Seizures – Chapter from BSAVA Manual of Canine and Feline Neurology 4th edition

Michael Podell, MS, DVM, DACVIM (Neurology)

The approach to and treatment of seizure disorders in small animals is similar in many respects to the treatment of various other ailments in veterinary medicine: an antecedent historical problem arises, a proper diagnosis is made to confirm the condition, and therapy is initiated to treat the underlying dis­ease or signs of the disease. However, important differences arise specific to the diagnosis and treat­ment of seizure disorders. Firstly, a specific under­lying aetiology is often not identified. Secondly, the clinician must often make a therapeutic decision based on historical accounts alone. Thirdly, treat­ment is often initiated when the animal is otherwise normal, with little ability to predict frequency of seizure recurrence. Finally, the quality of life of both the pet and the owner during the interictal period must be balanced with the ability to limit the sever­ity, frequency and duration of future seizure events.

Clinical signs

Classification of seizures and epilepsy into a univer­sally accepted, coherent and relevant scheme for clinicians has been an ongoing dynamic process in human epilepsy since the early 1980s. The standard­ized classification scheme for seizures and epilepsy established by the International League Against Epilepsy (ILAE) in the 1980s (Commission for ILAE, 1981, 1989) provided the first basis for a taxonomic foundation for an analytical approach in the diagnosis and treatment of epilepsy. This classification scheme is restricted by the following limitations:

• The reliance on the clinician’s ability to classify seizure types based on the presence of ‘impaired consciousness’
• The reliance on electroencephalographic features to classify seizure type
• The difficulty in distinguishing an ‘idiopathic’ disorder of confirmed undetermined aetiology from a ‘cryptogenic’ cause of highly suspect morphological disease of the brain (Engel, 2001).

The goal is to attempt to piece together a rational categorization for use in small animal epileptic patients adapted from the recommendations of the ILAE Task Force on Classification and Terminology (Engel, 2001). The purpose is to establish a common­ground mode of communication to allow diagnostic and therapeutic data to be tabulated for clinical outcome measures. The proposed scheme for seizure investigation consists of five consider­ations or ‘axes’ (Figure 8.1) as proposed by Engel (2001) and recently revised by Berg et al. (2010).

Axis 1: Seizure (ictal) phenomenology

Seizure:- Epileptic seizure - Non­epileptic episodes Epilepsy Status epilepticus

Axis 2: Seizure type

Self­-limiting (isolated)- Focal: - Sensory - Motor: - Elementary - Automatisms - Reflex - Generalized: - Tonic–clonic - Clonic - Myoclonic - Atonic - Absence - Reflex Clustered or continuous (status epilepticus):- Focal: - Sensory: aura continua - Motor: epilepsia pars continua - Generalized

Axis 3: Seizure syndrome

Familial (genetic) epilepsies Idiopathic epilepsies:- Focal - Generalized - Reflex epilepsies - Epileptic encephalopathies (progressive neurological dysfunction) - Myoclonic epilepsies

Axis 4: Aetiology

Genetic Structural or metabolic Unknown

Axis 5: Impairment from epilepsy

Temporary:- Motor - Sensory - Other Permanent:- Motor - Sensory - Other

8.1 Proposed diagnostic scheme (five axes) for dogs and cats with epileptic seizures (adapted from Engel, 2001).

Axis 1: Seizure (ictal) phenomenology (is it a seizure?)

A seizure can be defined as a non­specific, paroxys­mal, abnormal event of the body. An epileptic seizure is defined by the ILAE as ‘a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain’ (Fischer et al., 2005). Thus, an epileptic seizure has a specific neural origin. Absolute confirmation that a seizure is epileptic may be difficult as it requires simultaneous observation of behavioural and elec­troencephalographic changes. As a result, historical information is often used to diagnose an epileptic seizure. The clinical features of epileptic seizures can be separated into four components (Engel, 1989; Podell, 1996).

1. The prodrome is the time period prior to the onset of seizure activity. Owners report that they can ‘predict’ the onset of their pet’s seizures based on behaviour exhibited during this time, such as increased anxiety­related behaviour (i.e. attention­-seeking, whining), reluctance to perform normal activity patterns and increased hiding (especially in cats).

2. During this period, which can last from minutes to hours, animals can exhibit stereotypical sensory or motor behaviour (e.g. pacing, licking), autonomic patterns (e.g. salivating, urinating, vomiting) and even unusual psychiatric events (e.g. excessive barking, increased/decreased attention-­seeking).

3. The ictal period is the actual seizure event, manifested by involuntary muscle tone or movement and/or abnormal sensations or behaviour, lasting usually from seconds to minutes.

4. The postictal period follows the actual seizure and can last from minutes to days. During this time an animal can exhibit unusual behaviour, disorientation, inappropriate bowel and/or bladder activity, excessive or depressed thirst and appetite, or actual neurological deficits including weakness, blindness and sensory or motor disturbances. The latter problems are known as Todd’s paralysis and are often an indicator of a focal, contralateral cortical epileptic focus. Often owners observe only the postictal period as evidence that their pet has had a seizure.

Regardless of the cause, a patient’s epileptic seizures may be recurrent over time or may occur as a single event. If the patient has a chronic brain disorder characterized by recurrent epileptic sei­zures, then that patient has epilepsy. It should be noted that neither the term seizure nor epilepsy connotes the underlying aetiology of the disorder.

Status epilepticus can be defined as a state of continuous seizure activity lasting for 5 minutes or longer, or repeated seizures with failure to return to normality within 30 minutes (Huff and Fountain, 2011) (see Chapter 20). Epilepsia partialis continua is a continuous focal seizure involving the motor cortex (Engel, 2001). Although not well documented by an electroencephalogram (EEG) in animals, typ­ical manifestations include facial muscle movements with ‘chewing gum’ activity, repetitive eye and/or lip twitching and myoclonic jerking of limb muscles.

Several other paroxysmal ‘episodes’ of altered behaviour, body movement or neurological status may mimic epileptic seizures (see Chapter 18). Distinguishing these ‘episodes’ from epileptic seizures is just as important because an incorrect diagnosis could lead to failure to identify another serious medical condition, the administration of unnecessary medication to the patient, or undue
emotional and financial strain on the owner. Some common causes of paroxysms include syncope of cardiac origin, metabolic­related weakness (e.g. transient hypoglycaemia, endocrine diseases) and acute toxicities. One helpful distinguishing feature is the lack of a postictal period following these ‘epi­sodes’. With syncope, a rapid return to conscious­ness or ability to walk within seconds to a minute is typical, although some animals will urinate during or immediately after the event. Neurological episodes that are not epileptic seizures may be acute vestibu­lar attacks (with ataxia, falling, rolling, etc.), cataplec­tic/narcoleptic events (sudden loss of consciousness with excitement), hypertonic syndromes in Cavalier King Charles Spaniels and Soft­coated Wheaton Terriers, muscle cramping syndromes in Scottish and Border Terriers or fulminant myasthenia gravis (rapid loss of the ability to walk; see Chapter 9).

Axis 2: Seizure type

Seizures are classified as:

• Self-­limiting (isolated) – one seizure within 24 hours
• Clustered – two or more seizures, lasting < 5 minutes each, within 24 hours but separated by a normal interictal period
• Continuous – seizures lasting 5 minutes or longer, or without return to a normal interictal period between seizures (see Status multiple seizure types clip on DVD).

Within each category, seizures are divided into either focal or generalized. Focal seizures are the manifestation of a discrete, epileptogenic event in the cerebral cortex (Cascino, 1992). The focal nature of this seizure type is associated with a higher incidence of focal intracranial pathology (Podell et al., 1995). Focal seizures can be elemen­tary motor seizures, commonly seen as facial mus­cle twitching, or manifested by more abnormal behavioural disorders (see Focal motor seizure clip on DVD). Progressive involvement of the facial, neck and/or shoulder or limb muscles is known as a ‘Jacksonian’ march seizure event. More complex behaviour patterns with focal seizures include impaired consciousness, often with bizarre behav­ioural activity. Previously termed complex partial or psychomotor seizures, these events are now classi­fied as automatisms or automotor seizures (Engel, 2001) (see Complex partial seizure (automatism) clip on DVD). Animals may show ‘fly­biting’ behav­iour patterns, become aggressive without provo­cation, howl incessantly, become restless or exhibit a variety of motor disturbances. Cats may show a variety of abnormal behaviours or motor signs, including drooling, hippus, excessive vocalization or random, rapid running behaviours indoors. Whenever a focal seizure is suspected, the clinician should be suspicious of a focal cerebral disturbance and plan the diagnostic work­up accordingly.

