Canine Idiopathic Epilepsy

Any dog can be affected by idiopathic epilepsy (IE). Getting a diagnosis of IE can be crushing for any dog owner. You are worried about not only controlling your dog's seizures but ensuring their quality of life.

Although antiepileptic drugs will remain the foundation of treatment for dogs with IE, there is a mountain of research for additional supportive therapies, such as medium-chain triglycerides, decanoic (C10) and octanoic (C8) acid.

Weekend Market

Seizures in dogs with idioapthic epilepsy.

Idiopathic epilepsy was defined by the International Veterinary Epilepsy Task Force (IVETF) as a “disease of the brain, characterized by an enduring predisposition to generate epileptic seizures.” Clinically, this definition is usually applied to dogs that have I equal to or greater than two

unprovoked seizures, more than 24 hours apart. Most dogs are diagnosed with epilepsy between 1-6 years of age. Over two-thirds of dogs will require medicating with multiple anti-epileptic drugs (AEDs) and struggle to achieve adequate seizure control. Approximately 30% of dogs will have less than a 50% reduction in seizure frequency and may experience server-side effects of AEDs such as polyphagia, polydipsia, sedation, and ataxia.

It is generally accepted that there are multiple structural and or functional neurological abnormalities that predispose animals to recurrent seizures. These include genetic mutations, developmental disorders or malformations, toxic insults, or traumatic injury. Seizures themselves are

Pathophysiology

initiated by a combination of factors, including increased neuronal firing frequency and hyper-synchronization.

Increased neuronal firing frequency can be generated by changes in synaptic transmission and the resting membrane potential. Synaptic transmission plays a crucial role in seizure production, and faults at almost every step of it can result in the generation of a seizure. The major excitatory and inhibitory neurotransmitters in the nervous system are glutamate and GABA, respectively. Their relationship is not as simple as excitation or inhibition but can be affected by different co-transporters, particularly in the early stages of life.

initiated by a combination of factors, including increased neuronal firing frequency and hyper-synchronization.

Increased neuronal firing frequency can be generated by changes in synaptic transmission and the resting membrane potential. Synaptic transmission plays a crucial role in seizure

The major excitatory and inhibitory neurotransmitters in the nervous system are glutamate and GABA, respectively. However, their relationship is not as simple as excitation or inhibition but can be affected by different co-transporters, particularly in the early stages of life.

In the typical neuron, the resting membrane potential is set low enough to prevent continuous firing but high enough to generate an action potential. There are a number of both intra- and extracellular mechanisms that play an essential role in maintaining homeostasis and normal neuronal functions. These include but are not limited to ATPase sodium-potassium pumps, glia cells, inhibitory and excitatory neurotransmitters, and blood-brain barrier (BBB) transporters. The transmembrane potential (-70 mV) is usually maintained by a high intracellular concentration of potassium ions and a high extracellular concentration of sodium ions (alongside many other ions). This balance is partly maintained throughout ATPase pumps (sodium and potassium pumps) and glial cells. Changes in extracellular ion concentration can result in excessive neuronal firing. This is particularly relevant in how seizure activity may propagate further seizure activity. When a seizure occurs, an excessive rise in extracellular potassium may occur. This excessive rise in potassium can change the resting membrane potential, which can further depolarise neurons.

The synchronization of neuron activity plays a vital role in generating a seizure. However, it is thought to be caused again by several mechanisms, including glutamatergic interconnections and the growth of excitatory neuron axon collaterals. The latter of these two is likely to contribute to epileptogenesis (the reorganization/plasticity of the nervous system to develop epilepsy).

In most cases, seizures are self-limiting, with several processes that can lead to seizure cessation. These include:

Depletion of glutamate or ATP;
GABA inhibitor;
Changes in ionic levels;
Adenosine release; and
Changes in intra- and extra-cellular pH.

to hyperpolarise

Major Neurotransmitters

GABA is the major inhibitory neurotransmitter. GABA agonists are the first line and mainstay of therapy for many patients with epilepsy. As shown in the figure below, GABA binds at the β2+/α1 interface on GABA ligand-gated ion channel receptor, causing the receptor to open and an influx of chloride ions

of the presynaptic axon terminal and low levels of glutamate are released, AMPA receptors open. At this same level of stimulation, NDMA receptors only partially open, and become blocked by an Mg2+ ion. Therefore, under such conditions (weak glutamate stimulation) the depolarization and subsequent excitatory postsynaptic potential will be mediated primarily by the AMPA receptors.

With significant stimulus, the AMPA receptors can depolarise the postsynaptic neuron membrane sufficiently to expel the Mg2+ ion from the NMDA channel, allowing a sudden exacerbated influx of Na+ and Ca2+ ions into the postsynaptic neuron. AMPA receptors are heavily involved in epilepsy electrochemical events, in particular the paroxysmal depolarization shift (the causes of the EEG spike) and the electrographic seizure discharge.

the cell, making it harder for an action potential to be generated.

