Novel Approaches to Feline Epilepsy
ACVIM 2008
Michael Podell, MSc, DVM, DACVIM (Neurology)
Northbrook, IL, USA

Feline epilepsy is a prevalent problem in veterinary medicine, yet one in which there is a paucity of evidence-based scientific information available to guide clinicians in their diagnostic or treatment approaches. Many times information pertaining to canine epilepsy is transferred to the cat. But, as we all know, cats are not dogs. They have a more diverse genetic make-up, lead a more sheltered existence, can often live twice as long as dogs, and have a much different innate drug metabolism system. Moreover, cats often exhibit unusual seizure manifestations, not seen in any other species. Finally, if all of these differences were not enough disparity, there is a very limited amount of valid data on the antiepileptic drug (AED) treatment options available. Paradoxical to this lack of a clinical database, however, is the relatively large block of past decades of basic neuroscience information on the pathophysiology of epileptic seizures in cats. The purpose of this lecture is to guide clinicians through the maze of scattered basic and clinical data with the goal of formulating a more logical and rationale approach to the diagnosis and treatment of feline epilepsy.

Are These Events Really Seizures?

Of first and foremost importance in epilepsy treatment is to determine whether the described event is an epileptic seizure. One should be suspicious of an epileptic seizure for any paroxysmal onset event characterized by a change in behavior and/or motor movements of finite duration. The clinical features of epileptic seizures can be separated into four components.1,2 The prodrome is the time period prior to the onset of seizure activity. Owners report that they can "predict" the onset of their cat's seizures by behaviors exhibited during this time, such as increased anxiety related behaviors (attention-seeking, vocalizing), change in appetite, or increased hiding. The aura is the initial manifestation of a seizure. During this time period, animals can exhibit stereotypic sensory or motor behavior (e.g., pacing, licking), autonomic patterns (e.g., salivating, urinating, vomiting) or even unusual psychic events. The ictal period is the actual seizure event manifested by involuntary muscle tone or movement, and/or abnormal sensations or behavior lasting usually from seconds to minutes. Following is the post-ictal period, which can last from minutes to days. During this time, an animal can exhibit unusual behavior, disorientation, inappropriate bowel/bladder activity, excessive or depressed thirst and appetite, and/or actual neurologic deficits of weakness, blindness, and sensory and motor disturbances.

Seizure types are first classified as either being self-limiting (isolated) or clustered (2 or more within 24 hours) and/or continuous (status epilepticus). Within each category, seizures are divided into being either focal or generalized. Focal seizures are the manifestation of a discrete, epileptogenic event in the cerebral cortex.3 The focal nature of this seizure type is associated with a higher incidence of focal intracranial pathology.4 Focal seizures include elementary motor seizures, commonly seen as facial muscle twitching or more complex behavior patterns with impaired consciousness and/or bizarre behavioral activity. Previously termed complex partial or psychomotor seizures, these events are now classified as automatisms, or automotor seizures.5 Cats may show a variety of abnormal behaviors and/or motor signs, to include drooling, hippus, excessive vocalizations, and/or random, rapid running behaviors throughout the house ("running fits").

Generalized seizures are subdivided into tonic-clonic, clonic, myoclonic, atonic, or absence types. Generalized seizures originate from both cerebral hemispheres from the start, or progress secondarily from focal seizures.1 Unlike focal seizures, generalized seizures are not necessarily associated with focal cerebrocortical disease. Tonic-clonic seizures are the most common generalized seizure type described in cats. Myoclonic epileptic seizures consist of rhythmic limb and/or head jerk-like movements, often with preservation of consciousness. Absence seizures are characterized in people by an abrupt, short-lived impaired consciousness without change in muscle tone. Recurrence rate is often very high on a daily basis. Definitive diagnosis requires EEG confirmation of an epileptic seizure during an event. This seizure type has not been confirmed in the cat.

