EPILEPTIC SEIZURES IN THE CAT Gualtiero Gandini, DVM, Dipl. ECVN; Dipartimento di Scienze Mediche Veterinarie - Università di Bologna Via Tolara di Sopra, 50 – 40064 – Ozzano Emilia (BO) Email: [email protected]

Epileptic seizures are an important part of feline neurology because, although less represented than in the dog, they represent one of the frequent causes of referral in feline neurology. Although there is growing literature about it, much of what is known in terms of aetiology, diagnosis and treatment is extrapolated from experiences in the dog. This should be carefully remembered, to avoid wrong choices, especially regarding therapeutic treatment. 1 - DEFINITIONS; CLASSIFICATION OF EPILEPSY AND EPILEPTIC SEIZURES Epilepsy and epileptic seizures are not synonymous. The term epileptic seizure defines ‘‘a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” The term epilepsy) defines “a disease of the brain characterized by an enduring predisposition to generate epileptic seizures”. This definition is usually practically applied as having at least two unprovoked epileptic seizures >24 h apart. In veterinary medicine, the classification of epileptic seizures follows different criteria. Particularly used are those that consider:  the frequency  the aetiology  the modality of the clinical expression Classification according to the frequency of epileptic seizures - Epileptic seizures are classified as single seizures if the interval between a crisis and the next is greater than 24 hours, cluster seizures if the interval between two subsequent crises is less than 24 hours. Status epilepticus is when the ictal phase of an epileptic seizures lasts for more than five minutes or when there is no complete recovery of consciousness between one seizure and the other. This situation certainly represents the most serious occurrence for the life of the animal and must be treated vigorously and in the shortest possible time. Classification according to the aetiology of epileptic seizures – Up to the recent past, in veterinary medicine subdivision included idiopathic (or primary) epilepsy, secondary (or symptomatic) epilepsy, and cryptogenic epilepsy. According to the most recent classification of the International Veterinary Epilepsy Task Force (IVETF), epilepsy in veterinary medicine is classified as Idiopathic epilepsy, Structural epilepsy and Epilepsy of unknown cause. Idiopathic epilepsy (idiopathic defined as a disease in its own right, “per se”) should be seen as the overarching and bridging term, which can be sub-classified into three sub-groups reflecting the advancements in the field: 1. Idiopathic epilepsy (genetic epilepsy) - a causative gene for epilepsy has been identified/confirmed genetic background 2. Idiopathic epilepsy (suspected genetic epilepsy) – a genetic influence supported by a high breed prevalence (>2 %), genealogical analysis and/or familial accumulation of epileptic individuals 3. Idiopathic epilepsy (epilepsy of unknown cause) - epilepsy in which the nature of the underlying cause is as yet unknown and with no indication of structural epilepsy. Idiopathic Epilepsy does not recognize structural or metabolic alterations that can justify the occurrence of seizures. The cat affected by idiopathic epilepsy is a patient who, except for the occurrence of crises, is absolutely normal. Structural epilepsy is characterized by epileptic seizures which are provoked by intracranial/cerebral pathology including vascular, inflammatory/infectious, traumatic, anomalous/developmental, neoplastic and degenerative diseases confirmed by diagnostic imaging, cerebrospinal fluid examination, DNA testing or post mortem findings. Reactive seizures refer to extracranial metabolic dysfunctions that cause a cerebral perturbation.

