Efficacy of medium chain triglyceride oil dietary supplementation in reducing seizure frequency in dogs with idiopathic epilepsy without cluster seizures: a non-blinded, prospective clinical trial
Pet-specific demographics, antiepileptic drug treatment, bodyweight, relative test food ingestion and seizure data View this table: View popup Table 3 Effect of the diet in all dogs (n=21) and only dogs that experienced single seizure events per day (n=16) for each of the measurements (mean±se) between baseline and the end of the study Of the 21 dogs, 14 dogs continued to only have single seizure events on a given day during the entire test period, whereas 5 dogs experienced either 1 or 2 cluster seizures, and 2 dogs had no seizures observed. Acceptance of the food was good (>70 per cent of ration) to excellent (100 per cent of ration) in 19 out of the 22 dogs in the first month and throughout the remainder of the test period. As a result of feeding the diet for 84 days, the mean seizure day rate significantly declined (P=0.002) by 42 per cent (1.4 seizure days/month; median=1.0) compared with the baseline (2.5 days/month; median=2.0) ( table 3 ). At baseline, seizure days/month ranged from a minimum of one to a maximum of six, whereas after the diet phase it ranged from 0 to a maximum of 3.67 days/month. Of the 21 dogs, 9.5 per cent (2 of 21 dogs) became seizure free, 42.9 per cent of dogs (9 of 21 dogs) had ≥50 per cent reduction in seizure days and 33.3 per cent (7 of 21 dogs) had <50 per cent reduction. In addition, three dogs (14.2 per cent) had no change, whereas two dogs (9.5 per cent) had an increase in seizure days. Overall, 16 of 21 dogs (76.2 per cent) experienced fewer seizure days with the test diet. For total seizure frequency, feeding the diet resulted in a 32 per cent decline (P=0.04) (1.7 seizures/month: median=1.0) compared with baseline (2.5 seizures/month; median=2.0; table 3 ). Generally similar to seizure day rate, the relative proportion of dogs that became seizure free was 9.5 per cent (2 dogs), 42.9 per cent had ≥50 per cent reduction (9 dogs) and 33.3 per cent (7 of 21 dogs) had <50 per cent reduction. One dog (4.8 per cent) had no change and four dogs (19.0 per cent) had an increase in seizure frequency. Overall, 16 of 21 dogs (76.2 per cent) experienced a lower seizure frequency with the test diet. After reviewing the seizure data for each dog, five dogs had experienced at least one cluster seizure during the trial phase. Of these five dogs, there was no apparent pattern in the occurrence of the cluster seizures while on the test diet. A post hoc statistical analysis was performed that excluded the five dogs that experienced cluster seizures at some point during the treatment period ( table 3 ) because the aim of the study was to especially study its effects on dogs with single seizures. The mean seizure day rate (1.0 seizure days/month) for the test phase significantly (P50 per cent seizure reduction (frequency and seizure day rate) when compared with the study population reported by Law and others, in which 47.6 per cent (10 of 21 dogs) achieved >50 per cent reduction in seizure frequency and 38.0 per cent (8 of 21) achieved >50 per cent reduction in seizure day rate. A more recent study used the direct supplementation of an MCT oil performed by the pet owner by adding on top and mixed in with their dog’s existing diet. 33 This MCT oil supplement trial included 28 dogs with IE and were provided supplementation equivalent to 9 per cent MCT oil as metabolic energy calculated. Most notable from this study was that only 18 per cent of the 28 dogs achieved more than 50 per cent seizure reduction or seizure freedom. 33 The observations of dietary effect of seizure reduction reported here are statistically significant. Although, it is reasonable to consider important limitations to these results, as the number of animals involved in the study were not a large number of observations and around 30 per cent of the effect seen could possibly be due to the placebo, 47 regression to the mean, or Hawthorne effects. However, this multicentre field study does confirm two former placebo-controlled, double-blinded studies described above, 27 33 and the diet was well tolerated by most dogs, with 90 per cent of participating vets and 100 per cent of owners recommending to continue with the diet. It is also important to consider that there was an improvement in QoL and some of the side effects related to ataxia and sedation. From the five dogs that experienced the onset of cluster seizures during the study period, the authors can remark that two of them decreased the number of seizures during the study, one showed no effect and the other two increased the number of seizures compared with day 0. In addition, there was no obvious trend