Seizures are the most common neurologic problem in small-animal medicine. Overall, the incidence of idiopathic epilepsy (the most common cause of seizures in dogs) is between 0.5 and 5% of the pet dog population; some breeds, however, have much higher incidences of epilepsy within the breed. Clients are often emotionally distraught because of the violent, unpredictable nature of seizures. An accurate diagnosis is the first step in management. The underlying cause of the seizures is identified and treated if possible. In the case of idiopathic epilepsy, there is no cure, and management usually entails the daily administration of medication. Optimal management of this syndrome depends on the veterinarian and client working together as a team, with the client actively participating in decisions. With proper treatment, the patient and client can usually maintain a good quality of life. Managing seizure disorders presents a major challenge to the veterinarian, especially when a dog does not respond to “standard” (i.e. phenobarbital, bromide) therapy. A refractory epileptic is a dog who has poor seizure control, despite documented evidence of plasma drug concentrations of two or more typically effective antiseizure drugs that are within what is considered the therapeutic range. Such refractory cases account for between 25 and 30% of all epileptics. The therapeutic range is a range of plasma drug concentrations for a specific drug within which most patients are expected to achieve adequate seizure control. The therapeutic range is often a somewhat arbitrarily derived scale and should be used only as a guideline. A responder is a patient that has experienced at least a 50% reduction in seizure frequency following the addition of a specific antiseizure intervention (e.g. addition of a new drug). Owners may arrive at the veterinarian’s office following their pet’s first seizure, fully expecting their veterinarian to make their pet seizure-free. It is very important for the clinician to inform the pet owner that a small percentage of epileptics become seizure free with drug therapy (estimate of about 15% in dogs vs. 70–90% in people); success is typically considered a reduction in the frequency and duration of seizures. Nonetheless, the goal of anticonvulsant therapy should be to eliminate seizure activity in the patient, or come as close to this goal as possible, without subjecting the patient to unacceptable side effects of drug therapy. A common misconception concerning seizure management is that the achievement of no more than one seizure per month should be the goal of therapy. Such a goal would be of little benefit to the dog presenting with a history of monthly seizure activity. Alternatively, a dog that seizures daily prior to drug intervention and experiences two seizures per month afterwards would be incorrectly considered a treatment failure, using such arbitrary criteria. Concerns over potential side effects of drug therapy are based primarily on the use of phenobarbital and bromide. With the advent of the alternative anticonvulsant drugs to be discussed in this chapter, improved seizure control is often possible without concurrent adverse side effects. The veterinarian does need to consider, however, that all drugs have the potential for adverse effects on the patient, some of which can be serious.

An epileptic seizure is the clinical manifestation of excessive and/or hypersynchronous electrical activity in the cerebral cortex. Neurons are inherently excitable. Defects that alter the excitability of a group of neurons can lead to marked and prolonged depolarization, called a paroxysmal depolarizing shift. This can involve neurons in a specific region of the brain (leading to a focal seizure) or involve the entire cerebrum (leading to a generalized seizure). Excessive depolarization can also spread from a focal hyperexcitable area (seizure focus) and excite other areas of the brain. Although the precise mechanisms involved are incompletely understood, theories include:

1. Inadequate neuronal inhibition—major inhibitory neurotransmitters include gamma-aminobutyric acid (GABA) and glycine.
   
2. Excessive neuronal excitation—major excitatory neurotransmitters include aspartate and glutamate.
   
3. A combination of A and B.

Idiopathic epilepsy is currently considered to represent a group of heterogeneous heritable disorders. In humans and (to a more limited degree) dogs, genetic epilepsy disorders have been identified. Some of these involve abnormal ion channels in the brain and some are suspected to be due to abnormal axonal organization. Regardless of the molecular basis of a specific patient’s epilepsy disorder, there is a tendency in humans and dogs for untreated (or inadequately treated) epilepsy to worsen over time (i.e. increased frequency and/or duration of seizures). Proposed mechanisms for worsening seizure activity over time include kindling and mirroring. Kindling refers to recruitment over time of previously nonhyperexcitable neurons into a group of hyperexcitable neurons (the seizure focus) via constant stimulation of these neurons by the seizure focus within a cerebral hemisphere. Mirroring is similar to kindling, but involves recruitment of neurons into the seizure focus from the opposite cerebral hemisphere via the corpus callosum. Although any breed of dog can be afflicted with idiopathic epilepsy, there are a number of breeds that are predisposed to this disorder (Box 9.1).