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Classification according to the clinical modality of expression of the epileptic seizures – According to the most recent classification of the International Veterinary Epilepsy Task Force (IVETF), seizures are classified as focal seizures, generalized seizures and focal seizures evolving to become generalized. According to the modern definition, a focal seizure is " An epileptic seizure with clinical signs indicating activity which starts in a localised area in the brain ". These seizures will present with focal motor (e.g. contractions of a lip or eyelid), autonomic (e.g. dilated pupils, hypersalivation or vomiting) or behavioural (e.g. anxiousness, restlessness, unexplainable fear reactions or abnormal attention seeking to the owner) signs alone or in combination. The new classification tends to abolishes the rigid distinction between the former simple focal seizures and complex focal seizures. A generalized seizure is “an epileptic seizure with clinical signs indicating activity involving both cerebral hemispheres from the start.” In dogs and cats generalized epileptic seizures predominantly present as tonic, clonic or tonic-clonic epileptic seizures. As a rule, the animal will lose consciousness during convulsive epileptic seizures. Salivation, urination and/or defecation may often also occur. A focal seizure evolving to become generalized is “an epileptic seizure which starts in a localized area in the brain and spreads subsequently to involve both hemispheres”. In dogs and cats, the seizure starts with localized motor, autonomic and/or behavioural signs rapidly followed by convulsions. Salivation, urination and/or defecation often also occur during the episode. In the dog, a generalized tonic-clonic convulsive crisis is usually divided into three phases: the prodromal phase, the ictal phase, and the post-ictal phase. In the cat, the presence of the first phase is very controversial, so here we are just describing the ictal and post-ictal phases. The ictal phase is the proper seizure phase, which usually lasts for a few dozen seconds up to 3-4 minutes. The ictal phase has been well described in the dog, where the animal can show initially a phase of rigidity followed by the fall on one side with by loss of consciousness and hypertonicity of all the limbs and, subsequently, generalized tonic-clonic contractions. There may be coexisting vegetative signs such as hypersalivation, defecation, and urine loss. In the cat, the ictal phase of the crisis can be particularly violent. The postictal phase may be very short or last for several hours to days. Typically, the animal is disoriented, may have behavioural abnormalities such as repetitive vocalisation, compulsive locomotion failing to avoid obstacles, be tired, ataxic, hungry or thirsty, express a need to urinate, defecate or appear exhausted and sleep for a longer period of time. Postictal blindness or aggression may also be present. Often the owner understands that his own animal had an epileptic seizure because he discovers the post-ictal phase. The veterinarian should never draw conclusions about the results of the neurological examination before 24 to 48 hours have passed since an epileptic seizure, because the encountered deficits might be attributable to reversible dysfunctions typical of the post-ictal phase. Physiopathogenesis of the epileptic seizure - In the mechanism of developing an epileptic seizure, the imbalance between the excitation and inhibition mechanisms at the level of the brain neurons is of crucial importance. The most important feature of all epileptic seizures is the persistent increase in neuronal excitability. In the normal brain, there are sophisticated mechanisms serving to prevent synchronous and excessive depolarization of adjacent neurons. The excitation of some neurons automatically activates inhibitory neuronal circuits that have the purpose of creating an "inhibitory surround" of hyperpolarized cells to prevent exaggerated diffusion of stimuli that, uninterrupted, could lead to a hypersynchronous and paroxysmal hyperexcitation which is at the basis of the epileptic seizure. In the epileptic brain, for various reasons, the impossibility of blocking excessive neuronal excitation occurs. Hence, first the formation of an aggregate of neurons in a hyperexcitative shift and, subsequently, the recruitment of other adjacent neurons and the development of an epileptogenic focus that can spread, through intra- and inter-ephemeral connections, to other areas of the brain. If a critical number of neurons are recruited, the epileptic seizure occurs. Epileptic seizure is still considered by many authors as the result of an inability of inhibitory systems to perform their modulatory function on the cerebral activity.

