M. Chandler1; H. Volk2
Energy for the Brain
Brain tissue consumes a large amount of energy in proportion to volume, largely to sustain the electric charge of neurons. The brain derives most of its energy from oxygen-dependent glucose metabolism, which provides a substrate for ATP. During exercise, blood lactate is increased and can be metabolized by the brain to provide energy; however, its contribution to brain energy requirements is small.
Ketones (e.g., β-hydroxybutyrate and acetoacetate) provide an important alternative brain energy source, especially in starvation where they provide up to 60% of the requirement. Long-chain fatty acids (LCFA) are oxidised by β-oxidation to form acetyl-CoA, which is normally further oxidized by the citric acid (TCA) cycle. If the TCA cycle is challenged (e.g., due to low amounts of intermediates such as oxaloacetate), acetyl-CoA is used instead to synthesize ketones. The brain has limited ability to utilise LCFA, likely due to low enzymatic capacity of neuronal mitochondria for β-oxidation, although an inability of LCFA to cross the blood-brain barrier may play a role.1
Triglycerides are comprised of three fatty acid (FA) carbon (C) chains and a “backbone” of glycerol. The attributes of fats are due to the carbon chain length and the degree of hydrogen saturation. Less hydrogens means more double C:C bonds, resulting in mono (one double bond) or polyunsaturated fats (PUFAs). Triglycerides with long-chain fatty acids (LCFA) usually have 16 to 22 carbons, medium-chain triglycerides (MCTs) have 6 to 12 carbons, and short-chain fatty acids have less than 6 carbons. The most useful medium-chain fatty acids (MCFA) appear to be octanoic acid (C8; caprylic acid) and decanoic acid (C10; capric acid). Unlike LCFA, MCFAs are oxidized in brain astrocytes and provide a glucose-sparing effect. MCFAs were thought to be absorbed passively across the intestinal mucosa into the portal blood, although it has been suggested that they are absorbed by the intestinal lymphatics like LCFAs in dogs.2 MCFA are transported into hepatocytes through a carnitine-independent system.
MCT oils are typically a mixture of saturated triglycerides, C8:0 (65–75%) and C10:0 (23–35%), with 1–4% of C6:0 and C12:0. Coconut and palm kernel oils are used for the commercial extraction of MCT. Coconut oil contains about 65% MCFA. MCT oils contain few essential fatty acids and should not be the sole dietary fat. Food with 15% MCT was not palatable for beagles, although no signs of toxicity were noted.3 Ketosis produced by diet differs from pathological ketosis (e.g., in diabetes mellitus); the amount of blood ketones is much lower, and acidosis is not recognized.
Ketones and Ketogenic Diets (KD)
MCTs are metabolized by the liver into ketone bodies, even without starvation. MCTs provide more ketones/calories than LCFA triglycerides. Ketones readily cross the blood-brain barrier. As glucose metabolism is disrupted with epilepsy, ketones are potentially a good energy source, and diets supplemented with MCT show an increase in blood β-hydroxybutyrate in dogs.
LCFA ketogenic diets (fat as 75–80% of the calories) have been used in the treatment of human epilepsy, especially children with refractory seizures; however, peripheral utilization of ketones is more efficient in dogs. They are more resistant to nutritional ketosis.4 A ketogenic diet trial failed to show a decrease in canine seizure frequency, and it had to be stopped due to some dogs developing pancreatitis.5 Some evidence suggests that omega-3 fatty acids reduce human seizures6 but supplementation did not reduce seizure frequency or severity in 15 dogs with idiopathic epilepsy (IE)7.