A multitude of non-epileptic events are present in cats that need to be distinguished from potential epileptic seizures. Video evaluation obtained by the owner can be extremely useful for this purpose. First, loss of consciousness without motor activity and a rapid recovery should be first evaluated as a syncopal event with appropriate evaluation of the cardiovascular system. Obsessive-compulsive behaviors may also mimic epileptic seizures. Cats may exhibit difficult to distract, stereotypic, repetitive licking behaviors of objects or themselves as an obsessive-compulsive behavior. Feline hyperesthesia syndrome is a poorly understood phenomenon characterized by paroxysmal cutaneous twitching over the epaxial muscles and extreme reaction to touch. Controversy exists on the etiology of this syndrome, with a primary myopathy suspected. Pain, which appears to be the primary component of this disease, may also be factor in a number of other acute onset signs of abnormal behavior in cats.

Why Is This Cat Seizuring?

Etiology

The differential diagnosis of epileptic seizures can be divided into four main etiologic categories: Idiopathic (IE), symptomatic (or secondary) (SE), probably symptomatic (PSE), and reactive epileptic seizures. Idiopathic epilepsy is diagnosed if no underlying cause for the seizure can be identified and is presumed to be of genetic origin. True IE is much less common in the cat due to the more diverse genetic background of most cats.6 Prospective larger population studies with complete neurodiagnostic testing, however, have not been reported to determine the true incidence of IE in cats. Similar to dogs, however, I have diagnosed the majority of idiopathic cases in younger cats between 1 through 7 years of age. Spontaneous temporal lobe epilepsy has been experimentally induced in the cat after amygdala kindling.7 Kittens (< 6 months age) were more susceptible to develop epilepsy than similarly kindled adult cats due to failure to sustain cortical postictal depression. More recent research on this model suggests that a critical period exists in kindled kittens for the onset of spontaneous temporal lobe epilepsy but that early detection and treatment results in a more favorable prognosis.8 These studies demonstrate that idiopathic temporal lobe epilepsy may spontaneously develop in cats whereby kindling occurs during a critical period of development.

Symptomatic epileptic seizures are the direct result of structural forebrain pathology. Developmental disorders are more common to occur in the kitten and may include hydrocephalus, focal cortical dysplasia or storage disorders. Encephalitic diseases are more common in the younger to middle-age cat (kitten through 7 years of age), and appears to be more prevalent in outdoor exposed pets. Infectious diseases include feline infectious peritonitis (FIP), toxoplasmosis, and cryptococcosis. All three of these agents may be restricted to the brain, without any systemic clinical signs. The presence of seizures with FIP does not correlate with degree of inflammation and typically carries a poor prognosis.9 Immune-mediated or non-FIP viral encephalitis and/or vasculitis has been reported in the cat that is often steroid-responsive. Cerebrovascular accidents (stroke) in cats typically present as per acute onset, lateralized cerebral signs of disorientation, circling, and hemiparesis. Both ischemic and hemorrhagic stroke can occur. The middle cerebral artery is a predilected location for ischemic stroke. Feline ischemic encephalopathy is an idiopathic entity thought to be secondary to arteriolar vasospasm. Thromboembolic disease may also occur from cardiovascular, parasitic, or other infectious diseases. Intracerebral hemorrhage is most likely to occur secondary to hypertension from underlying systemic causes, to include renal disease, hyperthyroidism, or coagulopathy. Primary cerebral neoplasm is most likely to occur in older cats (>10 years of age), with benign meningioma the most common tumor type followed by metastatic lymphoma. Toxicity is rare in cats, but should be considered with plant or drug exposures (e.g., metronidazole).