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2 – CLINICAL APPROACH TO THE EPILEPTIC CAT The clinical approach to a cat referred because, according to the owner, has suffered from a "seizure", requires considerable clinical expertise as very different diseases can produce the complained symptomatology. It is therefore essential to follow rigorous clinical and diagnostic procedures to demonstrate, for subsequent steps, the real involvement of the Central Nervous System, whether it is a primary episode or rather secondary to other extra- and intracranial diseases. An appropriate diagnostic protocol has to be performed to allow (whenever possible) an etiological diagnosis. Signalment and anamnesis - In the epileptic patient, the accurate collection of anamnestic information is of crucial importance, as it is extremely rare for the veterinarian to see directly the epileptic seizure. To furtherly complicate everything, a significant percentage of cats taken to visit for an epileptic seizure, are totally normal at the clinical examination. It is therefore crucial for the development of the diagnostic procedure to understand whether the signs observed by the owner are really those related to an epileptic seizure or represent an episode related to dysfunction of other systems, first of all the cardiovascular system. Signalament should not be overlooked because, although seizures can occur at any time in the life of the animal, there are important correlations between the age, breed and the nature of the episodes. In the cat, Idiopathic Epilepsy occurs most frequently between one and five years of age. Conversely, younger subjects are mainly exposed to contagious infectious diseases or congenital anomalies. Any adult / elderly animal who is brought to the visit for the onset of seizures should be considered as potentially affected by an intracranial, primary or secondary neoplasm. The episode must be thoroughly investigated, asking first in what context has happened, whether with the cat at rest or during physical activity. Syncope (transitional hypoxia of the cerebral tissue) may arise due to the inability of the cardiovascular system to support the oxygen demand arising from physical activity. Especially during the first seizures, it is extremely unlikely that the owner was able to notice important details. It is therefore essential to try to guide the history with appropriate questions to check whether the animal had a start of focal signs or immediately generalized. It will also be important to ask whether the typical phenomena of seizures have occurred, in particular if hypersalivation, urine and/or stool loss, mydriasis, tooth bristle, generalized tremors, tonic-clonic and/or pedal movements. All of these signs are unlikely for pathologies that produce syncopal crises, while they are more typical of epileptic seizures. Then, it is important to ask how the cat recovered from the event, i.e. whether there was a post-ictal phase, characterized by temporary and reversible neurological dysfunctions attributable to a kind of "neuronal fatigue" after the convulsive episode. At this point, it is recommended to find out if there have been similar episodes in the past or not. If so, it is important to know whether the clinical manifestations of these episodes were similar to what was just described for the last crisis, that is, whether the “seizures” have been presented with a particular sequence. This is of great help to the clinician to confirm a suspect of epilepsy. It is extremely important that the owner gives information on the condition of the cat during the interictal phase, that is, the interval between a crisis and the other (excluding the immediate post-ictal phase). The finding of change of behaviour (hyperactivity, unjustified aggression, lack of attention to environmental stimuli), loss of cognitive functions (typically, not recognizing known people or presenting inappropriate urination), phenomena of disorientation and compulsive gait are signs indicating a disease causing dysfunction of the prosencephalon functions and, hence, of structural epilepsy. Finally, it may also be of great help for future management, that the owner keeps a record of epileptic seizures, describing in great detail the types of seizures, the onset time, together with any ongoing therapy. Obviously, the family history (in the search for relatives affected by similar signs), vaccination and environment should not be forgotten. The physical and neurological examination - Epileptic seizure or Syncope? A complete physical examination, including neurological, cardiologic and respiratory examination should be performed to clarify whether the crisis was due to a neurological or other system disorder. Confirmation of a syncope must be obtained through the thorough execution of a diagnostic work-up aimed to document the presence of problems with the heart or respiratory system. Specifically, electrocardiography, chest x-ray and two-dimensional, M-mode and Doppler echocardiography must be considered. 3