Generalized seizures are subdivided into tonic–clonic, clonic, myoclonic, atonic or absence types (Berg et al., 2010; Poma et al., 2010) (see Generalized tonic–clonic seizure and Myoclonic and atonic seizures clips on DVD). The terms con­vulsive (grand mal) and non­convulsive (petit mal) seizures are no longer in use. Generalized seizures originate from both cerebral hemispheres from the start, or more commonly progress secondarily from focal seizures (Engel, 1989; Berendt and Gram, 1999) (Figure 8.2). Unlike focal seizures, general­ized seizures are not necessarily associated with focal cerebrocortical disease.

Reflex seizures can be focal or generalized and occur in response to a trigger (e.g. photostimu­lation). Whilst this type of seizure is well described in human medicine, with numerous different triggers reported (Engel, 2001), recognized triggers have not been reported commonly in veterinary medicine. A notable exception is myoclonic epilepsy in Wire­-haired Dachshunds with Lafora disease in which seizures are triggered by auditory and visual stimuli (Lohi et al., 2005; Webb et al., 2009). Another phe­nomenon reported in human medicine is epileptic spasms. Epileptic spasms are currently classified as a discrete seizure type, as it has yet to be deter­mined whether these events have a focal or general­ized onset based on electroclinical data from humans (Berg et al., 2010).

Axis 3: Seizure syndrome

By definition, a syndrome is a group of signs or characteristics that defines a particular abnormality. Epilepsy syndromes are not well defined in vet­erinary medicine, although familial (genetic) epilep­sies are now being identified with segregation analysis (see Chapter 7). A number of dog breeds have been identified with either proven or highly suspect familial epilepsy, including Belgian Terv­ uerens (Famula and Oberbauer, 2000), Vizslas (Patterson et al., 2003), Keeshonds (Hall and Wallace, 1996), Retrievers (Jaggy et al., 1998), Shetland Sheepdogs (Morita et al., 2002) and Border Collies (Hulsmeyer et al., 2010).

The majority of epileptic syndromes in dogs are suspected to be genetic in nature and are currently classified as idiopathic; although, this term is now falling out of favour in human medicine (see Axis 4). An epileptic syndrome (such as myoclonic epilepsy) can theoretically have several different aetiologies. The term epileptic encephalopathy has been used to describe electroclinical syndromes associated with a greater probability of encephalopathic signs attributable to the onset and progression of epileptic seizures (Hermann et al., 2006). Inherent with this term is the ability to reverse the clinical signs with improvement of cognition and behaviour, especially with early and effective seizure control with drug therapy (see Axis 5).

Axis 4: Aetiology

The differential diagnosis of epileptic seizures due to underlying brain disease can be divided into three main aetiological categories based on the ILAE reclassification scheme (Berg et al., 2010): genetic, structural/metabolic, and unknown causes. The goal of this scheme is to create a classification system in which each cause contains only one dimension and is not used to imply other causes.

• Genetic – epilepsy that is the direct result of a known or presumed genetic defect. Either precise molecular genetic studies that have identified a genetic mutation or familial studies that appropriately demonstrate a genetic component are acceptable criteria for inclusion.
• Structural or metabolic (formerly symptomatic/ secondary or reactive) – epileptic seizures that are directly related to either an underlying brain or metabolic disease.
• Unknown (formerly probable symptomatic/ cryptogenic) – the cause of the epileptic seizures has yet to be determined.

It should be noted that the term idiopathic epilepsy has been removed from this scheme as it only connotes our inability to determine the underlying cause.

Axis 5: Impairment from epilepsy

Inclusion of signs that are related to epilepsy allows evaluation for persistence of functional and structural neurological changes associated with seizures. The majority of signs in cats and dogs are transient, such as disorientation, visual impair­ ment, salivation, incontinence and altered beha­ viour. Dogs have been found to demonstrate transient structural changes such as cerebral oedema of the temporal lobe on magnetic reso­ nance imaging (MRI) of the brain (Mellema et al., 1999), and altered cerebral metabolism on proton MR spectroscopy after seizures (Neppl et al., 2001). Symptomatic temporal lobe epilepsy with associated hippocampal neuronal loss appears not to be present in idiopathic epileptic dogs (Buckmaster et al., 2002). More permanent neuro­ pathological deficits can occur, especially in dogs or cats with very prolonged seizure activity (Koestner, 1989).

Lesion localization

Seizures are the manifestation of a change in fore­ brain activity. Thus, by default, all animals with epi­leptic seizures are classified as having a forebrain neurolocalization (Figure 8.3). For this discussion, the forebrain is defined as the diencephalon and telencephalon as one functional unit. Neurological deficits associated with forebrain lesions include changes in behaviour, wide circling patterns, head turns to the side of the lesion, contralateral hemipa­resis and conscious proprioceptive deficits, as well as contralateral vision loss (cranial nerve (CN) II), facial muscle weakness (CN VII) and facial hypo­algesia (CN V) (see Chapters 2 and 9). Any combi­nation of these signs should alert the clinician to the possibility of a forebrain lesion.

Pathophysiology

Epilepsy represents a heterogeneous disease con­sisting of diverse aetiologies, electrophysiological and behavioural seizure patterns, and responses to pharmacological intervention. As such, the patho­genesis of epilepsy is multifactorial. Genetically determined seizure susceptibility factors play a cru­cial role in the response of the brain to triggering or precipitating factors, also known as the seizure threshold. The seizure threshold in humans has been shown to decrease during sleep (in particular stage 2 sleep), where the hypersynchrony of sleep facilitates both the initiation and propagation of focal seizures in the parietal and occipital lobes (Herman et al., 2001). Seizures in these individuals may be activated by unrecognized changes in neuronal activity, or intrinsic neurochemical transmission, or by environmental stimuli or stresses that do not cause seizures in the normal brain.

A basic tenet in the mechanism of epilepsy is the presence of an imbalance in excitatory and inhibi­ tory neurotransmission. A seizure develops when the balance shifts towards excessive excitation. Much research has been focused on the role of glu­tamate and its receptor complex, the N­methyl­D­ aspartate receptor (Lipton and Rosenburg, 1994). Glutamate is the principal excitatory neurotransmit­ter in the brain and plays an important role in the modulation of cognitive, motor, memory and sen­sory functions of the central nervous system (CNS) (Figure 8.4). The overabundance of excitatory influ­ences in the immature brain is also important in developmental neuronal plasticity of the mammalian nervous system (Lipton and Rosenburg, 1994; Veliskova et al., 1994).

As the brain matures, the balance of excitation and inhibition becomes a finely tuned process. Conditions leading to excessive excitation or loss of inhibition result in depolarization of neurons without normal regulatory feedback mechanisms. The result is a paroxysmal depolarization shift of a neuronal aggregate. In response to this sudden change in brain activity, local surrounding inhibitory zones are established to try to prevent the spread of this epilep­togenic activity (Figure 8.5). Gamma­aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain involved in this process. If inhibition is unsuccessful, other neuronal aggregates are excited through thalamocortical recruitment, intrahemispheric association pathways or interhemispheric commis­sural pathways. Successful recruitment of a critical number of areas with synchronized depolarization then leads to a seizure (Figure 8.6).

Ion channel mutations have been linked to a vari­ ety of epilepsies considered idiopathic in humans (Escayg and Goldin, 2010; Meisler et al., 2010). The majority of genes identified to date for human idio­pathic epilepsy are inherited disorders of ion chan­nels, known as channelopathies (Noebels, 2003). Each ion channel is a protein complex comprising several subunits. Excessive influx of sodium, block­ade of efflux of potassium or altered calcium flux can lead to repetitive neuronal firing. Specific func­tional genetic mutations have been identified for each of these ion channels in humans (Noebels, 2003). Although similar mutations have yet to be identified in animals, the presence of familial epi­lepsy in the dog makes this possibility a high like­lihood in the near future.