Probably symptomatic, or cryptogenic, epileptic seizures are believed to be due to an underlying unidentified brain disease that is not suspected to be of genetic origin. While this sounds somewhat of a nebulous disease category, it has particular implications when understanding why certain animals may be refractory to therapy. Examples of cases that may fit into this category would be prior head trauma in patients with normal imaging, post-encephalitic seizures developing at a later date, and undetected hypoxic or vascular events of the brain post-anesthesia or birth trauma. Over half of the cases described one prospective study were characterized with PSE, with all but one greater than 1 year of age.10

Reactive epileptic seizures are a reaction of the normal brain to transient systemic insult, toxic reaction, or physiologic stresses. Any age cat may be affected. Younger cats (< 1 year of age) should be assessed for a portosystemic shunt. These kittens often will exhibit other behavioral changes and/or stereotypic motor movements prior to developing epileptic seizures. Seizures have also been associated with hypoglycemia in kittens and insulinoma in older cats, sodium and calcium imbalance, thiamine deficiency, and advanced renal disease.

Historical Data

An important component in approaching a seizure case is acquiring a thorough and accurate history. Inquiries regarding the seizure event should include the description, time of day, duration, and post-ictal effects. The purpose is to establish overall frequency, seizure type, patterns of occurrence, relationship to daily activity (exercise, sleep, etc.), and severity of post-ictal effects. It is recommended to develop a charting technique to quantify seizure frequency and severity to aid in objective evaluation of therapeutic success.

Diagnostic Testing

The sequence of diagnostic testing for any animal with seizures should proceed from the least invasive to the more invasive (and expensive) diagnostic modality. The minimal required database includes a complete blood count, chemistry panel, urinalysis, blood pressure and thoracic radiographs. Basic screening should also include a retroviral screen for feline leukemia and feline immunodeficiency virus infection, total T4 level, and Toxoplasma gondii serum antibody testing. As the correlation of a positive serum FIP titer to the presence of an active central nervous system infection is low, this diagnostic test is not recommended. Additional testing is based upon the age, seizure type, seizure frequency, and neurologic examination findings. Cats under 1 year of age should also be evaluated for hepatic disease with a serum bile acid study and an abdominal ultrasound to evaluate for a porto-systemic shunt. Any cat with hypertension, hypoglycemia or renal disease should also undergo an abdominal ultrasound.

Advanced diagnostic testing is recommended for any cat that cannot be identified with an underlying cause on the initial diagnostic testing. The reasons for this recommendation are that cats have a lower prevalence of IE, age is not a known definitive predictor of intracranial disease, and an accurate diagnosis allows for a more definitive treatment approach. A MRI scan of the brain is recommended over a CT scan due to the ability to detect more subtle architectural brain abnormalities with greater accuracy. CT scanning is recommended, however, with head trauma or high suspicion for intracerebral hemorrhage due to the ability to detect bone and hemorrhage in a rapid, well-controlled anesthetic setting. Cerebrospinal fluid analysis (CSF) is an important test that helps to complete the diagnostic picture. My preference is to collect CSF only after a MRI brain scan, as the presence of an intracranial neoplasm with cerebral edema may place the patient at an undue risk of brain herniation with collection. CSF PCR analysis is recommended for infectious disease, to include FIP, Cryptococcus, or toxoplasmosis if clinically indicated.

How Should I Treat This Case?

First Line Treatment

As in the dog, phenobarbital (PB) is the recommended first line AED in the epileptic cat.11 The pharmacokinetic properties are similar to that in the dog, with a more prolonged elimination half-life range found (Table 1). However, the cat is more sensitive to the sedative effects, does eliminate the drug slower, and does not appear to develop metabolic tolerance from autoinduction of the p450 cytosolic liver enzymes. Thus, the initial therapeutic range is lower, typically between 10-20 µg/ml and dosing can be highly individualized. Most cats can be treated with 1-2 mg/kg/day, with once daily dosing initially at night. Subsequent increases to twice daily dosing can be instituted as needed. Idiosyncratic reactions include blood dyscrasias, dermatitis, and persistent, unusual behavior disturbances. Predictable, dose-dependent adverse effects include polydipsia, polyuria, polyphagia. While cats are relatively resistant to the hepatotoxic effects of PB, careful monitoring of liver function is necessary with serum levels above 30 mg/dl. Trough serum drug concentrations are recommended at 14, 60, 90 and 180 days or if 3 or more seizures occur. Overall, the PB can be used successfully in the cat with proper monitoring.