Glutamate is one of the main excitatory neurotransmitters in the brain. Glutamate acts on AMPA and/or NMDA receptors, usually causing excitation. AMPA receptors are more sensitive to glutamate than the NMDA receptor. This difference in sensitivity means that when there is weak stimulation of the presynaptic axon terminal and low levels of glutamate are released, AMPA receptors open.

Reaching a diagnosis

A Diagnosis of idiopathic epilepsy is often made once other differentials have been ruled out such as cardiac disease or paroxysmal dyskinesias. The diagnostic workup can be affected by logistical and economic limitations in general practice. Ideally, a patient’s history, signalment, and exam are interpreted against complete blood count, serum chemistry profile, and urinalysis.

Further testing, including thyroid, bile acids, fructosamine, glucose: insulin ration, creatine kinase, lactate abdominal and thoracic imaging and ionised calcium, and cobalamin levels, may be undertaken if indicated. Heavy metal (such as lead), toxoplasma, and cryptococcus testings (or other region-specific infectious diseases) are also recommended.

Advanced magnetic resonance imaging and analysis of the cerebral spinal fluid may be indicated in some patients to help rule out structural abnormalities. Broadly, this may include patients outside the age range of 6 months to 6 years, patients that have neurological abnormalities beyond the postictal period, patients with refractory or cluster seizures or patients that have experienced a status epilepticus episode. The gold standard for diagnosis IE is EEG, however, it is generally not available or standard in veterinary medicine

Antiepileptic drugs (AEDs) have been the mainstay of therapy to cease current seizures and reduce the likelihood or frequency of reoccurring. Unfortunately, there are no current evidence-based standardized guidelines. Still, patient and owner factors are considered, and treatment is tailored on a case-to-case basis, with the usual considerations being compliance, cost, side effects, and underlying pathologies/comorbidities.

An overview of treatment

The major first-line and mainstay drugs used in the treatment of canine epilepsy (such as diazepam and phenobarbitone) work on GABA receptors. GABA is the major inhibitory neurotransmitter in the central nervous system. As seen in the figure below, GABA binds at the β2+/α1 interface on GABA ligand-gated ion channel receptor, causing the receptor to open and an influx of chloride ions to hyperpolarise the cell. GABA agonists, such as diazepam, increase either the time or the frequency that GABA receptors remain open, hyperpolarising the neuron and making it harder for an action potential to be generated.

While pharmacological treatments work well as an option alone for some dogs, unfortunately, over two-thirds of dogs on AEDs will continue to experience seizures, with around 30% of dogs on two anti-epileptic drugs having less than a 50% reduction in seizure frequency. Whatmore, most AED drugs do not have significant neuroprotective effects, but in contrast have major clinical side effects such as polyphagia, polydipsia, polyuria, ataxia, sedation, and lethargy, as well as other systemic effects such as drug-induced hepatopathy, raises concerns for patients immediate and ongoing quality of life as well the emotional and financial strain upon owners.

Treatment of status epilepticus

Most seizures are self-limiting, lasting less than 3 minutes. Status epilepticus is loosely defined as seizures lasting for > 5 minutes or clusters of seizures without sufficient time to recover in between.

This is believed to be due to several reasons, including;

Loss of GABA induced inhibition;
Overexpression or excitation of the excitato neurotransmitters glutamate on AMPA and NDMA receptors; and
Overexpression of BBB transporters.

Resistance to GABA-ergic drugs may occur in some cases due to changes in ion channels and the over-expression of NDMA receptors. In these cases, NDMA antagonists such as ketamine can be beneficial. Overexpression of BBB transporters (endothelial P-glycoprotein) can flush anti-epileptic drugs out of the brain, resulting in insufficient concentrations to be effective. Thus, the use of alternative routes such as intranasal diazepam or NDMA antagonists should be considered for the management of status epilepticus.

Intranasal is the only route of diazepam administration that can circumvent the BBB, as can be absorbed via the olfactory and trigeminal nerves. Lipophilic drugs with low molecular weights are best absorbed via this route.

Evidently, there is a large unmet need to aid in the improvement of patient’s quality of life via adjunctive treatment options for dogs diagnosed with epilepsy.

Medium-chain triglycerides

and may reduce some side effects associated with AEDs.

The benefits of MCTS may include;

Improve glucose metabolism and energy levels.
A reduction in oxidative stress;
Reduced seizure frequency;
Decreased neuroinflammation and free radicals;
Decrease epileptogenesis and epigenetic changes; and
A reduction in side effects of AEDs;

Medium-chain triglycerides
(decanoic and octanoic acid)

There are dietary add ons that have positive cognitive and anti-epileptic effects in humans and dogs. One of the most promising of these are medium-chain fatty acids, or MCTs, in particular decanoic acid (C10). Decanoic acid works as a non-competitive AMPA receptor inhibitor, increases catalase and glutathione, .increases mitochondria biogenesis,

50%-65% octanoic acid (C8) and 30%-50% decanoic acid (C10 (3).png