Canine and Feline Epilepsy

Diagnosis and Management

Luisa De Risio, Simon Platt

• Publisher: CAB International
• Year: 2014
• Print ISBN: 9781780641096
• eBook ISBN: 9781789243857
• Topic: Medicine
• Subtopic: Veterinary Medicine

Epilepsy is one of the most familiar chronic neurological diseases and is a common yet challenging presentation in veterinary surgeries. This book covers seizure pathogenesis, classifications, diagnostic investigations, emergency treatments and longer term treatments, with a large section on pharmacological intervention. Filling a considerable gap in the veterinary literature, it includes tables and charts for quick reference during emergencies. Seizures can be very distressing to animals and owners, yet not all seizures are the result of epilepsy, a neurological condition. This book discusses how to distinguish between epileptic and non-neurological seizures, and provides case studies to illustrate different occurrences of epilepsy.

1 Pathophysiology of Seizure Activity

Simon Platt BVM&S MRCVS Dipl. ACVIM (Neurology) Dipl. ECVN
Professor Neurology and Neurosurgery Service, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA

Several decades have been devoted to the study of the pathophysiology of epilepsy. Increasing knowledge in the field has only contributed to a partial understanding of the underlying mechanisms. Nevertheless, insight into the pathophysiology of epilepsy and its underlying histological and neurochemical alterations has contributed to rational development strategies of new anti-epileptic medications (AEMs). Although various epileptic syndromes in people have been shown to differ pathophysiologically, they apparently share common ictogenesis-related characteristics such as increased neuronal excitability and synchronicity. Emerging insights point to alterations of synaptic functions and intrinsic properties of neurons as common mechanisms underlying hyperexcitability. Progress in the field of molecular genetics has revealed arguments in favour of this hypothesis as mutations of genes encoding ion channels were recently discovered in some forms of human epilepsy.

Epileptic seizures arise from an excessively synchronous and sustained discharge of a group of neurons. The single feature of all epileptic syndromes is a persistent increase of neuronal excitability. Abnormal cellular discharges may be associated with a variety of causative factors such as trauma, oxygen deprivation, tumours, infection and metabolic derangements. However, no specific causative factors are found in many dogs and cats suffering from epilepsy.

Underlying causes and pathophysio-logical mechanisms are (partially) understood for some forms of epilepsy, at least in people, e.g. epilepsies caused by disorders of neuronal migration and monogenic epilepsies. For several other types of epilepsy, current knowledge is only fragmentary. This chapter will review several areas that are understood to contribute to the evolution and maintenance of epilepsy. The genetics of epilepsy are discussed in Chapter 6.

The Electrical Basis of Nerve Cell Function

At the most fundamental level, the nervous system is a function of its ionic milieu, the chemical and electrical gradients that create the setting for electrical activity. Therefore, some of the most easily appreciated controls on excitability are the ways the nervous system maintains the ionic environment. An example is the electrical basis of resting membrane potential. Resting potential is set normally so that neurons are not constantly firing but are close enough to threshold so that it is still possible that they can discharge, given that action potential generation is essential to CNS function. The control of resting potential becomes critical to prevent excessive discharge that is typically associated with seizures.

Normally a high concentration of potassium exists inside a neuron and there is a high extracellular sodium concentration, as well as additional ions, leading to a net transmembrane potential of −60 mV (Scharfman, 2007). If the balance is perturbed (e.g. if potassium is elevated in the extracellular space), this can lead to depolarization that promotes abnormal activity in many ways (Somjen, 2002): terminals may depolarize, leading to transmitter release, and neurons may depolarize, leading to action potential discharge. Pumps are present in the plasma membrane to maintain the chemical and electrical gradients, such as the sodium–potassium ATPase, raising the possibility that an abnormality in these pumps could facilitate seizures. Indeed, blockade of the sodium–potassium ATPase can lead to seizure activity in experimental preparations (Vaillend et al., 2002), suggesting a role in epilepsy (Grisar et al., 1992). The sodium–potassium pump is very interesting because it does not develop in the rodent until several days after birth, and this may contribute to the greater risk of seizures in early life (Haglund et al., 1985; Fukuda and Prince, 1992). In addition to pumps, glia also provide important controls on extracellular ion concentration, which has led many to believe that glia are just as important as neurons in the regulation of seizure activity (Duffy and MacVicar, 1999; Fellin and Haydon, 2005). Thus, the control of the ionic environment provides many potential targets for novel anticonvulsants. It is important to bear in mind that seizures, by themselves, can lead to the changes in the transmembrane gradients. For example, seizures are followed by a rise in extracellular potassium, a result of excess discharge. This can lead to a transient elevation in extracellular potassium that can further depolarize neurons. Thus, the transmembrane potential is a control point that, if perturbed, could elicit seizures and begin a ‘vicious’ cycle, presumably controlled by many factors that maintain homeostasis, such as pumps and glia.