What Can I Do When The Seizures Continue to Occur?

Multi-drug therapy is reserved for those cases in which seizures still occur at frequency of 4 or more per 12 month period and where phenobarbital therapy has been optimized to a blood level of 25 mg/dl or greater. The goal is to add a complementary medication without increasing risk of adverse effects (Table 1). Benzodiazepines: Diazepam is recommended for cats refractory to PB as an alternative, but not concomitant, AED due to risk of enhanced hepatotoxicity. The dose range is 0.5 to 2.0 mg/kg divided two to three times per day. Gradual adaptation is necessary to prevent excess sedation. Diazepam is metabolized to the active metabolites, nordiazepam and oxazepam. Potential complications include similar behavior problems as describe for PB therapy, physical dependence and possible withdrawal seizure activity, and acute fulminant hepatic necrosis. The latter problem is an idiosyncratic reaction that can be fatal.12 All cats treated with diazepam should have liver enzymes monitored within the first week of therapy and again within one month. The drug should be discontinued if any liver enzyme elevation is observed. Clonazepam is my preferred alternative to diazepam in the cat, as it does not undergo hepatic microsomal metabolism, has a more prolonged elimination half-live, and therefore, may not produce an idiosyncratic hepatic reaction. The recommended starting dose is 0.5 mg once to twice daily. Clorazepate is another long-acting benzodiazepine that the author has used successfully, although the precise pharmacokinetic properties of this drug are not well-elucidated in the cat. The recommended dose range is 3.75-7.5 mg PO QD to BID. Similar precautions are necessary as described with diazepam.

Bromide

Bromide therapy in cats is not recommended as a standard therapy due to the relatively high prevalence of adverse respiratory problems.13 Cats can develop cough and more severe respiratory signs suggestive of an allergic asthmatic disease.

Gabapentin

Gabapentin has the advantage of exclusive renal excretion, but appears to have limited anticonvulsant properties in cats. Cats may exhibit increased sedation and will benefit by a gradual increment in dosing over 1 to 2 weeks. I recommend starting at 5-10 mg/kg daily for 3-5 days, then increase to q 12 hours. Further increases are dependent upon response to therapy. The manufacturer solution is not recommended due to the relatively high xylitol concentration and risk of hypoglycemia.

Levetiracetam (Keppra®)

Levetiracetam is the S-enantiomer of the ethyl analogue of piracetam that binds to SV2A, a synaptic vesicle protein, which correlates to anticonvulsant potency.14 The drug is well-absorbed, has a relatively short elimination half-life of 4-8 hours (in dogs), is available as parenteral formulation, and has minimal adverse effects. No pharmacokinetic data could be found for cats. Levetiracetam is my first choice as an add-on medication to phenobarbital, especially with symptomatic epilepsy. Gradual adaptation in dosing is recommended. My experience is that cats refractory to phenobarbital therapy may require a peak serum concentration above 30 mcg/ml for optimal efficacy.

Topiramate (Topamax®)

Topiramate is a sulphamate-substituted monosaccharide with a mechanism of action of blockade of seizure spread by rapidly potentiated GABA activity in the brain. Topiramate was an effective anticonvulsant in amygdala kindled cats,15 and suppressed both regional cortical blood flow and depolarization.16 While no pharmacokinetic data is available for cats, the elimination half-life is short in the dog (2-4 hours), but may exhibit prolonged pharmacodynamic activity in the brain due to high affinity receptor binding. In my experience, this medication has been most useful to treat automatisms (especially running fits) and focal seizure activity. Gradual adaptation in dosing is recommended. Inappetance is a major adverse effect with higher doses.