1. 
   

   Primary generalized seizures

   
   

   Primary generalized seizures are those in which the initial clinical signs reflect involvement of both cerebral hemispheres. Impairment of consciousness is common and may be the initial sign. Motor manifestations are bilateral. Generalized tonic-clonic seizures, formerly called grand mal seizures, are the most common type of seizures in dogs and cats.

   
   
   
   
   1. 
      

      Generalized tonic–clonic seizures (Video 18)

      
      

      The first part of the seizure is the tonic phase, during which there is sustained contraction of all muscles. The animal suddenly loses consciousness and falls to its side in opisthotonus with the limbs extended. Breathing is often irregular or absent, and cyanosis is common. The patient often salivates, urinates, or defecates. The tonic phase lasts for a minute or so and then gives way to the clonic phase, during which there is paddling or rhythmic jerking of the limbs and chewing movements. The clonic phase lasts a variable period of time but usually no more than several minutes. Some animals suffer milder generalized tonic–clonic seizures in which consciousness is maintained.

      
      
   2. 
      

      Tonic seizures

      
      

      During a tonic seizure, the abnormal motor activity consists only of generalized muscle rigidity without a clonic phase.

      
      
   3. 
      

      Clonic seizures

      
      

      These seizures consist of paddling and jerking with no tonic component.

      
      
   4. 
      

      Atonic seizures

      
      

      These rare seizures are manifested as sudden, often brief, losses of muscle tone. There may be a brief drop of the head or the patient may suddenly collapse to the ground.

      
      
   5. 
      

      Myoclonic seizures (Video 14)

      
      

      These are characterized by brief, shocklike contractions that may be generalized or confined to individual muscle groups. There are other causes of myoclonic jerks; not all myoclonic jerks are seizures.

      
      
   6. 
      

      Absence seizures

      
      

      Generalized absence seizures in people are defined as abrupt, brief losses of consciousness associated with a specific pattern on electroencephalography (EEG). These were formerly called petit-mal seizures, although this term is often used erroneously by veterinarians to refer to any sort of mild seizure. True absence seizures are uncommonly recognized in veterinary medicine and characterized by brief episodes of unresponsiveness, sometimes accompanied by facial twitching and mild limb jerking and 4 Hz spike-and-wave complexes on EEG.

   
   
2. 
   

   Focal (partial) seizures

   
   

   Focal seizures are those in which the initial clinical signs indicate abnormal activity in one region of a cerebral hemisphere. Simple focal seizures do not impair consciousness, which is recognized as the ability to respond normally to stimuli, such as sound or touch. When consciousness is impaired, the seizure is classified as a complex focal seizure. Any portion of the body may be involved during a focal seizure, depending on the region of the brain affected. Motor signs, autonomic signs, and behavior signs are most common.

   
   
   
   
   1. 
      

      Focal seizures with motor signs

      
      

      Motor signs include rhythmic contractions of facial or masticatory muscles, abnormal movements of one limb, and turning the head to one side.

      
      
   2. 
      

      Focal seizures with autonomic signs

      
      

      Autonomic signs include hypersalivation, vomiting, gagging, diarrhea, and apparent abdominal pain.

      
      
   3. 
      

      Focal seizures with abnormal behavior

      
      

      Focal seizures in human patients can cause sensory symptoms such as abnormal skin or vision sensations. Such subjective sensations are difficult to verify in animals, but seizures manifested as licking or chewing at a region of the body and “fly-biting” are probably caused by similar sensations. Complex focal seizures may be manifested as impaired consciousness and bizarre behavior, such as unprovoked aggression or extreme, irrational fear (psychic or psychomotor seizures). In some cases, it is difficult to discriminate between a focal seizure and other types of episodes, such as syncope, narcolepsy, and behavioral disorders.