Epilepsy: idiopathic (primary) or structural (secondary)? After confirmation of the epileptic nature of the seizure, it is of crucial prognostic and therapeutic importance establish if the seizure was the consequence of an idiopathic or structural epilepsy or if the cat suffered from reactive seizures. For this goal, the first step is represented by the neurological examination. It is a good rule to do not examine a cat in the period immediately subsequent an epileptic seizure, because in the post-ictal phase temporary deficits that could mislead the diagnosis can be detected. As a rule, primary epilepsy does not show interictal neurological abnormalities, whereas they may be observed in case of secondary epilepsy. It is therefore advisable to draw definitive conclusions on the results of the examination of an epileptic patient only when has been visited at least 48 hours after the last seizure. On the neurological examination, special attention should be paid to the presence of forebrain signs, as epileptic seizures always result from cortical (primary or secondary) dysfunction. The signs of forebrain dysfunction often produce less evident signs than those found after injuries of other regions of the SNC. Therefore, it is extremely important to give relevance to apparently mild dysfunctions. The forebrain functions are related to the processing of external stimuli and the production of responses that use associative processes (e.g. attributing meaning to a particular behaviour or gesture), emotional reactions and cognitive functions. Forebrain lesions, as outlined above, will result in the loss of the ability to relate to the surrounding environment, abnormal and/or exaggerated behaviours, and the loss of cognitive functions. The most common signs of forebrain dysfunction include disorientation, compulsive and afinalistic gait (e.g. circling), head pressing. The circling can be a tight turn on itself. this finding shows the presence of a forebrain lateralized focal lesion ipsilateral to the direction of movement (Figure 1)

A B

D C

Figure 1: (A  D) cat with right compulsive circling associated to a forebrain ipsilateral lesion.

Forebrain lesions generally do not produce major mentation abnormalities, such as stupor and coma, much more characteristic of a brain stem injury. Gait changes are related to compulsion rather than to a direct effect on the circuits of the voluntary movement. Typically, in the presence of a forebrain syndrome, at a fairly normal gait may be associated severe deficiency of conscious proprioception, consisting mainly in the delay or absence of the response to the proprioceptive positioning test. The examination of the cranial nerves does not normally show alterations besides a possible deficiency in the menace reaction and cotton ball tests.

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Ultimately, it can be stated that a patient suffering from idiopathic epilepsy has no neurological abnormalities in the interictal period. Conversely, the cat showing neurological deficits in the interictal phase and on the neurological examination is affected by structural epilepsy or reactive seizures. Once more, it should be remembered that many diseases that primarily affect the forebrain (particularly the tumours) do not produce clear signs, so the clinician must be ready to give relevance even to the sole finding of a decreased menace reaction. Finally, it is not excluded that structural epilepsy may occur with a normal neurological examination.

3 – DIFFERENTIAL DIAGNOSES (VITAMIN D) The results of the neurological examination should be related to the signalament data and the anamnestic information to formulate the list of hypotheses on the clinical differential diagnosis. On the basis of this list, the most appropriate diagnosis work-up will be set. Signalament data should be taken seriously when formulating diagnostic-differential hypotheses. If the first seizure has occurred before one year of age or, on the contrary, in animals over 5 years of age, the possibility of secondary epilepsy must be considered seriously. In particular, in adult/elderly animals, epileptic seizures are one of the first and most important signs of cerebral neoplasia. The presence of lateral or focal signs may represent a structural disease, such as a neoplasia, abscess, granuloma or vascular disease. Instead, multifocal signs should focalize the clinician to suspect an inflammatory or infectious disease. According to the VITAMIN D scheme, apart from I (Idiopathic Epilepsy) and M (metabolic disorders), all the other voices of the VITAMIN D indicate structural disorders of the nervous system responsible for structural epilepsy. Some diseases are common to dogs and cats, while others affect a specific species. Table 1 shows a list of the various diseases that can cause epileptic seizures in the cat.

V Vascular Ischemic encephalopathy, polycitemia, hemorrhage

FIP criptococcosis

rabies non suppurative meningoencephalitis I Inflammatory/infectious ie toxoplasmosis aberrant parasites bacterial meningoencephalitis

T Trauma recent, remote

A Anomalous Hydrocephalus, lissencephalus

Hypoglicemia toxic: Pb, OP, etilene glicol, otehrs

Hypocalcemia electrolyte imbalance M Metabolic Hepatic encephalopathy Thiamin deficiency Uremic encephalopathy

I Idiopathic idiopathic epilepsy

meningioma choroid plexus papilloma/carcinoma N Neoplastic glioma limphoma ependimoma metastases of extra-neural tumours D Degenerative Storage diseases

Table 1: Common causes of epileptic seizures in the cat, according to the acronym VITAMIN D. (OP=organophosphates; Pb=lead) – modiffied from Bernardini M: Neurologia del cane e del gatto 2010, Poletto Editore.