The ionic basis of the action potential is another example of a fundamental aspect of neurobiology that can suggest potential mechanisms of seizures. Neurons are designed to discharge because of an elegant orchestration of sodium and potassium channels that rely on chemical and ionic gradients across the cell membrane. Abnormalities in the sodium channel might lead to a decrease in the threshold for an action potential to occur if the method by which sodium channel activation is controlled alters in any way (i.e. sodium channels are activated at more negative resting potentials or sodium channel inactivation is impaired). Indeed, it has been shown that mutations in the subunits of the voltage-dependent sodium channels can lead to epilepsy. A specific syndrome, generalized epilepsy with febrile seizures, is caused by mutations in selected genes responsible for subunits of the voltage-dependent sodium channel (Meisler et al., 2001). The mutation does not block sodium channels, presumably because such a mutation would be lethal, but they modulate sodium channel function. This concept, that modulation, rather than essential function, is responsible for genetic epilepsies, has led to a greater interest in directing the development of new anticonvulsants at targets that are not essential to, but simply influence, CNS function.

Synaptic Transmission

Research into seizures has gravitated to mechanisms associated with synaptic transmission, because of its critical role in maintaining the balance between excitation and inhibition. As more research has identified the molecular mechanisms of synaptic transmission, it has become appreciated that defects in almost every step can lead to seizures. Glutamatergic and γ-aminobutyric acid (GABA)-ergic transmission, as the major excitatory and inhibitory transmitters of the nervous system, respectively, have been examined in great detail. It is important to point out, however, that both glutamate and GABA may not have a simple, direct relationship to seizures. One reason is that desensitization of glutamate and GABA receptors can reduce effects, depending on the time-course of exposure. In addition, there are other reasons. GABA-ergic transmission can lead to depolarization rather than hyperpolarization if the gradients responsible for ion flow through GABA receptors are altered. For example, chloride is the major ion that carries current through GABAA receptors, and it usually hyperpolarizes neurons because chloride flows into the cell from the extracellular space. However, the K+Cl− co-transporters (KCCs) that are pivotal to the chloride gradient are not constant. In development, transporter expression changes, and this has led to evidence that one of the transporters, NKCC1, may explain seizure susceptibility early in life (Dzhala et al., 2005). The relationship of glutamate to excitation may not always be simple either. One reason is that glutamatergic synapses innervate both glutamatergic neurons and GABA-ergic neurons in many neuronal systems. Exposure to glutamate could have little net effect as a result, or glutamate may paradoxically increase inhibition of principal cells because the GABA-ergic neurons typically require less depolarization by glutamate to reach threshold. It is surprisingly difficult to predict how glutamatergic or GABA-ergic modulation will influence seizure generation in vivo, given these basic characteristics of glutamatergic and GABA-ergic transmission.

Synchronization

Excessive discharge alone does not necessarily cause a seizure. Synchronization of a network of neurons is involved. Therefore, how synchronization occurs becomes important to consider. There are many ways neurons can synchronize. In 1964, Matsumoto and Ajmone-Marsan found that the electrographic events recorded at the cortical surface during seizures corresponded to paroxysmal depolarization shifts (PDS) of cortical pyramidal cells occurring synchronously (Matsumoto and Marsan, 1964). These studies led to efforts to understand how neurons begin to fire in concert when normally they do not. Glutamatergic interconnections are one example of a mechanism that can lead to synchronization. Indeed, studies of the PDS suggested that the underlying mechanism was a ‘giant’ excitatory postsynaptic potential, although it was debated widely at that time if this was the only cause (Johnston and Brown, 1984). Thus, pyramidal cells of cortex are richly interconnected to one another by glutamatergic synapses. Gap junctions on cortical neurons are another mechanism for synchronization. Gap junctions allow a low-resistance pathway of current flow from one cell to another, so that coupled neurons are rapidly and effectively synchronized. It was thought that gap junctions were rare, so it was unlikely that they could play a major role, but further study led to the appreciation that even a few gap junctions may have a large impact on network function (Traub et al., 2004). Another mechanism of synchronization involves, paradoxically, inhibition.

Many GABA-ergic neurons that innervate cortical pyramidal cells, such as the cell type that controls somatic inhibition (the basket cell), make numerous connections to pyramidal cells in a local area. Therefore, discharge of a single interneuron can synchronously hyperpolarize a population of pyramidal cells. As GABA-ergic inhibition wanes, voltage-dependent currents of pyramidal cells become activated. These currents, such as T-type calcium channels and others, are relatively inactive at resting potential, but hyperpolarization relieves this inhibition. The result is a depolarization that is synchronous in a group of pyramidal cells (Scharfman, 2007).