In the initial stages of epilepsy, an animal may possess only a single or limited number of epileptic foci. With recurrent seizure activity, the number of cells with an intrinsic pattern of high spontaneous firing activity (pacemaker cells) increase in the epileptic focus (known as kindling). An increase in the number of pacemaker cells is highly correlated with an increase in seizure frequency in experimental models of epilepsy (Wyler et al., 1978). Further­ more, a mirror focus of actively firing epileptogenic neurons may develop in a homologous region on the opposite hemisphere. If this happens, the num­ber of epileptic foci can multiply rapidly. The signif­icance of these changes is that, as a patient continues to seizure, there is an increased number of areas of the brain that are randomly and spon­taneously able to initiate a seizure. Thus, the suc­cessful medical management of this patient will be challenged. Prevention of this sequence relies primarily on the early identification of the underlying aetiology of the seizure disorder, followed by the initiation of appropriate medical therapy.

Differential diagnosis

The differential diagnosis of epileptic seizures is cur­rently divided into three main aetiological categories (Figure 8.7):

• Genetic (formerly idiopathic)
• Structural or metabolic (formerly symptomatic/secondary and reactive)
• Unknown (formerly probable symptomatic/cryptogenic).

Genetic epilepsy

Genetic

Channelopathies [8] Unknown genetic causes [8]

Structural or metabolic

Developmental anomaly [9]:- Focal: - Focal: - Focal: Neoplasia [9]:- Extra­axial: meningioma, bone tumours - Intra­axial: glial tumours, metastasis - Intraventricular: ependymoma, choroid plexus tumours Infectious [11]:- Viral - Bacterial - Rickettsial - Fungal - Protozoal - Parasitic Inflammatory diseases [11]:- Granulomatous meningoencephalitis - Necrotizing meningoencephalitis - Eosinophilic meningoencephalitis - Meningoencephalitis of unknown origin Toxicity:- Lead [9] - Organophosphates - Ethylene glycol Traumatic [20] Vascular [9]- Ischaemic: - Thromboembolic - Idiopathic: - Feline ischaemic encephalopathy - Haemorrhagic: - Hypertension related - Coagulopathy Organ failure:- Hepatic [9] - Renal [9] Electrolyte imbalance:- Hyponatraemia or hypernatraemia [9]- Hypocalcaemia [13] Energy deprivation:- Hypoglycaemia [9]- Thiamine deficiency [11]

Unknown

Prior head trauma in patients with normal imaging Post­encephalitic seizures developing months to years later Undetected hypoxic or vascular events of the brain post­ anaesthesia In utero or birth trauma

8.7 Differential diagnosis of seizures in the dog and cat. The numbers in square brackets denote chapters where these conditions are discussed in detail.

A diagnosis of genetic epilepsy is most common in purebred dogs with the first onset of seizures between 1 and 5 years old, a normal interictal neu­ rological examination, and if there is a lengthy initial interictal period (>4 weeks) (Podell et al., 1995). A genetic basis has been reported in numerous dog breeds, including: Belgian Shepherd Dogs, Poodles, Beagles, Springer Spaniels, Vizslas, Irish Wolf­ hounds, Lagotto Romagnolos and Retrievers (Patterson et al., 2003, 2005; Casal et al., 2006; Jokinen et al., 2007; Licht et al., 2007; Berendt et al., 2008, 2009; Oberbauer et al., 2010). The mutation causing myoclonic epilepsy in Miniature Wirehaired Dachshunds has been determined. These dogs suffer from Lafora disease and have a mutation in the EPM2 gene (Lohi et al., 2005). True genetic epi­lepsy is much less common in cats due to their more diverse genetic background (Quesnel et al., 1997; Schriefl et al., 2008; Kuwabara et al., 2010). As such, all cats should be evaluated for underlying structural or metabolic seizures before a diagnosis of genetic epilepsy is made (Pákozdy et al., 2010).

Structural or metabolic epileptic seizures

These types of epileptic seizures are the direct result of either structural brain pathology or meta­bolic disease. Dogs of any age can develop struc­tural epileptic seizures. Younger animals are more prone to developmental and encephalitic diseases, whilst older dogs (>7 years of age) are more likely to develop intracranial neoplasia. As expected with underlying cerebral pathology, these animals are more likely to exhibit focal or multifocal neurological deficits. However, focal lesions in ‘silent’ cortical areas of the brain (e.g. olfactory, pyriform and occi­ pital lobes) may have seizures as the only neuro­logical problem. This type of seizure is common in cats and can be caused by felie infectious peritoni­ tis (FIP) and meningioma (Barnes et al., 2004; Tomek et al., 2006; Timmann et al., 2008).

Metabolic (formerly reactive) epileptic seizures are a reaction of the normal brain to transient sys­ temic insult, toxic reaction or physiological stresses. Animals of any age may be affected. Small­breed dogs are more predisposed to develop seizures sec­ ondary to portosystemic shunts at a younger age. Typically, a higher seizure frequency occurs initially until the underlying metabolic or toxic insult is cor­rected, but evidence of systemic illness is often present concurrently (Brauer et al., 2011).

Neurodiagnostic investigation

Historical data

The most important component in approaching a seizure case is acquiring a thorough and accurate history. Enquiries regarding the seizure event should address a description of the event, time of day, duration and post­ictal effects. The purpose is to establish overall frequency, seizure type, patterns of occurrence, relationship to daily activity (e.g. exer­cise, sleep) and severity of postictal effects. It is recommended that a charting technique measuring seizure frequency and severity should be developed to aid objective evaluation of future therapeutic suc­cess. Owners should be provided with a calendar to record the frequency and description of all observed and suspected seizures.

The interictal status of cerebrocortical function (between seizures and after the post­ictal period) can be evaluated by asking questions concerning the animal’s behaviour, vision, gait and sleep/wake pat­ terns. For example, if the dog is more withdrawn or attention seeking, showing any unusual episodes of aggression or irritability, or fails to follow simple com­mands, then a structural cerebral problem should be suspected. Likewise, subtle gait disturbances (stum­bling up or down the stairs), visual disturbances (occasionally bumping into objects on one side) and restless sleep patterns may indicate structural fore­ brain problems.

Diagnostic evaluation

The sequence of diagnostic testing for any animal with seizures should proceed from the least to the most invasive (and expensive) modality.

• A complete blood count (CBC), biochemistry panel (including blood glucose), urinalysis and blood pressure measurement should be performed for all animals being evaluated for an epileptic seizure. For dogs, additional testing is based upon the age, breed, seizure type, seizure frequency and neurological examination findings.
• Dogs
• Other individual tests for toxin exposure (e.g. plasma lead, serum cholinesterase assay), parasitic or rickettsial infection, or systemic illness are based on the clinical picture at the time of presentation.
• For cats, basic screening should include a retroviral screen for feline leukaemia and feline immunodeficiency virus and testing for serum antibodies to Toxoplasma gondii. Testing for the virus that causes feline infectious peritonitis is not recommended, as the correlation between a positive titre and active CNS infection is low.
• All dogs ≥7 years old with an initial onset of seizures, regardless of the seizure pattern or frequency or neurological examination, should undergo advanced imaging of the brain with MRI or computed tomography (CT). Due to the high incidence of symptomatic epilepsy in cats, the author recommends that advanced imaging of the brain be performed in all epileptic cats.
• Cerebrospinal fluid (CSF) analysis is recommended in any animal with multifocal neurological deficits or lesions observed on MRI or CT. The presence of an abnormal CSF analysis has been found to be highly associated with the presence of underlying brain parenchymal lesions as detected on MR images (Bush et al., 2002). In addition, CSF can also be abnormal due to the seizures themselves (Goncalves et al., 2010).
• Although EEG analysis is beneficial for identifying underlying epileptic foci in the dog (Berendt et al., 1999), the overall usefulness of this test for determining diagnosis and treatment has yet to be proven. For further information on EEG, see Chapter 4.

