≤/. At the end of the study (day became seizure free was . per cent ( dogs), . per ), three dogs decreased the level of sedation, and cent had ≥ per cent reduction ( dogs) and . per three remained in the same level. cent ( of  dogs) had < per cent reduction. One dog Finally, pet owner survey results indicated that  of (. per cent) had no change and four dogs (. per  owners ( per cent) would recommend the diet for cent) had an increase in seizure frequency. Overall,  epileptic dogs. Of the veterinarians that responded to of  dogs (. per cent) experienced a lower seizure the survey,  ( per cent) would recommend the diet frequency with the test diet. for epileptic dogs,  would not and  did not provide an Aer reviewing the seizure data for each dog, ve answer. dogs had experienced at least one cluster seizure during the trial phase. Of these ve dogs, there was no apparent Discussion pattern in the occurrence of the cluster seizures while To expand the veterinary management options for on the test diet. A post hoc statistical analysis was canine patients with ASD treated IE, a commercially performed that excluded the ve dogs that experienced available diet enriched with . per cent MCT oil (as fed cluster seizures at some point during the treatment basis) plus a blend of other nutrients was offered to pet period (table ) because the aim of the study was to owners as an open-label feeding trial to prospectively especially study its eects on dogs with single seizures. evaluate seizure outcomes resulting from dietary The mean seizure day rate (. seizure days/month) for management as an adjunct to ASD treatment. This study the test phase signicantly (P<.) declined by  per builds on existing canine research that demonstrated cent compared with the baseline seizure day rate (. the clinical efficacy of a diet enriched with MCT oil in days/month) for  non-cluster seizure dogs. None of two double-blinded, placebo-controlled, prospective these  dogs had any worsening of seizure day rate or diet clinical trial with a population of ASD(s)-resistant seizure frequency ( per cent) and . per cent of dogs IE dogs., In the study by Law and others, the diet ( of ) were seizure-free throughout the entire -day contained . per cent MCT oil (as fed basis) compared feeding trial. Overall, . per cent of dogs ( of ) with . per cent added MCT oil in this current study. had greater than a  per cent reduction in seizure days Previous unpublished work from Nestlé Purina and seizure frequency, with . per cent of dogs ( of revealed that ketone production is dose-dependently ) experiencing greater than a  per cent reduction increased with MCT inclusion. However practically, the in seizures. Only two dogs (. per cent) had either no inclusion level of  per cent MCT oil (as fed basis) to change or a  per cent reduction in number of seizures. a diet has limitations because of reduced palatability Dogs were being treated with a variety of ASDs. observations, as demonstrated in a study of the benefits Fourteen out of  dogs were being treated with of an MCT oil-enriched food fed to dogs with canine phenobarbital (range .–. g/mL) either cognitive dysfunction syndrome. alone or combined with KBr (range – mg/ Similarly, this compilation of case studies revealed dL), levetiracetam or imepitoin. In addition, ve dogs that nearly  per cent of the study population ( of were being treated with imepitoin alone. Two dogs ) became seizure free while on the commercial diet. were treated with a combination of phenobarbital, This is similar to previous observations in which  VETRECORD|  per cent of dogs ( of ) were seizure free when fed a rst-opinion veterinary clinics participated in the diet containing . per cent MCT oil, but experienced recruitment and management of the patients that seizures when fed the placebo food absent of MCTs. spanned over ve dierent countries across Europe, Furthermore, this current data revealed a similar whereas the other study was performed in a single response rate of participants (. per cent;  of  dogs) referral hospital setting and conducted entirely through to achieve > per cent seizure reduction (frequency the Royal Veterinary College Clinical Investigation and seizure day rate) when compared with the study Center referral hospital in the UK. Secondly, the level population reported by Law and others, in which of MCT oil (. per cent) diered relative to other . per cent ( of  dogs) achieved > per cent studies referenced above. Thirdly, the recruited pet reduction in seizure frequency and . per cent ( of population was focused on a less severe type of IE with ) achieved > per cent reduction in seizure day rate. tier  diagnosis. And nally, to obtain clinically relevant Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. A more recent study used the direct supplementation of data acquired by collaborating vets and their clients, an MCT oil performed by the pet owner by adding on the data represent a compilation of case studies, and top and mixed in with their dog’s existing diet. This consequently did not have a placebo-controlled arm MCT oil supplement trial included  dogs with IE and of the experimental design. A reasonable limitation were provided supplementation equivalent to  per cent underlying this study is based on the utilisation of an MCT oil as metabolic energy calculated. Most notable unblinded diet treatment experimental design that from this study was that only  per cent of the  dogs could impart a bias on the study participants, as well as achieved more than  per cent seizure reduction or because of recent reports of placebo eects. Many studies seizure freedom. on epilepsy were designed to evaluate for a positive The observations of dietary eect of seizure reduction response to therapy, which is dened as a ≥ per cent reported here are statistically signicant. Although, it is reduction in seizures.  