Zonisamide (Zonegran®)

Zonisamide is a substituted 1,2-benzisoxazole derivative that works by both blocking the propagation of epileptic discharges and suppressing focal epileptogenic activity.17 In dogs, zonisamide is well-absorbed, has a relatively long-half life, and high protein-binding affinity. Zonisamide is hepatic metabolized, and thus is influenced by concurrent administration of other similarly metabolized drugs. Broad-spectrum antiepileptic activity has been reported against a variety of seizure types, with particular improvement in the treatment of adult myoclonus epilepsy. Major adverse effects in people include a higher incidence of renal calculi formation, sedation and gastrointestinal disorders. Information is still being obtained on the potential use in cats.

Unraveling the Mystery: Can This Condition be an Autoimmune Disease?

An interesting parallel between people with temporal lobe epilepsy and epileptic cats exists: Both populations exhibit adult-onset complex partial seizure activity, may have selective hippocampal changes on MRI scanning indicative of cytotoxicity, are more likely to develop drug-resistant epilepsy, and have identifiable histopathologic necrosis and/or sclerosis in the hippocampus and related pathways.18,19 Recently, over 50% of the patients evaluated with temporal lobe epilepsy and hippocampal sclerosis were found to have signs consistent with an autoimmune process with autoantibody directed against neuronal voltage-gated potassium channels.19 This condition of limbic encephalitis does not correlate with inflammatory reaction in the CSF.20 Immunosuppressant therapy can be curative without the need for further AED therapy.21 Could a subset of feline epilepsy be similar to limbic encephalitis? Is the autoimmune reaction a cause or effect of the seizure events? Further information will be provided to these intriguing questions.

Table 1. Summary of the antiepileptic drugs available to treat epilepsy in cats.

Antiepileptic drug

T 1/2 (hr)

Therapeutic range

Initial dose

Potential adverse effects

Phenobarbital

34-43

10-30 mg/dl

1-2 mg/kg/day (q12-24 hr)

Sedation, hepato/ blood toxicity

Diazepam

15-20

500-700 ng/ml (nordiazepam)

5-10 mg q 8-12 hrs

Acute hepatic necrosis, sedation

Clonazepam

Unknown

500-700 ng/ml (nordiazepam)

0.5 mg q 12-24 hr

Acute hepatic necrosis, sedation

Gabapentin

Unknown

Unknown

5-10 mg/kg q 8-12 hr

Sedation, ataxia

Topiramate

Unknown

Unknown

12.5-25 mg q 8-12 hr

Sedation, inappetance,

Levetiracetam

Unknown

10-50 mcg/ml

10-20 mg/kg q 8-12 hr

Sedation

References

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2.  Podell M. (1996): Vet Clinics of North America--Small Animal Pract 26, 779-809.;

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8.  Shouse MN, et al. (2004) Brain Res. 1027:126-43.;

9.  Timman D, et al (2007). J Fel Med Surg Epub;

10. Barnes H, et al (2004) J Am Vet Med Assoc 225:1723-26.;

11. Parent JM, Quesnel AD. (1996). Vet Clinics of North America Small Animal Pract 26, 811-25;

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14. Kaminski RM, et al (2007) Neuropharm. Epub.;

15. Nakamura F, et al. (1993): Jpn J Psych: 47:394-5.;

16. Ackerman S, Goadsby PJ. (2005) Neuroreport 22:1383-1387.;

17. Ito T, et l. (1980): Arzneimittel-Forschung 30, 603-609;

18. Fatzer R, et al (200) J Vet Int Med 14:100-4.;

19. Bien CG, et al. (2007) Neurol. 69:1236-44.;

20. Jarius S, et al (2007) J Neuro Sci, Epub;

21. Tuzun E, Dalmau J. (2007) Neurologist 13:261-71.

Speaker Information
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Michael Podell, MSc, DVM, DACVIM (Neurology)
Animal Emergency & Referral Center
Northbrook, IL


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