In addition, video segments of events can be extremely helpful for clinicians to determine whether an epileptic event has occurred. Owners should be encouraged to video an event if possible and to try and distract the animal to determine whether the event can be terminated with external stimuli. Distractability often implies a non­epileptic event.

Treatment

Management of epilepsy in cats and dogs often requires a lifetime commitment by the owners. The owner must be willing to medicate their pet several times per day, travel to emergency clinics at unpre­dictable times, follow up with periodic re­evaluations and diagnostic testing, and watch their pet carefully for adverse effects of therapy. The balance between quality of life and therapeutic success is often a key issue for an owner to continue treating their pet (Chang et al., 2006). Despite all of the time, finan­cial and emotional commitment, a significant portion of dogs may still continue to have seizures. Thus, proper client education is critical in preparing own­ers for understanding their pet’s condition and the potential associated lifestyle changes. In particular, owners need to know that a diagnosis of epilepsy implies an increased risk of premature death with the prognosis dependent on a combination of veter­inary expertise, therapeutic success and the motiva­tion of the owner (Berendt et al., 2007).

Decision-making strategies for AED therapy

The decision regarding when to start AED treat­ment is based on a number of factors, including aetiology, risk of recurrence, seizure type and its effect on the patient, as well as the risk of treat­ment. Risk factors for seizure recurrence are not well established for cats and dogs. A number of rel­ative risk factors have been identified in epileptic people, including current or previously defined cer­ebral lesions or trauma, the presence of interictal EEG epileptic discharges (up to 90% recurrence rate) and a history of marked post­ictal adverse effects (Todd’s paralysis) (Scottish Intercollegiate Guidelines Network – Guideline 70). Evidence­ based guidelines from several international groups are well established for humans based on the risk:benefit ratio and predictability factors of drug effect (American Academy of Neurology (A AN), 2004). From these guidelines, several common­alities exist for guiding clinical practice including confirmation of an epileptic seizure event and seizure type, obtaining a definitive diagnosis, know­ ledge that recurrent seizure activity is correlated with poorer long­term treatment success, and the influence of treatment on the patient’s quality of life (Stephen and Brodie, 2009). Thus, the decision to treat is a reflection of the treatment goals to reduce or eliminate epileptic events, reduce seizure sever­ity, avoid adverse effects, and reduce seizure­ related mortality and morbidity.

Initiating treatment

Whilst similar information is not as readily available for the veterinary patient population, extrapolation is possible to provide rationale treatment guidelines. Overwhelming evidence exists in humans that there is no benefit in starting treatment after a single unprovoked event (Glauser et al., 2006). However, the earlier AED therapy is initiated, the better the potential outcome may be for seizure control (Freitag and Tuxhorn, 2005; Chadwick, 2008).

Reasons to initiate AED therapy include:

• Structural epilepsy is diagnosed
• Status epilepticus has occurred
• Two or more isolated seizures occur within a 6-­month period
• Two or more cluster seizure events occur within a 12-­month period
• The first seizure is within 1 month of a traumatic event
• Severe or unusual post­ictal effects are present (e.g. prolonged blindness, aggression).

Drug selection

AED selection is based on a number of factors, including seizure type, efficacy and tolerability. Evidence­based guidelines established by the IL AE, AAN and Standard and New AED Trials (SANAD) provide probability­based recommendations. Despite these guidelines, no evidence exists that any single AED provides a better outcome for adults with unpro­voked epilepsy when early treatment is initiated. Monotherapy is still the recommendation for new onset epilepsy. The use of a single AED has the advantages of no drug interactions, more predictable pharmacokinetic and pharmacodynamic properties, less potential for adverse effects, and less expense to the client.

AEDs are classified into three broad mechanistic categories which decrease either the seizure onset or spread of seizures (Figure 8.8):

• Enhancement of inhibitory processes via facilitation of the action of GABA (Figure 8.9)
• Reduction of excitatory transmission
• Modulation of membrane cation conductance.

Unfortunately, several limitations exist in the selection of AEDs for use in veterinary medicine, including toxicity, tolerance, inappropriate pharma­cokinetics and expense (Podell, 1998). In the past, many of the AEDs useful for humans could not be prescribed for small animals, due either to inappro­priate pharmacokinetics (too rapid an elimination) or potential hepatotoxicity. The result was that the most commonly used AEDs in veterinary medicine were from the same mechanistic category, that of enhancing inhibition of the brain. However, newer AEDs with alternative mechanisms of action are now available, allowing a broader selection of treat­ment options.

The efficacy and safety profiles of AEDs are determined in large part by their pharmacokinetic properties. Drugs that are the easiest to use by the general population are ones that have the most favourable pharmacokinetic properties (Bourgeois, 2000). Ultimately, an AED with the most desirable pharmacokinetic profile has complete bioavailability, is available as a parenteral formulation, and has an elimination half­life suitable for daily or twice­daily dosing, linear elimination kinetics, no auto-induction of enzymatic biotransformation, no pharmacokinetic interactions with other drugs, rapid brain penetra­tion, a volume of distribution with a single compart­ment, low and non­saturable protein binding, and no active metabolites. The ideal AED has not yet been formulated for any species.

Tolerability is a major consideration for drug selection. Adverse effects can be divided into tran­sient, persistent and life­threatening (idiosyncratic or predictable). Most transient adverse effects are avoidable with titration dosing and dissipate within several weeks. Persistent effects are either CNS dose­dependent associated with sedation, ataxia, vertigo or cognitive impairment, or metabolic­related with hormonal imbalances, metabolic syndromes and degenerative effects (e.g. osteoporosis). Severe life­threatening effects are mainly associated with either idiosyncratic bone marrow disease (e.g. aplastic anaemia) or predictable organ damage over time (e.g. hepatotoxicity).

Drug	Decreased seizure onset		Decreased seizure spread
	Enhanced Na+ channel inactivation	Enhanced GABA activated Cl— conductance	Reduced current through Ca2+ channels	Reduced glutamate- mediated excitation
Benzodiazepines		++
Bromide		++a
Felbamate	+	+		++
Gabapentin	+	++b	+	+
Lacosamide	++
Levetiracetam		++b		++
Phenobarbital		++	+	+
Rufinamide			++
Topiramate	+	+		+
Zonisamide	+		++
8.8 Summary of the mechanism of action of several currently available antiepileptic drugs. a Competitive displacement of chloride through activated GABA receptors. b Indirect GABA receptor activation via increased GABA activity. + = secondary mechanism; ++ = postulated primary mechanism.

First-generation AEDs

Benzodiazepines Bromide Carbamazepine Phenobarbital Phenytoin Valproate

Second-generation AEDs

Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Topiramate Zonisamide

Third-generation AEDs

Lacosamide Rufinamide

Next generation AEDs

Brivacetam Carisbamate Flurofelbamate Losigamone Remacemide Retigabine Seletracetam Tiagabine

8.10 Categorization of AEDs by generation of drug development.

AED generations

From the introduction of bromide in 1857 by Charles Locock to treat ‘hysterical’ epileptic fits in women, to the development of phenobarbital in the early 1900s, and the introduction of phenytoin, val­proate and carbamazepine in the early 1970s, the use of first­generation AEDs was limited by mech­anism, benefit and adverse effects. Not until the early 1990s did a revolution in drug development occur with the introduction of felbamate. The suc­ cession of second­generation drugs over the following two decades resulted in greater treatment success with a significant improvement in tolera­bility. Third­generation AEDs aimed at improving seizure control and patient quality of life are now available (Figure 8.10).

Success parameters

The treatment of epilepsy should be goal­oriented and approached in an objective fashion. Eliminating or significantly reducing the number and severity of seizures and maintaining a normal lifestyle for both the patient and owner are all important consider­ations. Whilst many drugs may provide initial improvement in seizure control, long­term efficacy is dependent on many factors. With only approximately 60–80% of human and canine epileptic patients responding to treatment, evaluating the reasons for recurrent seizure activity (refractory epilepsy) is important (Brodie et al., 2007).

These factors can be separated into three main variables:

• Disease­related
• Drug-­related
• Patient­-related.

Disease-related factors

Disease­related factors include the presence of an undiagnosed underlying brain disease, such as cor­tical malformation, prior trauma or an active disease process. Occult conditions can lead to localization­ related epilepsy, where epileptic foci develop drug resistance due to architectural brain changes.