In one study which combines reasonable to consider important limitations to these the results from three placebo-controlled trials, a large results, as the number of animals involved in the study proportion of dogs with IE responded to placebo alone, were not a large number of observations and around  with an approximately  per cent reduction in seizures per cent of the eect seen could possibly be due to the following placebo administration. However, the dogs placebo, regression to the mean, or Hawthorne eects. in the placebo group were on conventional ASD therapy However, this multicentre eld study does conrm two that could have aected the results and outcome. former placebo-controlled, double-blinded studies This placebo response has been attributed to the described above,  and the diet was well tolerated by regression to the mean eect, the natural waxing and most dogs, with  per cent of participating vets and waning course of epilepsy over time, the likelihood for  per cent of owners recommending to continue with improved patient care during participation in the trial the diet. It is also important to consider that there was and investigator and participant bias. The presence of an improvement in QoL and some of the side eects the strong placebo eect found in that report suggests related to ataxia and sedation. From the ve dogs that that results from non-blinded studies, particularly experienced the onset of cluster seizures during the those that involve a small number of animals and short study period, the authors can remark that two of them follow-up time should be interpreted with some caution. decreased the number of seizures during the study, one A further limitation to this study is the incomplete showed no eect and the other two increased the number collection of blood samples for ASD monitoring from of seizures compared with day . In addition, there was all dogs at both prefeeding and postfeeding time point, no obvious trend on when these cluster seizures were leaving open the fact that the authors could not clearly observed during the diet phase, as two dogs had clusters demonstrate ASD concentrations in the blood remained during month two, whereas three dogs had clusters in unchanged in all dogs throughout the study period. month three. Ultimately, this study demonstrates that However in a previous clinical assessment of feeding there was a similar signicant seizure reducing eect a diet containing MCT oil to epileptic dogs, ASD levels for IE dogs with single seizures, as well as for some dogs were measured. The ASD treatment regimens of the experiencing cluster seizures, as previously described dogs remained the same between the placebo and in the other aforementioned published studies. In MCT diet phases. There were no signicant changes in addition, these case studies conrm previous studies of serum concentrations of phenobarbital (P=.) or feeding an MCT oil containing diet to dogs with IE is safe KBr (P=.) between the placebo-standardised diet and tolerable, and with the available data, no change and MCT diet, respectively. Given that approximately in ASD blood levels were recorded (data available from  per cent ( out of ) of the dogs here showed no nine dogs) throughout the study. change in serum ASD level, and the prior ndings by This study diered in several distinguishing aspects Law and others, the authors would expect ASD serum from the former aforementioned studies and does concentrations in the other dogs were not altered. A have some additional limitations worth noting. The nal limitation is that chloride content of the previous rst notable distinguishing factor is that multiple diets from the six pets receiving KBr treatment was  | VETRECORD not specically measured before starting the trial to be accomplished by the dietary medium chain fatty to specically assess if therapeutic levels would be acid (MCFA) decanoic acid (C). Other research as altered. However, for consistency across the study and revealed that C and octanoic acid (C) fatty acids consistency to previous clinical trials, all ASD regimens fed to rats increased the seizure threshold and induced for all dogs were to remain unchanged throughout sedation, and reported to be related to primarily C the study. It is also important to note that Purina Pro causing an increased passage of tryptophan (Trp) into Plan NC NeuroCare has a chloride level of . g/ the brain. This anticonvulsant eect was abolished kcal. Although the authors do not have the information when Trp passage into the brain was blocked, thus of the chloride level for the pretrial diets fed to the ecacy of a ketogenic diet may be at least partly six dogs receiving KBr in the study, by estimating dependent on changes in Trp metabolism. Because that maintenance diets may likely contain chloride rats serve as a model in human medicine as well as in Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. levels around .–. g/ kcal, but could be as veterinary medicine, this mechanism of action could low as the minimum requirement of . g/ kcal possibly help explain the positive eects of MCTs on (American Association of Feed Control Ocials, ). seizure frequency in dogs. Further studies should be Thus, the test diet is at the high end of that range and conducted in order to conrm that this mechanism of consequently would have justied a potential elevation action also occurs in dogs. Interestingly, recent canine in KBr but would have confounded any observed diet serum metabolomics data generated during the clinical eect. study reported by Law and others has indicated that The mechanism by which an MCT-enriched diet IE dogs fed MCTs demonstrate global changes in provides clinical ecacy for some patients remains lipid metabolism, and even provide initial evidence unclear, but it is likely a multifactorial modality that to suggest that C: moieties are involved in these is underlying its eectiveness, such that MCTs and/ metabolic pathways. or their metabolites, in part, ameliorate some of the multiple metabolic dysfunctions that appears to be at Conclusion the root of the disease. The type of MCTs used in this The data reported above are consistent with the positive current diet study are from the same MCT oil ingredient effects (reduction in seizure frequency and days) of as previously used in IE dogs and with senior dogs to MCTs in dogs diagnosed with IE, in accordance with evaluate cognitive performance.  