      
      
   4. 
      

      Focal seizure evolving to a generalized tonic–clonic seizure

      
      

      A focal seizure may progress to a generalized motor seizure. The secondary spread can occur so rapidly that the initial focal component is missed. In fact, in the past, focal seizures were rarely recognized in animals, but with more detailed history and review of videotaped seizures, it is clear that many dogs with idiopathic epilepsy suffer focal seizures with secondary generalization.

   
   

   Occasionally, animals will display episodic involuntary movements of one or more body parts without an alteration of consciousness. It is unclear in these disorders whether the underlying cause is actually simple focal seizure activity or some other abnormality. Episodic head tremor occurs in Doberman Pinschers, English and French Bulldogs, Boxers and occasionally other breeds. Affected dogs suffer episodes of horizontal or vertical head tremor with no alteration in consciousness. Other types of episodic repetitive movements occur. These movement disorders may represent simple focal seizures, but some are more similar to human dyskinesias. Dyskinesias are involuntary movements due to abnormalities of the basal nuclei. Still another potential cause for these disorders is an abnormality of neuronal ion channels (ion channelopathies). These movement disorders are discussed in more detail in Chapter 10. Episodic movement disorders have been described in the following breeds: Scottish Terrier, Bichon Frise, Cavalier King Charles Spaniel, Norwich Terrier, Wheaten Terrier, Boxer dog, Chinook dog, and Border Terrier (Spike’s disease). Discerning between an involuntary movement disorder and focal seizure activity is sometimes based on EEG results and/or response to antiseizure drugs. Unfortunately, since many of the new antiseizure drugs act on neuronal ion channels (i.e. there is overlap between diseases and underlying molecular mechanisms responsible for those diseases), a positive response to one of these drugs does not necessarily provide a diagnosis of focal seizure disorder.

1. 
   

   Prodrome

   
   

   A prodrome is a long-term indication of a forthcoming seizure. The patient may exhibit abnormal behavior, such as restlessness, clinging to the owner, and uncontrolled vocalizing during the hours to days before a seizure. Prodromes are not always recognized.

   
   
2. 
   

   Aura

   
   

   An aura is the initial sensation of a seizure before there are observable signs. Auras usually last seconds to minutes and are caused by the initial abnormal electrical activity in the brain. In other words, the aura is the start of a seizure. Affected animals may hide, seek their owners, or seem agitated just before a seizure. The difference between a prodrome and an aura is that prodromes are long lasting and not associated with abnormal EEG activity, while auras are short lasting and caused by abnormal electrical activity.

   
   
3. 
   

   Ictus

   
   

   The ictus is the seizure itself.

   
   
4. 
   

   Postictal stage

   
   

   Postictal signs are transient abnormalities in brain function that are caused by the ictus and appear when the ictus has ended. These may include disorientation, restlessness, ataxia, blindness, and deafness. Postictal abnormalities usually resolve after several minutes, but they may last for days, especially after prolonged seizures.

1. Epilepsy is a condition characterized by recurrent seizures over a long period of time. From a practical standpoint, a useful definition is two or more seizures occurring over a period of at least 1 mo. Epilepsy is not a specific disease; it is a clinical sign.
   
2. Provoked seizures, also called reactive seizures, are seizures that occur at the time of a systemic disorder or brain insult. If the seizures stop when the underlying condition resolves, the patient does not have epilepsy, because the condition is not chronic. Seizures caused by acute toxicity are an example.
   
3. Idiopathic epilepsy, also called primary epilepsy, refers to recurrent seizures in which there is no identifiable brain abnormality other than seizures. It is likely that most, if not all, idiopathic epilepsies have a genetic basis. Most idiopathic epilepsies in human patients are now classified as genetic epilepsy and as the genetic basis of idiopathic epilepsies in dogs and cats becomes clarified it is anticipated that these will likewise be reclassified as genetic.
   
4. Structural/metabolic epilepsy, previously called symptomatic epilepsy or secondary epilepsy, refers to recurrent seizures that are caused by an identifiable lesion or other specific etiology.
   