Drug-related factors
Drug-­related factors include an ineffective mecha­nism of action, development of tolerance and alter­ation of the drug target or uptake over time (Loscher and Schmidt, 2006). Seizure­specific therapy tar­ gets a drug for a specific seizure type, and inappro­priate drug selection may result in poor control.

The reasons for drug tolerance or loss of effec­tiveness can be categorized as either metabolic (pharmacokinetic) or functional (pharmacodynamic). Metabolic tolerance is due to altered drug metabo­lism, which occurs in an unpredictable fashion. As such, a change in drug dosage does not result in a parallel change in serum drug level; for example, the auto-induction phase seen with phenobarbital in dogs occurs typically during the first 60 days of treatment. During this time, auto-induction of the cytochrome p450 enzyme system increases drug clearance and is not dose­dependent. Serum drug levels decline over time with the same dose until steady state clearance is achieved. Concomitant drug usage that either inhibits or stimulates the p450 system also alters hepatic metabolized AED levels.

Functional drug tolerance, also known as drug­ resistant epilepsy, is due to reduced drug transport through the blood–brain barrier, long term down­ regulation of the target receptor or genetic factors that alter cellular metabolism of the drug.

Patient-related factors

Patient-­related factors are now being discovered in relation to gene polymorphisms that affect AED pharmacokinetic or pharmacodynamic properties. As a result, altered drug metabolism or action is no longer predictable when compared with the general patient population. In addition, a placebo effect has been demonstrated in epileptic dogs, indicating that non­pharmacological therapeutic effects may play a role in canine epilepsy treatment (Munana et al., 2010). Not all epileptic patients can be controlled with a single AED and some animals require multiple medications for successful treatment.

Specific AED treatment for dogs

Figure 8.11 summarizes the AEDs available for the treatment of dogs; Figure 8.12 details those drugs not recommended.

First-generation AEDs

Phenobarbital: This drug, a phenyl barbiturate, has the longest history of chronic use of all AEDs in veterinary medicine. It is a relatively inexpensive, well tolerated drug that can be administered two or three times per day and has well documented success in preventing seizures (Farnbach, 1984; Schwartz­ Porsche et al., 1985; Parent and Quesnel, 1996; Boothe et al., 2012).

Pharmacology: Phenobarbital has a high bioavaila­bility, being rapidly absorbed within 2 hours and with a maximal plasma concentration obtained within 4–8 hours following oral administration (Ravis et al., 1989). Almost one­half of the drug is protein bound. The majority of phenobarbital is metabolized by the liver, with approximately one­third excreted unchanged in the urine. Phenobarbital is an auto­ inducer of hepatic microsomal enzymes (p450 sys­tem), which can progressively reduce the elimination half­life with chronic dosing.

Side-effects: Overall, phenobarbital is well tolerated at therapeutic serum concentrations in the dog. Idiosyncratic drug reactions to phenobarbital can be either behavioural or biochemically mediated. Behavioural changes, such as hyperexcitability, restlessness or sedation, may occur after starting treat­ment with the drug, but they appear not to be dose­related and resolve typically within 1 week. A more serious idiosyncratic reaction is development of an immune­mediated neutropenia or thrombocyto­penia in dogs (Jacobs et al., 1998), as well as anae­mia. Typically, this reversible blood dyscrasia occurs within the first 6 months of dosing. Rare acute, idio­syncratic hepatotoxic reactions may also be present, as evidenced by a rapid elevation of alanine aminotransferase (ALT) and abnormal dynamic bile acid levels. The drug should be stopped immediately if either neutropenia or dramatic elevations in ALT are noted, and the animal should be loaded with an addi­tional AED, such as potassium bromide (see below). Phenobarbital may also be a risk factor for the deve­lopment of superficial necrolytic dermatitis in dogs (March et al., 2004).

Chronic adverse historical effects usually revolve around polydipsic and polyphagic behaviour. As a result, dogs may develop psychogenic polydipsia with associated polyuria. The most common serum biochemical change with chronic phenobarbital ther­apy is elevation of the serum alkaline phosphatase level (Bunch et al., 1985). These changes can occur as soon as 2 weeks after initiating therapy. Neither endogenous adrenocorticotropic hormone (ACTH) nor the exogenous response to ACTH is altered by phenobarbital dosing (Dyer et al., 1994). Moreover, phenobarbital does not interfere with the low­dose dexamethasone suppression test, regardless of dose or treatment time (Foster et al., 2000). Serum total and free thyroxine (T4) concentrations may be low in dogs treated with phenobarbital (and in a few dogs the serum thyroid­stimulating hormone concen­tration may be elevated), resulting in a mistaken diagnosis of hypothyroidism (Kantrowitz et al., 1999).

Drug	Clinical pharmacology				Therapeutic range	Dosage	Efficacy	Major possible adverse effects
	T½ (hr)	Tss (d)	Vd (l/kg)	Protein Binding (%)
Bromide	20–46 days	100–200	0.45	0	Monotherapy: 1000–3000 mg/l with phenobarbital at 1500–2500 mg/l	40–60 mg/ kg orally q24h	Generalized seizures	Sedation; weakness; polydipsia; possible pancreatitis; possible behavioural disorders
Clorazepate	5-6	1-2	1.6	85	20–75 μg/ml (nordiazepam)	2–4 mg/kg orally q12h	Add on; generalized and partial seizures	Sedation; withdrawal seizures
Felbamate	5-6	1-2	1.0	25	25–100 mg/l	20 mg/kg orally q8h	Partial seizures	Blood dyscrasia; liver toxicity; induces p450 system
Gabapentin	2-4	1b	0.2	0	4–16 mg/l	10–20 mg/ kg orally q8–12h	Generalized and partial seizures	Sedation; ataxia
Levetiracetam	2-4	2-3	0.5	<10	Variable	20 mg/kg orally q8–12h	Add on or first line; generalized and partial seizures	Not greater than placebo; sedation; ataxia
Phenobarbital	24-40	10-14	0.8	40	20–40 mg/dl	2.5 mg/kg orally q12h	Generalized seizures	Sedation; polydipsia; liver toxicity; induces p450 system; blood dyscrasias
Zonisamide	15-20	3-4	1.5	50	10–40 μg/ml	5–10 mg/ kg orally q12h	Add on or first line; generalized and partial seizures	Sedation; ataxia; loss of appetite; keraconjunctivitis sicca; vomiting
8.11 AEDs available for treating epilepsy in dogs. T½ = elimination half-life; Tss = approximate time to steady state; Vd = volume of distribution.

Inappropriate

Toxicity: - Phenytoin (hepatic) - Primidone (hepatic) - Lamotrigine (cardiac) - Vigabatrin (blood dyscrasia) Inappropriate pharmacokinetics: - Carbamazepine (short elimination half­life) - Phenytoin (short elimination half­life) (hepatic) - Oral diazepam (inability to achieve therapeutic serum concentration)

Use with caution

Synergistic hepatic toxicity: - Phenobarbital and: - Felbamate - Zonisamide - Withdrawal seizures: - Phenobarbital - Clorazepate - Felbamate

8.12 AEDs inappropriate for use in the dog.

Three serious and potentially life-­threatening complications can occur with long­term phenobar­bital therapy:

• With time, physical dependence on the drug develops. Withdrawal seizures can occur as serum phenobarbital concentrations decline to between 15 and 20 μg/ml
• There may be the development of functional tolerance to the drug. Functional tolerance is the loss of drug effectiveness due to changes in drug–receptor interaction, change in drug distribution into the brain, or progression of an underlying disease state
• Potentially, the most life­threatening complication is drug­induced hepatotoxicity. Hepatotoxicity to primidone (which is metabolized predominantly to phenobarbital), either alone or in combination with other AEDs, has been shown to occur in experimental and clinical conditions in dogs (Bunch et al., 1985; Poffenbarger, 1985; Gaskill et al., 2005). Documentation of a serum phenobarbital concentration >35 μg/ml had the highest correlation with the development of hepatotoxicity (Dayrell­-Hart et al., 1991). All animals on chronic phenobarbital therapy should have a routine biochemistry panel performed every 6–12 months to monitor for the development of chronic hepatotoxicity. Bile acid and/or ammonia concentrations should be analysed to evaluate liver function if ALT levels suddenly increase or if the serum albumin level starts to decrease.