Initially in , evidence in the published literature.  The diet used a diet enriched with MCT oil was reported to improve in the study has been shown to be very useful as an cognitive performance in aged dogs, as demonstrated adjunct management strategy in dogs with IE. This is through a variety of neuropsychological tests. The important because even with ASD treatment, more than main mechanism of action proposed for these cognitive two-thirds of dogs with IE have seizures long-term and improvements was the generation of ketone bodies about one-third of dogs with IE continue to experience derived from the dietary source of MCTs, as an seizures that are difficult to control.– Thus, there alternative energy source for diminished brain energy is a great-unmet need to supply these canine patients metabolism that appears in aged dogs. However, with alternative and additional options to help support even though Law and others observed an increase in management of epilepsy, improve the QoL of the canine serum ketone concentrations in IE dogs fed the MCT oil- patients receiving ASDs, which will hopefully improve enriched diet, no relationship was observed between the QoL of the pet owners. seizure frequency and serum ketones. This is in contrast The palatability of the diet was good to excellent in to other evidence in children that suggests there is a the  per cent of the cases, which support the use of this direct relationship. Alternatively, or in conjunction type of MCTs in food for dogs. A survey of the vets and pet with ketones as an alternative energy source, MCTs owners that participated in this study indicated that  may contribute to the maintenance of the neuronal per cent of these vets and  per cent of owners would structure via increasing concentrations of PUFA in the recommend the diet for epileptic dogs. These results are brain, which have also been shown to decrease as a encouraging. However, larger randomised controlled consequence of ageing, but this evidence is lacking in trials with longer follow-up periods would be valuable canine studies of IE. and needed to understand the long-term benets of this In a recent study by a dierent laboratory, specic type of diet on canine epilepsy management. MCTs (decanoic acid) were fed to rodents and showed positive eects in seizure control, where pathological Contributors BZ, CJ-P, LC and JM designed the study with input from HAV. BZ, LC, JM and HAV handled and analysed the data. CdlF, MAW, AS, EL, BW-R, PM, GG, mechanisms or pathways involved may be similar to the MM, JCR, AV and AF recruited pets and conducted study. All authors reviewed final ones involved in ageing. A new mechanism of action dataset, then reviewed and participated in drafting manuscript. JM and BZ submitted manuscript. proposed in rats for explaining the antiseizure eect of Funding This study was fully funded by Nestlé Purina Research. MCTs is a direct eect via blocking the AMPA receptors Competing interests BZ reports a patent US Patent No. 9789079 issued. BZ (responsible of the excitatory neurotransmission and LC are employed within the R&D Department of Nestlé Purina PetCare to pathway) in the brain. This function has been proposed conduct nutrition research for the potential use in future commercial applications VETRECORD|  and products. JM and CJ-P are employed within the European team of Nestlé Purina  Berk BA, Packer RMA, Law TH, et al. Investigating owner use of dietary supplements in PetCare communicating on the scientific studies and products, and also organising dogs with idiopathic epilepsy. Res Vet Sci ;:–. clinical trials of the products. SA, CdlF, MAW, AS, EL, BW-R, PM, GG, MM, JCR, AV and  Law TH, Davies ESS, Pan Y, et al. A randomised trial of a medium-chain tag diet as AF were paid by Nestlé Purina PetCare for clinical services related to case recruitment treatment for dogs with idiopathic epilepsy. Br J Nutr ;:–. and conducting the trial and/or were provided the test food for the trial dogs by  Law TH, Volk HA, Pan Y, et al. Metabolic perturbations associated with the consumption Nestlé Purina PetCare, and do not have any other conflicts of interest to disclose. HAV of a ketogenic medium-chain tag diet in dogs with idiopathic epilepsy. Br J Nutr is a paid consultant for Nestlé Purina PetCare. ;:–.  Giordano C, Marchiò M, Timofeeva E, et al. Neuroactive peptides as putative mediators Data availability statement All data relevant to the study are included in the of antiepileptic ketogenic diets. Front Neurol ;:. article or uploaded as supplementary information. All available data are provided  Masino SA, Rho JM. Mechanisms of ketogenic diet action. In: Noebels JL, Avoli M, within the article. Rogawski MA, eds. Jasper’s Basic Mechanisms of the Epilepsies. th ed. Bethesda, MD: National Center of Biotechnology Information (US), : –. Open access This is an open access article distributed in accordance with the  Rho JM, Sankar R. The ketogenic diet in a pill: is this possible? Epilepsia ; Suppl Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which :–. permits others to distribute, remix, adapt, build upon this work non-commercially, and  Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia license their derivative works on different terms, provided the original work is properly ;:–. Printed by [British Veterinary Association - 081.035.060.208 - /doi/epdf/10.1136/vr.105410] at [07/04/2021]. cited, an indication of whether changes were made, and the use is non-commercial.  Berk B, Law T, Wessmann A, et al . 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