   
   
   1. 
      

      Structural

      
      

      Brain lesions that may cause seizures include degenerative diseases (e.g. storage diseases), hydrocephalus, neoplasia, infectious/inflammatory disease (e.g. meningoencephalomyelitis), trauma, and ischemic/vascular disorders.

      
      
   2. 
      

      Metabolic

      
      

      Metabolic disorders that may cause seizures include hepatic encephalopathy, hypoglycemia, electrolyte imbalances (e.g. hypocalcemia), and toxins (e.g. lead, ethylene glycol).

   
   

   In general, young animals are prone to infectious diseases, developmental disorders, and storage diseases. Young animals also are more likely to ingest toxins, such as lead. Older animals are at increased risk of neoplasia and vascular disorders. Metabolic causes are usually identified by laboratory analysis and historical evidence of toxin exposure. Diagnosis of structural brain lesions usually entails brain imaging and analysis of cerebrospinal fluid.

Idiopathic epilepsy is the most common cause of epilepsy in dogs. Cats with seizures often have an underlying identifiable cause, although idiopathic epilepsy does occur in cats. As mentioned previously, the majority of dogs with idiopathic epilepsy are likely to have specific heritable disorders as the cause of their seizures. There are several consistent features of idiopathic epilepsy in dogs.

1. The age of onset in dogs is usually 1–5 yrs of age, but it is not infrequent for seizures to begin at a young age (less than 1 yr; juvenile epilepsy) or at an older age (late-onset epilepsy). Dogs that have their initial seizure prior to 1 yr of age are frequently encountered. In one report, it was found that 75% of dogs that had their first seizure prior to 1 yr of age were diagnosed with IE (juvenile epilepsy). While it is certainly valid practice to screen young seizuring dogs for the presence of a portosystemic shunt (PSS), it should be kept in mind that this congenital anomaly is actually an uncommon cause of juvenile seizures in dogs. In one report of dogs in which age of seizure onset was > 5 yrs, 35% were diagnosed with primary (idiopathic) epilepsy. In another study of dogs with onset of seizure activity ≥ 7 yrs of age, no identifiable cause for seizures could be found in 21% of cases.
   
2. Idiopathic epilepsy is inherited in many breeds, including the Beagle, Belgian Shepherd, Belgian Tervuren, Bernese Mountain dog, British Alsatian, Border Collie, Dachshund, English Springer Spaniel, Finnish Spitz, Golden Retriever, Irish Wolfhound, Greater Swiss Mountain dog, Keeshond, Labrador Retriever, Lagotto Romagnolo, Petit Briquet Griffon Vendéen, Shetland Sheepdog, Standard Poodle, and Vizsla. But idiopathic epilepsy can occur in any breed of dog or cat.
   
3. Generalized tonic–clonic seizures and focal seizures with secondary generalization are the most common types of seizures, but other types of generalized or focal seizures can occur.
   
4. Seizures usually occur spontaneously and are more common at night or when the patient is resting or sleeping.
   
5. In a few patients, seizures are regularly elicited by a specific stimulus, called epilepsy with reflex seizures. The most commonly recognized stimuli in dogs are loud noises (typically lawn mower or snowblower engines) and visits to the veterinary hospital or groomer.
   
6. Initially, seizures are usually infrequent (every 4 wks or so), but without therapy or with inadequate therapy seizures tend to increase in frequency.

1. 
   

   Differential diagnosis

   
   

   The diagnostic evaluation is designed to determine whether the patient is having seizures, and, if so, the cause of the seizures. Seizures are recognized by their spontaneous onset, stereotypic signs, self-limiting time course, and exclusion of common imitators. Idiopathic epilepsy is a clinical diagnosis based on the typical age of onset, lack of interictal abnormalities, and exclusion of other causes. Symptomatic epilepsy should be suspected when seizures start before 1 yr or after 5 yrs of age, the patient suffers focal seizures, there is a sudden onset of multiple seizures, or there are interictal abnormalities detected on history, examination, or laboratory tests. Several disorders can be mistaken for seizures:

   
   
   
   
   1. Syncope is characterized by a partial or complete loss of consciousness, lack of violent motor activity, short duration, and lack of postictal signs. It is often associated with exercise and caused by cardiac or respiratory disease.
      