Administration and monitoring: The appropriate starting dose of phenobarbital for dogs is 2.5 mg/kg orally q12h (see Figures 8.11 and 8.13). An intra­ venous loading dose can be used to produce a rapid rise in serum blood concentration. This start­ ing dose is the only time a weight­based dosage is used. All future adjustments should be based on serum drug concentrations in conjunction with clinical assessment. The objectives of monitoring trough serum concentrations of any AED are:

• To determine whether a therapeutic value is present at the time when the lowest serum concentration is present, as dogs are most likely to seizure at this time
• To record that serum concentration fluctuates within the established therapeutic range for that drug when chronically administered (steady-­state concentration)
• To prevent toxic effects from occurring
• To individualize therapy.

Serial serum trough phenobarbital concentra­tions should be evaluated at: 14, 45, 90, 180 and 360 days after the initiation of treatment, at 6­month intervals thereafter, if the pet has more than two sei­zure events between these times, and at 2 weeks after a dosage change. Although blood level fluctuations may not be dramatic throughout the day in dogs with steady­state concentrations (Levitski and Trepanier, 2000), blood samples are best taken in the early morning, prior to dosing, in a fasted dog, to increase consistency in comparison with published information, maintain consistency in interpretation and remove diurnal or dietary­induced fluctuations of absorption (Maguire et al., 2000).

Adjustments in AED dosages are undertaken either to enhance the effect or to reduce the adverse effects. The most efficacious and safe trough thera­peutic phenobarbital range for the dog is 15–30 μg/ml. An optimal starting level is between 20 and 25 μg/ml. Increments of 5 μg/ml are beneficial if seizures are occurring at an equal frequency or worsening after 30 days of therapy. Adjustments of the trough phenobarbital levels can be calculated with the following formula:

A ≥20% drop in the trough serum concentration is often an indicator of poor administration compli­ance. Overall, phenobarbital is an AED that can pro­ vide excellent seizure control in idiopathic epileptic dogs (in approximately 85% of dogs seizures are eradicated) with careful serial monitoring of trough serum drug concentrations (Boothe et al., 2012).

Potassium bromide: Potassium bromide can be used as either monotherapy or as an add­on AED of choice in the dog. Concomitant potassium bromide and phenobarbital administration decreased seizure number and severity in the majority of dogs in sev­eral studies, with seizure­free status ranging from 21% to 72% of all treated dogs (Schwartz­Porsche and Jurgens, 1991; Podell and Fenner, 1993; Trepanier et al., 1998; Boothe et al., 2012). In gen­eral, many canine refractory idiopathic epileptic patients may benefit from potassium bromide. By allowing a reduction in the use of drugs metabolized by the liver, potassium bromide therapy may also reduce the incidence of hepatotoxicity.

Pharmacology: In the USA, bromide is typically given as the inorganic salt potassium bromide, usually as a solution of 200–250 mg/ml dissolved in double distilled water. In the UK several commercial formu­lations are available. Potassium bromide is a known mucosal irritant and capsules may result in gastric irritation due to the direct contact of a concentrated amount of the drug with the gastric lining. A starting dose of 40 mg/kg/day potassium bromide is slowly metabolized in the dog, with a median elimination half­life of 15.2 days, resulting in achievement of median steady­state concentrations of 2450 mg/l (March et al., 2002); apparent total body clearance is 16.4 ml/kg/day and the volume of distribution is 0.40 l/kg. Steady­state concentrations fluctuate between dogs, most likely due to individual differences in clearance and bioavailability. Dietary factors also alter serum drug concentrations, with high chloride diets resulting in excessive renal secretion and lower serum concentrations (Trepanier and Babish, 1995).

Side-effects: Potassium bromide is generally well tolerated in the dog. The most common adverse effects seen with potassium bromide and pheno­barbital combination therapy are polydipsia, poly­phagia, increased lethargy and mild ataxia with increasing serum concentration. Pancreatitis and gastrointestinal intolerance have also been reported (Gaskill and Cribb, 2000; Baird­Heinz et al., 2012). Potassium bromide may cause skin problems (bromoderma), although no substanti­ated reports exist currently. Intoxication to the point of stupor is rare, but pelvic limb ataxia, weakness and altered behaviour are more likely with serum concentrations >3000 mg/l (Rossmeisl and Inzana, 2009). Caution should be used when treating dogs with underlying renal insufficiency, due to reduced renal elimination (Nichols et al., 1996). Therapy for potassium bromide intoxication consists of intra­ venous normal saline administration to enhance renal excretion. Careful monitoring is advised as dogs may become more susceptible to seizure activity with lowering of the serum concentration.

Administration and monitoring: Potassium bromide can be administered at a starting dose of 40 mg/kg/ day when used as sole therapy or 30 mg/kg/day when used as an add­on drug to phenobarbital. Potassium bromide serum concentration should be measured at 1 month and at the first steady­state concentration (approximately 8–12 weeks). The rec­ommended goal is to achieve steady­state trough serum concentrations of 25 μg/ml for phenobarbital and 2000 mg/l for potassium bromide. The range is highly individualized according to the seizure pattern of each dog. Further reductions in phenobarbital can be attempted if a seizure­free period is main­tained for 6 months. The dosage is adjusted accord­ ing to the formulae given below.

Combined therapy: For concomitant phenobarbital and potassium bromide treatment, the new main­tenance dose can be calculated as follows:

Monotherapy: Potassium bromide monotherapy is recommended for dogs with underlying liver disease and those with less frequent seizure activity (

Dogs treated with potassium bromide alone should have a serum drug concentration at or above 2500 mg/l for optimal seizure control. Gradual increases in dose allow for better adaptation to the drug. For monotherapy, the new maintenance dose can be calculated as follows:

Benzodiazepines: These are a class of AEDs that interact with specific CNS benzodiazepine recep­tors which activate the GABAA chloride channel to hyperpolarize neuronal membranes (see Figure 8.9). Diazepam is the most widely used benzodiazepine in veterinary medicine and is best suited for the emergency treatment of seizures by intra­ venous and/or per rectum administration (see also Chapter 20). Chronic oral administration of diaze­pam is not recommended in the dog due to its lack of effectiveness in stopping seizures, its very short half­life, the potential for increased hepatic enzyme inhibition, physical dependence, and cross­toler­ance preventing effective use of intravenous diaze­pam in stopping seizures in an emergency (see Figure 8.12). Clorazepate, a long­acting benzodiaz­epine, is a diazepam pro­drug with more suitable pharmacokinetic properties for chronic use in the dog, but similar problems may arise as with chronic oral diazepam, especially the potential for severe withdrawal seizure activity (Scherkl et al., 1989). Pulse dosing of clorazepate in dogs has the poten­tial to stop cluster seizure events that are sepa­rated by several hours with a normal interictal period. A dose of 1 mg/kg q8h is recommended at the onset of the first seizure. Treatment is main­tained for 24 hours, followed by tapering to every 12 hours for 24 hours and then every 24 hours for one dose to prevent withdrawal seizure reaction (Scherkel et al., 1989). Unfortunately, this drug is no longer available in some countries.

Second-generation AEDs

Felbamate: This is a dicarbamate with proven abil­ity to block seizures induced by a variety of meth­ods. Felbamate is believed to increase the seizure threshold and prevent seizures from spreading by reducing excitatory neurotransmission in the brain. Neuroprotective effects have also been demon­ strated through this ability to alter excitatory neuro­transmission. In human clinical trials, felbamate has been shown to be most useful as monotherapy for the treatment of uncontrolled focal epilepsy.

Felbamate is metabolized by the hepatic micro­somal p450 enzymes, with increased metabolism in younger animals (Adusumalli et al., 1992). In dogs, the drug has a high bioavailability and protein­bind­ ing capability (see Figure 8.11 for dose). Effective control of complex focal seizure activity (automa­tisms) with documented therapeutic serum concen­trations has been shown with felbamate therapy in dogs (Ruehlmann et al., 2001). Felbamate is a non­ sedating drug.