4 - DIAGNOSTIC WORK-UP - The schema of the diagnostic work-up of the seizuring patient is based, at first, on the blood tests to exclude any metabolic dysfunction that may be the basis of the reactive seizures. Subsequently, to detect structural lesions of the nervous parenchyma, investigation shall consider Advanced Diagnostic Imaging (CT or MRI) and, possibly, the examination of cerebrospinal fluid. 5

In addition to the cell blood count (CBC), haematobiochemical profile and urinalysis, the diagnosis of metabolic diseases may require specific hematobiochemical tests such as, for example, bile acids and ammonia. Likewise, in front of the suspicion of an infectious etiology, it may be suggested to proceed with appropriate serological or PCR investigations. Even in the presence of a strong suspicion of a forebrain structural lesion, CBC and haematobiochemical profile are normally required because, although almost never altered by intracranial lesion, they provide necessary information to the anesthetist in prevision of CT or MRI examination and the cerebrospinal fluid tap. The advanced diagnostic imaging modality providing the best information on nervous parenchyma is the Magnetic Resonance Imaging (MRI) exam, which can also provide good visualization of CNS inflammatory lesions. Computed Tomography [CT]) is a second choice acceptable for the lower ability to detect brain structural disorders. The MRI sequences most frequently used in the examination of brain structures include pre- and post-contrast T1 weighted (T1-W) sequences, T2 -weighed (T2-W), and Flair (Attenuation Inversion Recovery). For the purpose of this abstract, the MRI detailed alterations of the various pathologies causing seizures (for which the reader is referred to specific texts) will not be detailed here. The T1-weighed sequences provide the better anatomic detail. In these sequences, the adipose tissue appears hyperintense (white) and fluids hypointense (black). The soft tissues have a characteristic intermediate intensity. After administration of paramagnetic contrast medium, some normal tissues (e.g. hypophysis) or pathologies (e.g. some neoplasms) appear more hyperintense. T2-weighed sequences have a minor anatomical detail, but are very sensitive in detecting pathologies in tissues. In T2-W images fluid and fluid-rich tissues appear to be extremely hyperintense (e.g. edema, inflammation, neoplasia). Fat intensity is variable, and milder when compared to that in T1-W images. FLAIR sequences are used in comparison with T2-W images to evaluate the characteristics of hyperintense lesions in T2, because in the FLAIR the intensity of pure fluids (such as CSF) is suppressed (thus becoming hypointense) while tissue lesions remain hyperintense. This has enormous clinical relevance because permits to define more in detail the type of lesions highlighted. The principles leading to the production of an image using Computed Tomography are similar to those of conventional radiology, since in both cases X-rays are used to create a sort of "attenuation map" of the examined patient. Cerebrospinal fluid analysis is crucial if an inflammatory etiology is suspected. The CSF exam evaluates the protein concentration and the cellular content of the liquor. This exam often confirms inflammatory / infectious disease, but rarely is able to provide specific information. The cellular component of the cerebrospinal fluid is considered normal up to a number of 5 cells per microliter. Quantitative cytological alteration may be characterized by an increase in the number of cells, called pleocytosis, ranging from a few units to several hundred cells. Pleocytosis is classified as mild (<50 cells / μl), moderate (<200 cells / μl) and severe (> 200 cells/μl). The pleocytosis can also be distinguished in neutrophilic, if there is a predominance of neutrophilic polymorphonucleated cells, lymphocytic, if most of the cells are lymphocytes, eosinophilic, in the case of eosinophilic polymorphonucleated cells and mixed, if characterized by the presence of different nucleated cell types (lymphocytes, monocytes, macrophages, neutrophils, some eosinophils and plasma cells). Since CSF tap may be contraindicated in the presence of intracranial pressure increase, this procedure, differently from the past, is performed after CT or MRI. However, it is worth pointing out the great utility of comparing information provided by CT or MRI with those obtained by examining the CSF. In veterinary medicine, electroencephalography, a procedure of major importance in the diagnosis of epilepsy in the human species, is very limited for technical-logistic reasons and is performed with the patient in general anesthesia (and hence for necessarily shorter periods when compared to humans) only in a few specialized centers. Finally, it should not be forgotten that, if a structural epilepsy is suspected in the elderly patient, a complete set of chest radiographs and eventually abdominal ultrasound should be performed before advanced diagnostic imaging.