   2. Narcolepsy is usually manifested as episodes of flaccid paralysis or loss of consciousness precipitated by excitement such as feeding, greeting, or play.
      
   3. Myasthenia gravis can cause stiffness, tremor, or weakness with normal consciousness. Clinical signs of myasthenia gravis may be induced by exercise. Some myopathies can cause similar clinical signs.
      
   4. Peripheral vestibular dysfunction is characterized by ataxia, head tilt, and abnormal nystagmus with no impairment of consciousness.
      
   5. Episodes of encephalopathy can cause disorientation, ataxia, blindness, and abnormal behavior. Hepatic encephalopathy is an example.
      
   6. Normal or abnormal movements during sleep consist of twitching, paddling, or vocalizing while the patient is asleep. Waking the animal can interrupt these, and there are no postictal signs.
      
   7. Behavior disorders, such as stereotypy, can cause specific patterns of bizarre behavior. These episodes can usually be interrupted, and there are no postictal signs. It should be kept in mind that behavioral disorders can occur in some dogs with idiopathic epilepsy as a component of the disorder or as a comorbid disease.
      
   8. Pain, especially neck pain, can cause episodes of muscle rigidity or stiffness and crying. Consciousness is not impaired.
   
   
2. History
   
   
   
   1. A detailed and accurate history is the cornerstone of diagnosis. A description of the seizures should be elicited from the client, including seizure frequency and duration, as well as whether there are any focal signs at the start of the seizure, such as turning the head to one side or any jerking of one limb. In some cases it helps if the client videotapes the episodes.
      
   2. Ask the client if the events occur at a certain time of day or in association with situations such as feeding or exercise.
      
   3. Also inquire about any known or suspected familial history of seizures, significant injuries or illnesses, vaccination status, diet, and potential exposure to toxins. Clients should be asked whether any interictal abnormalities—such as changes in behavior, gait, appetite, weight, or sleep habits—have been observed.
   
   
3. 
   

   Examination

   
   

   A thorough physical examination is important to detect signs of systemic illness that might suggest an underlying cause for the seizures. The clinician should perform a complete neurologic examination to detect any persistent neurologic deficits. Cerebral lesions often cause focal, relatively subtle deficits, such as delayed proprioceptive positioning on one side or blindness in one visual field. Be careful when interpreting the neurologic examination shortly after a seizure, because of the possibility of temporary postictal deficits. Repeating the examination at a later time may be necessary to determine whether any deficits persist.

   
   
4. Laboratory evaluation
   
   
   
   1. A CBC and serum chemistry profile is indicated to screen for metabolic causes of seizures.
      
   2. Serum bile acids are tested in young animals to identify PSS.
      
   3. Blood-lead determination should be performed in patients with possible exposure to lead, patients from areas with a high incidence of lead poisoning, and in animals less than 1 yr of age.
      
   4. Thyroid function is evaluated in adult dogs because hypothyroidism may complicate seizures, and phenobarbital can affect thyroid testing.
   
   
5. 
   

   Ancillary diagnostic testing

   
   

   Cerebrospinal fluid analysis and computed tomography (CT) or magnetic resonance (MR) imaging are indicated in dogs with interictal neurologic deficits, seizures refractory to drug therapy, or an onset of seizures at less than 1 yr or greater than 5 yrs of age. These tests are also indicated in any cat with seizures, because idiopathic epilepsy is less common in this species. Although patients with idiopathic epilepsy characteristically have normal MR imaging results, transient MRI brain lesions secondary to seizure activity are occasionally encountered. These lesions tend to be hyperintense on T2-weighted images, do not cause distortion of surrounding brain parenchyma, and tend to occur in several brain regions (e.g. pyriform, temporal, and frontal lobes and the hippocampus). EEG may be helpful in confirming epileptic activity when the veterinarian is unsure whether the events are seizures or nonepileptic episodes.