A higher incidence of aplastic anaemia and liver toxicity has been reported in humans, but these adverse effects have not been documented in dogs. Serial monitoring of the CBC and biochemistry panel is recommended at 1 month and every 3 months during treatment. The trough serum drug concentration is typically measured 1–2 weeks after initiation of treatment, with a therapeutic range between 25 and 100 mg/l. This drug is not currently available in the UK and needs to be imported on a special licence.

Gabapentin: This AED is most commonly used for neuropathic pain relief in small animals. Initially designed to mimic GABA in the brain, gabapentin can readily pass through the blood–brain barrier. However, once in the brain, gabapentin does not mimic the pharmacological properties of GABA nor does it bind to the GABA receptors. In preclinical studies, gabapentin effectively blocked seizures induced by a variety of proconvulsant methods. Evidence also suggests that gabapentin may facili­tate the extracellular transport of GABA out of cells to act on the GABAA receptor (Honmou et al., 1995). The dog is the only known species to partially bio­ transform the drug to N­methyl­gabapentin in the liver (Radulovic et al., 1995). A major benefit of the drug is that both the parent and metabolites are excreted renally; thus, it does not induce drug–drug interactions with other AEDs with hepatic metabo­lism (e.g. phenobarbital).

Gabapentin may also be beneficial as an add­on therapy for epileptic seizures secondary to hepatic disease (e.g. portosystemic shunting) and post­ traumatic or post­hypoxic delirium. Dosing every 8 hours is necessary due to the rapid elimination half­life (Kukanich and Cohen, 2011). Lower starting doses with gradual adaptation over time (e.g. once daily dosing for 3 days, then twice daily dosing for 3 days and then thrice daily dosing thereafter) is recommended to avoid excessive sedation, which is seen as a side effect in many dogs (see Figure 8.11). Reduced doses may be needed in patients with renal insufficiency. Serum monitoring is not recommended as the drug has a very high thera­peutic index and little drug–drug interaction. Preliminary clinical evaluation of this drug as an add­on therapy for refractory idiopathic epileptic dogs recorded an improvement in seizure fre­quency in approximately 50% of cases (Govendir et al., 2005; Platt et al., 2006). Pharmaceutical suspension formulations of gabapentin contain the artificial sweetener xylitol, which can induce hypoglycaemia and should be avoided in the dog and cat.

Topiramate: This is a sulphamate-­substituted mono­ saccharide which blocks the spread of seizures via rapidly potentiated GABA activity in the brain (Petroff et al., 2001). In humans, topiramate is well absorbed and primarily excreted renally as an unchanged drug. With a relatively long half­life of 20–30 hours, twice­daily dosing is recommended. With a relatively broad­spectrum activity against many seizure types and minimal adverse effects, topiramate is approved for use in both adult and paediatric human patients. Dosing ranges are between 25 and 50 mg/day per patient (Holland, 2001) but gradual dose titration is better tolerated (see Figure 8.14). No clinical studies have been published on the use of this drug in small animals to date; although, pharmacokinetics in Beagles have demonstrated a terminal half­life of 2–3.8 hours, no accumulation and no auto-induction or inhibition of enzymes (Streeter et al., 1995).

Zonisamide: This is a substituted 1,2-­benzisoxa­zole derivative that works by both blocking the propagation of epileptic discharges and suppress­ ing focal epileptogenic activity (Ito et al., 1980). Broad­spectrum anti-epileptic activity has been reported against a variety of seizure types, with particular improvement in the treatment of adult myoclonus epilepsy (Henry et al., 1988). Zoni­samide can be an efficacious and well tolerated drug in dogs with recurrent generalized seizures refractory to phenobarbital or potassium bromide therapy. Over 70% of dogs with refractory idio­pathic epilepsy responded well to zonisamide add­ on therapy in one study, with 58% responding favourably in another (Dewey et al., 2003; von Klopmann et al., 2007).

Pharmacology: Zonisamide is well absorbed, has a relatively long half­life (18–28 hours) and high pro­tein-­binding affinity (70%) (Booth and Perkins, 2008). The drug is highly concentrated in red blood cells due to high binding to carbonic anhydrase and other red cell protein components (Patsalos and Sander, 1994). Zonisamide is metabolized hepa­tically and thus influenced by concurrent administra­tion of other similarly metabolized drugs (Walker et al., 1988).

Side-effects: The major adverse effects include sedation, dry eye, ataxia, inappetence and vomiting. A higher incidence of renal calculi formation and gastrointestinal disorders is found in humans, but has not been documented in dogs. Metabolic acido­ sis and liver dysfunction has been documented in dogs receiving this medication (Cook et al., 2011; Miller et al., 2011; Schwartz et al., 2011). Patients with a history of sulfa drug hypersensitivity should not be prescribed zonisamide.

Administration and monitoring: Zonisamide is availa­ble as a generic medication in dosages of 25 mg, 50 mg and 100 mg. Parental and suspension formu­lations are not commercially available. A preliminary study demonstrated that dogs responded to treat­ment with a blood level close to 20 μg/ml (Dewey et al., 2003); a recent experimental study revealed that stable plasma concentrations were achieved in 3–4 days in dogs following oral administration (Fukunaga et al., 2010).

Combination therapy: Phenobarbital dosages should be reduced by 25% at the time of starting zonisamide due to the enhanced hepatic enzyme induction and clearance of zonisamide (Orito et al., 2008).

Levetiracetam: This is the S­enantiomer of the ethyl analogue of piracetam and has a unique mechanism of action mediated by binding to the presynaptic vesicular protein, SV2A, which decreases glutamate neurotransmitter release (Lynch et al., 2004). In dogs, the drug is well absorbed, is rapidly metabo­lized with an estimated elimination half­life of 4–8 hours, and is predominantly excreted renally (>80%) (Volk et al., 2008). However, wide fluctuations of drug metabolism occur in the dog. The initial dose of 10–20 mg/kg orally q12h is gradually incremented to ≥20 mg/kg orally q8h. The therapeutic range is not well defined and drug monitoring is recommended only to establish the pharmacokinetic pattern of the individual patient.

The drug is well tolerated, with sedation noted as the most common adverse effect (Patterson et al., 2008). The oral dose should be increased when dogs are receiving phenobarbital concurrently as lower serum levels can potentially be related to the induction of serum hydrolases (Moore et al., 2010, 2011). A parenteral formulation is available for intra­ muscular dosing or intravenous loading at 40–60 mg/kg over 15–30 minutes in a 1:1 diluted saline solution (Patterson et al., 2008). An oral syrup for­mulation is also available. Recent work suggests that levetiracetam may need to be given at higher doses in dogs refractory to phenobarbital therapy as it may not offer any advantage compared with a placebo at routine doses (Muñana et al., 2012). A new extended release formulation of levetiracetam has been shown to have a half­life in excess of 7 hours in dogs follow­ing oral administration, giving rise to the potential for once or twice daily administration (Platt et al., 2011).

Lamotrigine: This novel drug is chemically unre­lated to any current AEDs. Although efficacious in human epileptic patients, the drug is converted to a cardiotoxic 2-­N­methyl metabolite in dogs (Wong and Lhatoo, 2000), which is not found in humans. This drug is not recommended for use in dogs (see Figure 8.12).

Pregabalin: This is a structural analogue of GABA with a mechanism of action of voltage­gated cal­cium channel modulation, which decreases de­ polarization­induced calcium influx at the nerve terminals and ultimately reduces excitatory neuro­ transmitter release. The mean elimination half­life is estimated at 7 hours in dogs (Salazar et al., 2009). Metabolism appears to be predominantly via renal excretion with minimal protein binding and drug interaction. Efficacy as an add­on therapy for refractory partial seizures was found in several studies in humans and in a recent study in dogs (Dewey et al., 2009). A definitive therapeutic range has yet to be determined for humans and dogs. The initial dose recommendation is 4 mg/kg orally q8–12 hours. Adverse effects appear to be limited to sedation and ataxia.