on when these cluster seizures were observed during the diet phase, as two dogs had clusters during month two, whereas three dogs had clusters in month three. Ultimately, this study demonstrates that there was a similar significant seizure reducing effect for IE dogs with single seizures, as well as for some dogs experiencing cluster seizures, as previously described in the other aforementioned published studies. In addition, these case studies confirm previous studies of feeding an MCT oil containing diet to dogs with IE is safe and tolerable, and with the available data, no change in ASD blood levels were recorded (data available from nine dogs) throughout the study. This study differed in several distinguishing aspects from the former aforementioned studies and does have some additional limitations worth noting. The first notable distinguishing factor is that multiple first-opinion veterinary clinics participated in the recruitment and management of the patients that spanned over five different countries across Europe, whereas the other study 27 was performed in a single referral hospital setting and conducted entirely through the Royal Veterinary College Clinical Investigation Center referral hospital in the UK. Secondly, the level of MCT oil (6.5 per cent) differed relative to other studies referenced above. Thirdly, the recruited pet population was focused on a less severe type of IE with tier 1 diagnosis. And finally, to obtain clinically relevant data acquired by collaborating vets and their clients, the data represent a compilation of case studies, and consequently did not have a placebo-controlled arm of the experimental design. A reasonable limitation underlying this study is based on the utilisation of an unblinded diet treatment experimental design that could impart a bias on the study participants, as well as because of recent reports of placebo effects. Many studies on epilepsy were designed to evaluate for a positive response to therapy, which is defined as a ≥50 per cent reduction in seizures. 48 49 In one study which combines the results from three placebo-controlled trials, a large proportion of dogs with IE responded to placebo alone, with an approximately 30 per cent reduction in seizures following placebo administration. 48 However, the dogs in the placebo group were on conventional ASD therapy that could have affected the results and outcome. This placebo response has been attributed to the regression to the mean effect, the natural waxing and waning course of epilepsy over time, the likelihood for improved patient care during participation in the trial and investigator and participant bias. 48 The presence of the strong placebo effect found in that report suggests that results from non-blinded studies, particularly those that involve a small number of animals and short follow-up time should be interpreted with some caution. A further limitation to this study is the incomplete collection of blood samples for ASD monitoring from all dogs at both prefeeding and postfeeding time point, leaving open the fact that the authors could not clearly demonstrate ASD concentrations in the blood remained unchanged in all dogs throughout the study period. However in a previous clinical assessment of feeding a diet containing MCT oil to epileptic dogs, ASD levels were measured. 27 The ASD treatment regimens of the dogs remained the same between the placebo and MCT diet phases. There were no significant changes in serum concentrations of phenobarbital (P=0.423) or KBr (P=0.300) between the placebo-standardised diet and MCT diet, respectively. Given that approximately 50 per cent (10 out of 21) of the dogs here showed no change in serum ASD level, and the prior findings by Law and others, the authors would expect ASD serum concentrations in the other dogs were not altered. A final limitation is that chloride content of the previous diets from the six pets receiving KBr treatment was not specifically measured before starting the trial to specifically assess if therapeutic levels would be altered. However, for consistency across the study and consistency to previous clinical trials, all ASD regimens for all dogs were to remain unchanged throughout the study. It is also important to note that Purina Pro Plan NC NeuroCare has a chloride level of 0.20 g/100 kcal. Although the authors do not have the information of the chloride level for the pretrial diets fed to the six dogs receiving KBr in the study, by estimating that maintenance diets may likely contain chloride levels around 0.13–0.22 g/100 kcal, but could be as low as the minimum requirement of 0.03 g/100 kcal (American Association of Feed Control Officials, 2018). Thus, the test diet is at the high end of that range and consequently would have justified a potential elevation in KBr but would have confounded any observed diet effect. The mechanism by which an MCT-enriched diet provides clinical efficacy for some patients remains unclear, but it is likely a multifactorial modality that is underlying its effectiveness, such that MCTs and/or their metabolites, in part, ameliorate some of the multiple metabolic dysfunctions that appears to be at the root of the disease. 