The goal of therapy is to reduce the frequency and severity of the seizures to a level that does not substantially compromise the quality of life for the pet and family while avoiding serious side effects. Though infrequently addressed in the veterinary literature, there are data that support the assertion that idiopathic epilepsy does have a negative impact on lifespan for dogs with the condition, as has been demonstrated for human epilepsy. In one large prospective study, the most common reason for euthanasia in dogs with epilepsy was inadequate seizure control. Serious adverse effects of phenobarbital and phenobarbital/bromide treatment were reported as an important contributing factor in the decision to euthanize in that study. There is some evidence that males may be more predisposed to idiopathic epilepsy than females. In one study, neutered males with idiopathic epilepsy had shorter survival times than intact males; in this same study, neutered males were more likely to experience cluster seizures, and a history of cluster seizures overall (regardless of gender) had a negative impact on survival time.

Therapy is started once the risks of further seizures outweigh the risks of treatment. The risks of seizures include the seizures themselves as well as the emotional effects on the family. The risks of therapy include drug side effects and the effort and expense of daily medication and monitoring.

Patients with a single seizure, provoked seizures, or isolated seizures separated by long periods of time generally do not require treatment. Treatment is indicated for patients with any episode of unprovoked status epilepticus (SE), multiple seizures in a short period of time, or an underlying, progressive disorder responsible for the seizures. Patients treated early in the course of epilepsy may have better long-term control of their seizures compared to those that have multiple seizures before treatment is started. Establishing an arbitrary number of “acceptable” seizures per month (e.g. one seizure per month) to apply to epileptics is not recommended by the authors for several reasons. One reason, already mentioned, is that untreated seizure activity may lead to increased seizure frequency over time. In addition, a dog or cat that has seizures once a month will not benefit from this approach. In the authors’ experience, clients often do not consider monthly seizure activity an acceptable endpoint of therapy. In one study evaluating owners’ perspectives concerning epileptic dogs treated with phenobarbital and/or bromide, a seizure frequency of less than one seizure every 3 mos was perceived as adequate control. A more realistic measure of success of an antiseizure drug is a reduction of seizure frequency by at least 50%, with minimal drug side effects. The client needs to understand the goals of therapy, potential side effects, and cost and effort associated with treatment and monitoring. They should appreciate the importance of the regular administration of medication and need to know what to do if a dose is missed (in general, the missed dose is given as soon as the mistake is recognized, then the next dose is given on schedule). Having the client keep a log of the time, date, and characteristics of each seizure and any side effects helps in the assessment of therapeutic efficacy.

Because of the variability in pharmacokinetics among patients, initial dose recommendations are a general guide only. Because of sensitivity to side effects and lack of prior metabolic induction, most new patients are started at the lower end of the dose range. Autoinduction of metabolism will often require an increase in dose in the weeks to months after starting therapy. On the other hand, patients with frequent or severe seizures are often best managed by starting at the higher end of the dose range or using a loading dose. Once the seizures are controlled, the dose may need to be adjusted downward to minimize side effects. Any drug used should be given an adequate chance to work and should not be discarded prematurely. Antiseizure drugs often must be administered for several weeks or longer before obtaining maximum effects. Furthermore, it may take several months or more to adequately evaluate seizure control in a patient that has seizures separated by long periods of time. A common cause of poor seizure control is failure to maximize the dose before discarding a particular drug. This may lead to the need to backtrack at a later date for a second, more aggressive trial. This can be difficult, however, because once a client is convinced a particular drug is ineffective they are often reluctant to agree to a second trial. The therapeutic monitoring of serum drug concentrations can be helpful in determining the optimal dose. Indications for therapeutic monitoring include:

1. When steady-state blood levels are reached after starting treatment, changing dose, or immediately after a loading dose.
   
2. When seizures are not controlled despite an apparently adequate dose. This helps determine the need for dose adjustment before the drug is changed or a second drug is added.
   
3. When signs of dose-related toxicity occur, to determine whether a dose decrease is necessary.
   
4. Every 6–12 mos to verify that changes in pharmacokinetics or compliance have not caused blood concentrations to drift out of the intended range.