A more promising diet, based on MCTs, improved seizure control in the majority of cases in two placebo-controlled studies.8 MCTs have a higher ketogenic yield, which can improve brain metabolism. Furthermore, valproic acid—an anti-epileptic drug (AED)—is an MCT; its metabolites and other MCTs might have a similar anti-epileptic effect. There is now robust evidence that decanoic acid has anti-seizure effects, with a ground-breaking study revealing its mechanism of action. Decanoic acid was found to be a non-competitive AMPA receptor antagonist at therapeutically relevant concentrations (in a voltage and subunit-dependent manner), which results in direct inhibition of excitatory neurotransmission, and thus has an anticonvulsant effect.9 This is especially interesting, as most AEDs used in veterinary medicine work on increasing the function of the inhibitory brain pathways, which also explain the side effects frequently seen (e.g., sedation and ataxia).10,11 Decanoic acid readily passes the blood-brain barrier, with 60–80% of its serum concentration arriving in the brain.12
Interestingly, in experimental seizure models in which the direct seizure-reducing effect of decanoic acid has been effective, high concentrations of acetone or β-hydroxybutyrate had no effect.9
Thus, the effect on the AMPA receptor may be the main mechanism of action for an MCT diet. Another interesting potential mechanism is decanoic acid regulating mitochondrial proliferation13 and, therefore, protecting against mitochondrial dysfunction, which can be seen with intense seizure activity. The effect on improved mitochondrial function was also recently shown by a study highlighting de novo fatty acid generation of C17, potentially being responsible for some anti-seizure effects.14
An MCT-enriched diet was tested in a 6-month prospective, randomized, double-blinded, placebo-controlled crossover study in chronically AED-treated dogs with IE.8 The dogs were randomised to either the MCT or placebo diet and switched to the other diet after 3 months. Seizure frequency, severity, physical and neurological examination findings, drug serum concentrations, and clinical pathology data were analysed for dogs completing the study. The overall seizure frequency was significantly reduced by 13% on the MCT diet in comparison to placebo diet; 71% of dogs showed a reduction in seizure frequency, 48% of dogs showed a 50% or greater reduction in seizure frequency, and 14% of dogs achieved cessation of seizures. As many dogs experienced cluster seizures, the number of seizure days was assessed, which also significantly decreased on MCT diet. The MCT diet resulted in significant elevation of blood β-hydroxybutyrate concentrations in comparison to the placebo diet, but no significant differences were found for AED serum concentrations, visual analogue scores for sedation, ataxia, QoL, weight, and most laboratory values (there was a mild decrease in creatinine and mean cell Hb concentration on MCT diet). These results were reproduced in a similar study, strengthening the evidence that MCTs have a positive impact on canine epilepsy for some patients.
In addition to the demonstrated benefits of MCTs on seizure frequency, there are potentially beneficial effects on the behavioural comorbidities seen in canine epilepsy. A pilot study in children with autism showed an improvement in some of the social interaction, behavioural, and cognitive insufficiencies seen in these patients.15 In dogs, diets reportedly modify certain types of behaviours16 (e.g., certain types of aggression may improve on a low-protein diet17,18). Interestingly, a similar MCT diet, as used in the aforementioned epilepsy trial,8 has previously been shown to support cognitive health of aging dogs.19 The authors hypothesized that the improvement in cognitive function is explained by the diet providing the aged brain with a more effective energy source.
Interestingly, cognitive impairment and cognitive health might also need more consideration when managing epilepsy patients. Emerging research has highlighted signs of cognitive impairment in dogs with epilepsy, such as reduced trainability,20 increased signs associated with canine dementia, and deficits in spatial memory. Dogs with epilepsy were less trainable than control dogs.21 Dogs with epilepsy found it harder to obey a sit or stay command; were slower to learn new tricks; were more easily distracted by interesting sights, sounds or smells; and were less likely to listen to their owner or pay attention to them. Within the group of dogs with epilepsy, AEDs worsened behaviour (particularly potassium bromide and zonisamide), along with the use of multiple drugs simultaneously. In the second study, dogs with epilepsy showed more signs of cognitive dysfunction (‘canine dementia’) than control dogs.20 Dogs with epilepsy more commonly failed to recognise familiar people, had difficulty finding food dropped on the floor, and paced or wandered without direction or purpose. These signs were seen in young epileptic dogs under 4 years of age, and thus are unlikely to represent classic canine dementia seen in geriatric patients (a condition usually seen in dogs over 8 years of age). Within the group of dogs with epilepsy, those with a history of cluster seizures or a high seizure frequency were most likely to show these signs, which may reflect progressive brain damage from recurrent seizures. In a recent study22 using a task developed to measure signs of cognitive dysfunction in a clinical setting, dogs with epilepsy were found to show reduced performance in a spatial memory task than matched controls. While most control dogs were able to immediately find a food reward after a short period of ‘forgetting time,’ dogs with epilepsy spent longer searching for the reward. In conclusion, epilepsy is a far more complex brain disease than formerly thought. As research emerges about its comorbidities, our management considerations have to improve. It is ultimately about improving QoL of the patient and the owner, which may be achieved with a more holistic approach considering all factors involved.
References are available upon request.