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5 - TREATMENT OF EPILEPTIC SEIZURES In this abstract, therapy of epileptic seizures is discussed by referring to the cat affected by idiopathic epilepsy. Many of the claims made for the treatment of idiopathic epilepsy are transferable to the therapy of the cat affected by secondary epilepsy, at least for the management of epileptic seizures. Goals – Despite the new IVETF definition of therapeutic success, the practical goal of the therapy consists in achieving the reduction of frequency and severity of epileptic seizures and, in a minor percentage of cases, their disappearance. This goal has to be very clearly explained to the owner since the very beginning of the treatment, considering that her/his normal expectation is the total disappearance of the seizures. Unfortunately, it is usually impossible to maintain such expectation and, if not properly trained, the owner may be disappointed and distrust the vet. The vast majority of therapeutic failure originates from an inadequate communication between owner and vet, as shown by the fact that many owners decide independently to modify, taper or change the treatment. When starting the treatment? – “The earliest the treatment is started, the best it is”. To date there are no scientific data supporting this common statement. IE acts with a wide variety of phenotypic patterns and it is impossible to produce fixed specific rules in terms of drugs, dosages and treatment modalities. The general guidelines for the treatment of IE suggest starting the antiepileptic treatment after confirmation of the recurrence of the crises and, obviously, after the exclusion of other causes of epilepsy. There is general agreement to identify the frequency of two seizures in six months as the threshold for the initiation of treatment, which, on the contrary, has to be immediate in a cat suffering from cluster seizures or "status epilepticus". Choice of the antiepileptic drug (AED) and drug requisites – Generally speaking, AEDs should be able to block the epileptic seizures, stopping the abnormal depolarization of the neurons, with minimal side effects. IE therapy is indeed a symptomatic treatment, as it is not possible to act on the primary cause of the seizures. The "ideal drug" should be: • Able to penetrate the blood-brain barrier rapidly and in adequate amounts • Able to prevent and / or neutralize the paroxysmal depolarizing events in the brain • Easy to be administered, ideally no more than two times per day • Devoid of relevant side effects in the short and long term • Devoid of acute toxicity and, especially, chronic • Inexpensive. Unfortunately, there are no drugs matching all these requisites. Traditionally, it was suggested to start preferring monotherapy to combination of drugs. Currently, there are not strict criteria and what drives the choice of possible drug combinations is the coupling of good seizure control combined with the tolerability of the drug for that specific patient. The treatment of a naïve cat usually starts with the lower recommended dosages. Therapy of cats presented with clusters or very aggressive seizures may require to start with higher doses (including a loading dose) and subsequent adjustment of therapy. A mandatory criterion is that of "saving drugs." AED treatment must often be maintained throughout the whole life of the patient and can be less effective over time, both for an increased body's ability to eliminate the drugs and an inherent refractoriness of the disease during time. These issues should lead the veterinarian to be extremely cautious in "burning" the few therapeutic options available. Consequently, before changing an AED because "not effective", the vet should have acted in an extremely rigorous and consequential way, respecting doses and routes of administration.