23 The type of MCTs used in this current diet study are from the same MCT oil ingredient as previously used in IE dogs 27 and with senior dogs to evaluate cognitive performance. 47 50 Initially in 2010, a diet enriched with MCT oil was reported to improve cognitive performance in aged dogs, as demonstrated through a variety of neuropsychological tests. 50 The main mechanism of action proposed for these cognitive improvements was the generation of ketone bodies derived from the dietary source of MCTs, 50 as an alternative energy source for diminished brain energy metabolism that appears in aged dogs. 51 However, even though Law and others observed an increase in serum ketone concentrations in IE dogs fed the MCT oil-enriched diet, no relationship was observed between seizure frequency and serum ketones. This is in contrast to other evidence in children that suggests there is a direct relationship. 52 Alternatively, or in conjunction with ketones as an alternative energy source, MCTs may contribute to the maintenance of the neuronal structure via increasing concentrations of PUFA in the brain, which have also been shown to decrease as a consequence of ageing, 53 but this evidence is lacking in canine studies of IE. 54 In a recent study by a different laboratory, specific MCTs (decanoic acid) were fed to rodents and showed positive effects in seizure control, 55 56 where pathological mechanisms or pathways involved may be similar to the ones involved in ageing. A new mechanism of action proposed in rats for explaining the antiseizure effect of MCTs is a direct effect via blocking the AMPA receptors (responsible of the excitatory neurotransmission pathway) in the brain. This function has been proposed to be accomplished by the dietary medium chain fatty acid (MCFA) decanoic acid (C10). 55 Other research as revealed that C10 and octanoic acid (C8) fatty acids fed to rats increased the seizure threshold and induced sedation, and reported to be related to primarily C8 causing an increased passage of tryptophan (Trp) into the brain. 56 This anticonvulsant effect was abolished when Trp passage into the brain was blocked, thus efficacy of a ketogenic diet may be at least partly dependent on changes in Trp metabolism. Because rats serve as a model in human medicine as well as in veterinary medicine, this mechanism of action could possibly help explain the positive effects of MCTs on seizure frequency in dogs. Further studies should be conducted in order to confirm that this mechanism of action also occurs in dogs. Interestingly, recent canine serum metabolomics data generated during the clinical study reported by Law and others has indicated that IE dogs fed MCTs demonstrate global changes in lipid metabolism, and even provide initial evidence to suggest that C17:0 moieties are involved in these metabolic pathways. 28 Conclusion The data reported above are consistent with the positive effects (reduction in seizure frequency and days) of MCTs in dogs diagnosed with IE, in accordance with evidence in the published literature. 27 33 The diet used in the study has been shown to be very useful as an adjunct management strategy in dogs with IE. This is important because even with ASD treatment, more than two-thirds of dogs with IE have seizures long-term and about one-third of dogs with IE continue to experience seizures that are difficult to control. 57–59 Thus, there is a great-unmet need to supply these canine patients with alternative and additional options to help support management of epilepsy, improve the QoL of the canine patients receiving ASDs, which will hopefully improve the QoL of the pet owners. The palatability of the diet was good to excellent in the 86 per cent of the cases, which support the use of this type of MCTs in food for dogs. A survey of the vets and pet owners that participated in this study indicated that 90 per cent of these vets and 100 per cent of owners would recommend the diet for epileptic dogs. These results are encouraging. However, larger randomised controlled trials with longer follow-up periods would be valuable and needed to understand the long-term benefits of this type of diet on canine epilepsy management. References ↵ Moore SA . A clinical and diagnostic approach to the patient with seizures . Top Companion Anim Med 2013 ; 28 : 46 – 50 . doi:10.1053/j.tcam.2013.07.002 pmid: http://www.ncbi.nlm.nih.gov/pubmed/24070681