Third-generation AEDs

Lacosamide: This is a functionalized amino acid proven to decrease neuronal discharge frequency and synaptic excitability (Halford and Lapointe, 2009). The postulated mechanisms of action include selective slow inactivation of sodium chan­nels and novel binding to collapsin response media­ tor protein­2. In humans, the drug is well absorbed, has minimal first­pass effect with predominant renal excretion, low protein binding, favourable drug–drug interactions with other AEDs, and is well tolerated. Clinical trials in humans have demonstrated a com­ parable decrease in seizure frequency with that of levetiracetam and zonisamide at a dose of 100–200 mg orally q12h. A parenteral formulation is available for intravenous loading. The author has used lacosamide successfully to treat refractory idiopathic epilepsy in dogs at a dose range of 5–10 mg/kg orally q12h.

Rufinamide: This novel drug is structurally unre­lated to any other AED. Its main mechanism of action is related to prolongation of the inactive state of the sodium channel, thus preventing neuronal depolarization. In humans, the drug is absorbed slowly and has low bioavailability. Renal excretion is high and no induction of the hepatic p450 system has been found, although other hepatically metabo­lized drugs decrease the serum concentration. Of a total of 9 double­blinded studies in humans, 5 revealed a positive effect of rufinamide to treat refractory partial seizures but not generalized seizures (Biton, 2009). Initial dosing ranged from 10–40 mg/kg orally q24h, with dose­ dependent adverse effects of sedation, fatigue and dizziness noted. A parenteral formulation is not available. No data were found regarding clinical use in dogs or cats.

Specific AED treatment for cats

Figure 8.14 summarizes the AEDs available for the treatment of cats.

Drug	T½ (hr)	Therapeutic range	Initial dose	Potential adverse effects
Clonazepam	Unknown	500–700 ng/ml (nordiazepam)	0.5–1 mg orally q12–24h	Acute hepatic necrosis; sedation
Diazepam	15-20	500–700 ng/ml (nordiazepam)	2.5–10 mg orally q8–12h	Acute hepatic necrosis; sedation
Gabapentin	3	Unknown	5–10 mg/kg orally q8–12h	Sedation; ataxia
Levetiracetam	2-5	10–50 μg/ml	10–20 mg/kg orally q8–12h	Sedation
Phenobarbital	34–43	10–30 mg/dl	1–2 mg orally q12–24h	Sedation; hepatotoxicity; blood dyscrasia
Topiramate	Unknown	Unknown	12.5–25 mg orally q8–12h	Sedation; inappetence
Zonisamide	35	Unknown	5–10 mg/kg orally q24h	Sedation; anorexia; vomiting; somnolence; ataxia; diarrhoea (Hasegawa et al., 2008)
8.14 AEDs available for treating epilepsy in cats. T½ = elimination half-life.

Clonazepam can be used as an alternative to diazepam in the cat, as it does not undergo hepatic microsomal metabolism, has a more prolonged elimination half­life and, therefore, may not pro­duce an idiosyncratic hepatic reaction. The recom­mended starting dose is 0.5 mg/cat orally q12–24h. Clorazepate is another long­acting benzodiazepine that the author has successfully used, although the precise pharmacokinetic properties of this drug are not well understood in the cat. The recom­mended dose range is 3.75–7.5 mg/cat orally q12–24h. Similar precautions as described for dia­zepam are necessary.

Potassium bromide: This is not recommended as a standard therapy in cats due to the relatively high prevalence of adverse respiratory problems (Boothe and George, 2002). Cats can develop a cough and more severe respiratory signs suggestive of an aller­gic asthmatic disease, which can be fatal in some cases (Wagner, 2001). The author no longer recom­mends the use of potassium bromide in cats.

Second-generation AEDs

Gabapentin: This is a useful AED in the cat due to its exclusive renal excretion. However, cats may exhibit increased sedation and benefit from a grad­ual increment in dosing over 1–2 weeks. The author recommends starting at 5–10 mg/kg orally q24h for 3–5 days, then increasing to twice daily dosing. Gabapentin has an approximate half­life of 3 hours in cats (Siao et al., 2010). Further increases are dependent upon the response to therapy. Both solu­tion and capsular formulations of the drug are avail­ able, but the oral solution is not recommended. The drug can be used both as monotherapy and an add­ on medication.

Levetiracetam: This is an effective add­on AED and is well tolerated in cats (Bailey et al., 2008). Levetiracetam appears to be rapidly metabolized and has an elimination half­life of under 4 hours. Up­titration dosing starting at 10 mg/kg orally q24h to eventually achieve a dose of 20 mg/kg orally q8h over a 10­day period is recommended. Monitoring drug levels is typically not necessary due to the high degree of safety and non­hepatic metabolism. However, caution should be used in cats with renal disease.

Treatments in development

The future of epilepsy treatment is undergoing multi­ faceted, exponential growth. Many new AEDs are currently in clinical trials throughout the world. A common denominator for drug development is the ability to define pharmacoresistant therapy by both drug action and patient pharmacogenomics. Brivaracetam and selacetam are analogue drugs of levetiracetam formulated with significantly greater SV2A protein binding for higher potency. Preliminary studies in humans have demonstrated efficacy against refractory complex partial and myoclonic seizures (French et al., 2007). However, brivaracetam has been found to have a low margin of safety for hepatotoxicity in a small number of normal dogs (von Rosenstiel, 2007). Carisbamate blocks voltage­gated neuronal calcium channels and, in humans, is predominantly excreted renally with minimal adverse effects. It is effective against a wide range of seizure types (Luszckzi, 2009). Retiagabine directly activates voltage­gated potas­sium channels (Kv7 subunit), preventing parox­ysmal burst discharges. It is also useful against a variety of seizures (Luszckzi, 2009).

With the advent of more advanced diagnostic capabilities to map localization­related epilepsy, conventional surgical and radiosurgical interven­tion can now provide curative outcomes previously never imagined. Vagal and brain stimulators have introduced a physiological method of changing the baseline seizure threshold of the brain, by altering cholinergic synaptic release to produce an inhibi­tory influence on the ascending thalamocortical pathways (Muñana et al., 2002). Whilst veterinary surgeons may not incorporate all of these modali­ties into clinical practice as yet, the future potential to help our patients grows every day as well.

Emergency treatment

Hospital emergency treatment for seizures

A rapid, reliable protocol for the emergency man­agement of seizures in dogs and cats is provided in Chapter 20. The physiological sequelae of frequent or continuous seizure activity (status epilepticus) leading to increased intracranial pressure and neu­ronal necrosis include systemic arterial hyperten­sion, loss of cerebrovascular regulation, disruption of the blood–brain barrier and cerebral oedema.

At-home emergency treatment for seizures

The financial and emotional constraints of provid­ing recurrent emergency therapy can be over­ whelming for the owner and result in euthanasia of the animal. It is important to discuss methods by which the owner can provide emergency treatment for their pet at home if the animal is prone to clus­ter seizures. Diazepam per rectum (DZPR) therapy by owners of dogs with primary epilepsy and gen­eralized cluster seizures has been associated with a significant decrease in the number of cluster sei­zure events in a 24-­hour period, and a decrease in the total number of seizure events when compared with an identical time period without such therapy (Podell, 1995). As a consequence of this there was a significant decrease in the total cost for emer­gency care per dog, when compared with a similar period prior to the onset of use of DZPR therapy.

Pharmacokinetic studies of DZPR therapy in normal dogs have demonstrated that chronic phenobarbital therapy in the dog reduces the total benzodiazepine concentration after intravenous and per rectum administration, presumably due to the increased hepatic clearance of diazepam and/ or its metabolites, oxazepam and nordiazepam (Wagner et al., 1998). Administration of diazepam at a dosage of 2 mg/kg per rectum for dogs on chronic phenobarbital therapy achieved effective plasma benzodiazepine concentrations >300 μg/l with minimal adverse effects. A dose of 1 mg/kg is recommended without concurrent phenobarbital therapy. This dose can be given up to three times in a 24­hour period but should not be given within 10 minutes of a prior dose. No information is reported for rectal AED therapy in the cat.

References and further reading

Available on accompanying DVD

DVD extras

• Generalized tonic–clonic seizure
• Complex partial seizure (automatism)
• Myoclonic and atonic seizures
• Focal motor seizure
• Status multiple seizure types

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