ANTIEPILEPTIC DRUGS In table 1 are listed the antiepileptic drugs (AEDs) divided by generations depending on the date of marketing. The drugs reported in table 1, with the only exception of Imepitoin, are molecules designed for the treatment of epilepsy in humans and, in some cases, subsequently transferred to veterinary medicine. In bold blue are the most commonly used drugs in veterinary practice for cats and in bold black the ones with veterinary scientific reports on clinical or pharmacological properties. The other drugs in the table are not used in cats and dogs due to toxicity or pharmacokinetics properties that make them unsuitable. Finally, for many molecules of new generation, there are still no studies on the dog and cat. 7

Table 1: Antiepileptic drugs listed according to the generation (year of delivery on the market) (modified by De Risio, 2014) OLD GENERATION NEW GENERATION

First generation Second generation Third generation “Next” generation (1957-1988) (1989 - 2007) (2008- 2009) (2010- 2013) Bromide Felbamate Lacosamide Imepitoin Phenobarbital Gabapentin Rufinamide Brivaracetam Benzodiazepines Zonisamide Fluorfelbamate Primidone Levetiracetam Tiagabine Phenytoin Pregabalin Losigamone Carbamazepin Topiramate Retigabine Valproate Lamotrigine Remacemide Oxcarbazepine Seletracetam Vigabatrin

The two most commonly used drugs in the treatment of feline IE belong to the first generation: Phenobarbital (PB), a barbiturate described for the first time in 1912, and Diazepam. Among the new generation AEDs, there is some experience of the use of Levetiracetam in the cat. Imepitoin is a recently introduced drug (2013), targeted initially for the dog with the ambitious aim of replacing the phenobarbital as drug of choice for the canine IE treatment. Currently, a very recent paper has demonstrated Imepitoin safety. The characteristics of the main AEDs currently used in the treatment of feline epilepsy will be briefly discussed below, referring to specific texts for a more extensive discussion of their pharmacological properties and clinical use. Phenobarbital - Phenobarbital belongs to the class of barbiturates and, since its discovery over a hundred years ago, is at the forefront in the treatment of epilepsy in humans and domestic animals. The PB mechanism of action is quite well known and results in hyperpolarization of the neuronal membrane, which is obtained through several mechanisms. PB enhances the direct inhibitory effect of gamma-aminobutyric acid (GABA) acting on the same receptor complex which opens chloride channels. Other proposed mechanisms include interaction with glutamate receptors to decrease neuronal excitatory post synaptic currents and inhibition of voltage-gated calcium channels resulting in decreased calcium influx into neurons. Phenobarbital is a lipid-soluble drug well absorbed after oral administration, reaching a peak blood 4-6 hours after oral administration. PB circulates partially bound to plasma proteins (about 45% in the dog) and is substantially metabolized in the liver. In the dog, PB has a significant ability to induce the production of liver enzymes responsible for its catabolism. In the cat it seems teat PB treatment does not significantly increases hepatic enzymes activity. PB in cats has a half-life ranging between 34 and 50 hours. The "steady state" is reached after 10-15 days of treatment. The starting dosage in the cat is 2 mg/Kg administered orally every twelve hours. In most cases, this dosage is generally sufficient for a good control of seizures, at least for the first year of therapy. Chronic administration of PB produces side effects that are generally well tolerated by patients if the phenobarbitalemia remains in the therapeutic range (for most laboratories: 15-30μg/ml). The most common "chronic" side effects associated with the administration of PB are represented by polyphagia (and the consequent weight increase), polyuria and polydipsia. Phenobarbital is toxic in animals with liver disease. The clinical signs of liver toxicity include anorexia, ataxia, sedation, jaundice and ascites. In general,