Some of the changes that develop within the brain of individuals with epilepsy also promote synchronization. Such changes are of interest in themselves because they may be one of the reasons why the seizures are recurrent. These changes include growth of axon collaterals of excitatory neurons, typically those that use glutamate as a neurotransmitter and are principal cells. An example is the dentate gyrus granule cell of hippocampus. In animal models of epilepsy and in patients with intractable temporal lobe epilepsy (TLE), the axons of the granule cells develop new collaterals and the new collaterals extend for some distance. They do not necessarily terminate in the normal location but in a novel lamina, one that contains numerous granule cell dendrites. Electron microscopy has shown that the new collaterals innervate granule cell dendrites, potentially increasing recurrent excitatory circuits. Some argue that recurrent inhibition increases as well as recurrent excitation, but the fact remains that new synaptic excitatory circuits develop that are sparse or absent in the normal brain (Nadler, 2003; Sloviter et al., 2006). The resultant ‘synaptic reorganization’ not only can support synchronization, potentially, but it also illustrates how the plasticity of the nervous system may contribute to epileptogenesis.

Kindling and Epileptogenesis

Goddard (1967) was the first to describe that periodic stimulation of neural pathways progressively leads to recurrent behavioural and electrographic seizures. Kindling procedures have provided a substrate for the study of the role of enhanced synaptic efficacy in seizure disorders. It is now considered to be a first choice experimental procedure in the study of the potential mechanisms of epileptogenesis. The phenomenon can be evoked in various brain regions, but amygdala kindling is most frequently used in epilepsy research as a model for complex focal (partial) seizures (Fisher, 1989). Although kindling has been shown to be phenomenologically different from other types of plastic changes in the central nervous system, there are many points of similarity between kindling and the process of long-term potentiation (Sutula et al., 1989).

Kindling has been shown to depend upon functional as well as structural changes in glutamatergic synapses. The anticonvulsant effects of glutamate receptor blocking agents like N-methyl-D-aspartate (NMDA) antagonists seem to be at least partly due to their inhibitory effects on in vitro kindling.

Ictogenesis

Excitability is a key feature of ictogenesis that may originate from individual neurons, neuronal environment or a population of neurons. Excitability arising from single neurons may be caused by alterations in membrane or metabolic properties of individual neurons (Traub et al., 1996). When regulation of environmental, extracellular concentrations of ions or neurotransmitters is suboptimal, the resulting imbalance might enhance neuronal excitation. Collective anatomic or physiologic neuronal alterations may convert neurons into a hyper-excitable neuronal population. In reality, these three theoretical mechanisms are thought to interact during specific ictal episodes. Each epileptic focus is unique as the differential contribution of these three concepts leading to ictal events is thought to differ from focus to focus.

Excitability arising from individual neurons

Functional and perhaps structural changes occur in the postsynaptic membrane, thus altering the character of receptor protein-conductance channels, thereby favouring development of paroxysmal depolarizing shifts (PDS) and enhanced excitability. Epileptic neurons appear to have increased Ca2+ conductance. It may be that latent Ca2+ channels are used, that the efficacy of Ca2+ channels is increased or that the number of Ca2+ channels is chronically elevated. However, development of burst activity depends on the net inward current and not on the absolute magnitude of the inward current. When extracellular K+ concentrations are increased (as during seizure activity), the K+ equilibrium across the neuronal membrane is reduced, resulting in reduced outward K+ currents. The net current will become inward, depolarizing the neuron to the extent that Ca2+ currents will be triggered. This results in a PDS and a burst of spikes (Dichter and Ayala, 1987).

Excitability arising from neuronal microenvironment

Both functional and structural alterations occur in epileptic foci. The functional changes involve concentrations of cations and anions, metabolic alterations, and changes in neuro-transmitter levels. The structural changes involve both neurons and glia. Excessive extracellular K+ depolarizes neurons and leads to spike discharge. During seizures, changes in extracellular Ca2+ (a decrease of 85%) precede those of...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• Contents
• Preface
• 1 Pathophysiology of Seizure Activity
• 2 Pathophysiology of Pharmacoresistant Epilepsy
• 3 Classification of Seizures and Epilepsies
• 4 Reactive Seizures
• 5 Structural Epilepsy
• 6 Idiopathic Epilepsy and Genetics
• 7 Epidemiology of Canine Seizures
• 8 Epidemiology of Feline Seizures
• 9 Mimics of Seizure Activity: Disorders Confused with Epilepsy
• 10 Clinical and Diagnostic Investigation of the Seizure Patient
• 11 Introduction to Electroencephalography
• 12 Principles of Anti-epileptic Treatment
• 13 Phenobarbital
• 14 Bromide
• 15 Zonisamide
• 16 Levetiracetam
• 17 Gabapentin and Pregabalin
• 18 Felbamate
• 19 Topiramate
• 20 The New Additions: Lacosamide, Brivaracetam and Rufinamide
• 21 Benzodiazepines
• 22 Imepitoin (Pexion®)
• 23 Pathophysiology and Management of Cluster Seizures
• 24 Pathophysiology and Management of Status Epilepticus
• 25 Novel and Adjunctive Treatments
• Glossary of Pharmacological Terminology
• Glossary
• Index