Epileptogenesis and Companion Animals

Epileptogenesis is the process by which a normal brain develops into an epileptic brain. There are 3 distinct phases of epileptogenesis—the latent period before seizures occur, the occurrence of recurrent seizures, and in about 30% of patients, the development of refractory epilepsy. Understanding the basic epileptic circuit abnormalities associated with recurrent seizures via aberrations in glutamate, gamma-aminobutyric acid, and ligand- and voltage-gated ion channel activity can help the small-animal practitioner understand the mechanism of action of the antiepileptic drugs currently used for dogs and cats for new-onset and refractory epilepsy. Understanding the latest research results and theories about the pathophysiology of the latent period of epileptogenesis, where recurrent seizures have not yet developed, would help the practitioner understand possible target areas for future treatments to treat epilepsy by preventing it rather than just symptomatically preventing recurrent seizures. The current areas of focus of research on the latent period include neurodegeneration, neurogenesis, axonal sprouting, glial cell activation, invasion of inflammatory cells, angiogenesis, and subclinical alteration of ligand- and receptor-gated ion channels.

Introduction

Seizures are the most common clinical disorder in veterinary neurology.¹ Epilepsy is defined as a disorder with chronic recurring seizures more than 24 hours apart without a clear precipitating cause.² The causes of epilepsy are classified as symptomatic (secondary), reactive, or idiopathic (primary). The prevalence of epilepsy is 0.4%-1.0% in people³ and 0.5%-5.0% in dogs.4, 5 Idiopathic epilepsy (IE), also known as primary epilepsy, is characterized by chronic reoccurring seizures with no underlying structural brain lesion or other neurologic signs.⁶ IE is therefore, by definition, of unknown cause and presumed to be genetically influenced in humans and dogs.⁴ About 60%-70% of dogs with chronic seizures have IE. IE is far less prevalent in cats⁷; and secondary intracranial causes are more common in the cat than in the dog.⁸ Secondary epilepsy has identifiable brain pathology, and in companion animals, the causes include neoplastic, inflammatory, infectious, traumatic, vascular, and other disease processes.⁶ Although it was thought in the past that dogs with IE have generalized seizures, it is becoming increasingly apparent that many dogs with IE have focal-onset epilepsy with secondary generalization.5, 6 About 30% of human and canine epileptic patients have refractory epilepsy in which they still have frequent seizures despite being on therapeutic levels of 2 or more AEDs. It is likely that multiple and overlapping etiologies are at cause for genetic (idiopathic) and acquired causes of epilepsy.⁹

Seizures are caused by focal or generalized paroxysmal changes in neurologic function triggered by abnormal or synchronized electrical activity or both.¹⁰ Seizures are by their nature neurologic network events that require re-entrant activation of populations of neurons and therefore they are a neurologic circuit phenomenon.¹⁰ It is therefore important for the veterinary practitioner to have a basic understanding of neurotransmitters and neurologic circuits.

Most neurons in the brain are excitatory and utilize glutamate as the excitatory neurotransmitter, with the N-methyl-d-aspartate (NMDA) receptor being the most common glutamate receptor.² Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter and normally recurrent excitatory activation is minimized by intact inhibitory GABAergic feedback.¹ The pathophysiology of epilepsy is often suggested to be an imbalance between excitation and inhibition.⁵ Glutamate and GABA exert their effects via ligand-gated ion channels involving sodium, calcium, potassium, and chloride, and the balance of excitatory vs. inhibitory neurotransmission is also significantly affected by voltage-gated ion channels.

Currently available therapies for epilepsy include the following: (1) antiepileptic drugs (AEDs); (2) surgical removal of a seizure focus in people when it can be safely done; (3) ketogenic diet mainly for children; and (4) neuromodulation with implanted medical devices.

First-line therapy for epilepsy in people and companion animals is with AEDs. Despite the name—AED, current treatments for seizures are aimed at suppression of seizures and therefore are mainly symptomatic and do not address the underlying pathophysiology of the cause(s) of epilepsy. Traditionally, epileptogenesis has often been strictly defined as the time from an acute brain injury or other predisposition (such as genetic) through the time to development of recurrent seizures.¹¹ For the purpose of this review, a recently proposed, more-encompassing definition will be used, which includes the latent period of development of epilepsy as well as the progression after it is established.³ This review is not a comprehensive review of all theories and data related to epileptogenesis, rather the objective of this review is to highlight the most relevant information regarding epileptogenesis that affects the current treatment of companion animal epilepsy and also that which has promise for new therapies in the near future.