8 with plasma PB levels below 35μg/ml, signs of significant liver disease in healthy animals are not observed. Cat seems to tolerate PB quite well and, to date, there are no reports of liver toxicity in the feline species. Nevertheless, for the abovementioned reasons, it’s wise to test the liver function every six months. Since phenobarbital induces liver enzymes, blood tests should not only include assessment of ALP and ALT, which will obviously be increased without significance of liver disease, but also that of γGT, pre- and post-prandial bile acids and albumin. Acute toxicity and idiosynchratic reactions, albeit rare, are similar to dogs. Although the information in the literature regarding the cat is still relatively poor, the use of Bromide in the feline species has recorded some serious cases of bronchospasm and, for this reason, bromide is not recommended for the use in this species. Diazepam is still used in the management of cat's epilepsy. However, cases of severe hepatic necrosis associated with the use of diazepam have been reported. Many authors continue to prefer the phenobarbital for the cat and do not recommend the use of diazepam, in the long-term management of cat's epilepsy. Diazepam is administered per os, at a dosage ranging from 0.5 to 2 mg / kg divided into two doses. Acute liver necrosis, documented in the feline species following diazepam administration, is considered an idiosyncratic reaction, so it is extremely important to evaluate liver function in the first week and after the first month of treatment. Imepitoin - Imepitoin is a new AED recently distributed on the European market with the goal of becoming the first choice drug in the treatment of IE in the dog. Imepitoin has a classic mechanism of action, mainly potentiating the action of GABA, through binding to the benzodiazepine site of the GABAA receptor. Another antiepileptic effects consists in the blockage, with a dose-dependent action, of the voltage-gated Calcium channels. In the dog, Imepitoin, after oral administration, reaches quickly (in two hours), the plasma peak concentration and has an equally short half-life (less than two hours), allowing an immediate therapeutic action. Imepitoin pharmacodynamics properties demonstrate longer action with respect to its half-life, avoiding too frequent administration. The drug is metabolized by oxidation in the liver without involving, unlike phenobarbital, liver enzymes. Imepitoin does not produce tolerance and withdrawal phenomena are not reported when the drug is abruptly withdrawn. In the cat, a very recent paper has established it’s safety at the dosage of 30mg/kg for 30 days and show preliminary promising results. Levetiracetam – Levetiracetam is a recently introduced molecule, which has antiepileptic mechanisms not yet fully understood. It is believed that the drug modulates the release of neurotransmitters, acting on a specific protein (SV2A) of the vesicles in the presynaptic terminal. Levetiracetam, in human medicine, has proved to be one of the more effective and better tolerated new generation AEDs, resulting very effective in the treatment of epilepsy refractory to other drugs. In the cat, Levetiracetam is very well tolerated and free of side effects. However, the clinical data are still very limited. The drug half-life in the dog is around 3 hours, although it seems to stay in the brain for a longer time. The metabolism of Levetiracetam does not involve the liver, as it is removed for more than 80% by kidneys. The co-administration of phenobarbital decreases the half-life of the drug, while maintaining therapeutic levels. Administration protocols in the cat recommend a dose of 20 mg/kg orally three times per day. New generation AEDs generally do not produce hepatic microsomal enzyme induction and therefore do not need periodic assessment of serum levels to monitor therapy; this is the case of Imepitoin and Levetiracetam. When is possible to stop the treatment? Cats seem to have more possibility than dogs in developing a seizure-free state. Percentages up to 44% of epileptic cats achieving a seizures-fee state have been reported. Stopping therapy is always considered a risky choice because many cats after withholding of AEDs may have devastating relapses of epileptic seizures. Therapy should not be discontinued in patients with suspected genetic epilepsy as regularly, for obvious reasons, seizures recur. In the author’s experience, the relapse of epileptic activity can be dramatic and achieving and maintaining a good control of seizures is extremely difficult. The ideal candidate for therapy discontinuation should be free of seizures for at least one year. One possible approach is the following: make a 25% reduction in the daily dose of the drug and observe epileptic activity within six months. If no seizures have been documented, then the dose is reduced by a further 25% while keeping the observation periods of about six months between the subsequent reductions. If epileptic activity resumes, the patient should return immediately to former therapeutic levels. 9