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1 SEIZURES & EPILEPSY Dr. Richard A. LeCouteur Professor of Neurology & Neurosurgery School of Veterinary Medicine University of California Davis CA 95616 USA Seizure disorders occur frequently in dogs and cats. Estimates of seizure incidence during a lifetime vary from 0.5% to 5.7% of all dogs, and from 0.5% to 1.0% of all cats. Discussion of seizure disorders of all types must precede consideration of the clinical management of epilepsy. Such a broad approach is necessary because dogs and cats with a seizure disorder frequently have similar histories and physical signs despite a wide variety of underlying causes of cerebral dysfunction (including epilepsy). Similarities in clinical histories of dogs or cats with a seizure disorder reflect the similar pathophysiological mechanisms that underlie seizure disorders of all types. Classification of Seizures An epileptic seizure is a definable event that may be measured, recorded, and classified. Classification of epileptic seizures is well established in people [Table 1]. Therapy for epilepsy of people is best directed toward the seizure type. A description of seizures learned from a history (or occasionally by means of videotape) is the single most important factor in providing a correct therapeutic approach in people. Table 1: Classification of Seizures. I. Partial Seizures (Local, Focal) a. b. c. II. Simple Partial Seizures (consciousness not impaired) i. With motor signs ii. With somatosensory or special sensory signs iii. With autonomic signs iv. With behavioral signs Complex Partial Seizures (consciousness impaired) i. Beginning as a simple partial seizure & progressing to impairment of consciousness ii. With impairment of consciousness at onset Partial seizures evolving to secondary generalised seizures Primary Generalised Seizures (bilaterally symmetrical without local onset; consciousness may be impaired or lost) i. ii. iii. iv. v. vi. III. Absence seizures Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures Unclassified Epileptic Seizures (inadequate or incomplete data) A classification system specifically for cats and dogs does not exist. Many types of epileptic seizure that occur in animals, however, are similar to those described for people, and attempts have been made to classify epileptic seizures of cats and dogs by using a system of classification designed for people. A classification system that is designed specifically for dogs and cats is needed to permit understanding and comparison of prospective studies of anticonvulsant efficacy in animals. The initial step in the classification of epileptic seizures of dogs and cats is to categorise the seizures as either partial (focal) or generalised episodes. 2 Causes of Seizures The normal brain is capable of convulsing in response to a variety of stimuli within the central nervous system and to many external influences. Consequently, the causes of seizures are numerous. Disorders that induce seizures may arise either outside the nervous system (extracranial causes) or within the nervous system (intracranial causes) [Table 2]. Each of these groups of causes may be divided in turn into two categories: 1. “Symptomatic” Epilepsy This incudes (i) extracranial causes that are divided into those that originate outside the body (eg, toxic agents) and those that arise within the body but outside the nervous system (eg, hypoglycemia), and (2) Progressive intracranial causes of seizure disorders including those diseases that, in time, may affect an increasing volume of brain tissue (eg, neoplasia, encephalitis), and may produce clinical signs other than seizures. 2. “True” Epilepsy This includes non-progressive intracranial causes of seizures, including inherited, acquired, and idiopathic epilepsy. Table 2. Causes of Seizures. Clinically, it is essential to distinguish between progressive and non-progressive brain diseases that produce seizures. Therapy for progressive diseases requires not only control of seizures but also specific therapy for the underlying disease. If therapy of the underlying disease is not possible, the veterinarian should at least provide an accurate diagnosis and prognosis. On the other hand, it is seldom possible to make a precise etiologic or anatomic diagnosis in non-progressive seizure disorders of intracranial origin (ie, epilepsy). Once the non-progressive nature of the cause of a seizure disorder is established, therapy with an anticonvulsant medication is indicated. Extracranial Disorders. Extracranial disorders may alter brain metabolism and electrophysiology, leading to paroxysmal discharges and seizures. Because the disorders affect both hemispheres, primary generalised seizures usually occur, although other clinical signs may be superimposed on them. Extracranial disorders frequently result from various metabolic conditions, such as hypoglycemia, liver disease, hyperlipoproteinemia, renal disease, hypocalcemia, and hypothyroidism. Toxicoses, including lead or organophosphate poisoning, caffeine or theobromine toxicosis (from excessive chocolate consumption) may also result in seizures. Intestinal parasitism and hyperthermia are other extracranial causes of seizures. 3 Intracranial Disorders. Intracranial causes of seizures include malformations (eg, hydrocephalus), inflammatory disorders (eg, canine distemper encephalitis), nutritional disorders (eg, thiamine deficiency), neoplasia, cranial trauma, degenerative conditions (eg, storage diseases), and cerebral infarction. Affected animals typically present with progressive neurological disease. In some animals, such as animals with a previous history of cranial trauma, morphological brain lesions may have occurred long before the first seizures occur, and may be inactive but leave the brain in a seizure-prone state. In other animals, seizures may be an early sign of progressive brain disease, such as cerebral neoplasia, and may be the sole clinical sign for a prolonged period. With intracranial disease, secondary or primary generalised seizures occur in a wide variety of clinical manifestations, depending on the location and extent of the underlying lesion(s). The frequency of seizures may vary considerably, and the association with rest and sleep seems to be less pronounced than in idiopathic epilepsy (see later). Most intracranial diseases lead to other neurological or clinical signs during the interictal period, and these diseases may have a progressive or non-progressive clinical course. Epilepsy. The seizures seen in association with idiopathic epilepsy are caused by functional disorders of the brain in which both hemispheres are affected by paroxysmal neuronal discharges. Epileptic seizures are generalised and symmetrical from the onset. Morphological lesions are not observed in the cerebrum of animals with epilepsy, with the exception of animals with microdysgenesis (a condition where subtle alterations of embryo-foetal development, such as increased neuron density, may result in a lowered seizure threshold). However, lesions such as gliosis, atrophy, or laminar cortical necrosis, may occur secondary to severe seizures, clusters of seizures, or status epilepticus. These lesions may evolve into a secondary epileptic focus. Idiopathic epilepsy of dogs or cats usually begins with a single seizure. The seizures most often occur during or following a period of sleep or rest, and rarely occur during periods of activity. Seizure frequency is variable (days to months between seizures), however the time between seizures usually decreases as the disorder becomes more chronic. Intervals between seizures may be uniform, or highly variable. Clusters of seizures may occur over hours or days in some breeds of dog (eg, German shepherd dogs, Saint Bernard dogs, Irish setters). Diagnostic Approach A comprehensive case history, complete physical and neurological examinations, and a minimum data base consisting of results of hematological and serum chemistry analyses should be obtained for all animals suspected of having a seizure disorder, even if only one seizure has been observed. On the basis of this information a list of differential diagnoses should be made. Further clinical laboratory, toxicological, or radiographical procedures may be indicated after the results of these initial tests are known [Table 3] . Differential Diagnosis Information obtained from the history, physical, and neurological examinations and the results of a minimum data base may be used to form a list of differential diagnoses. Idiopathic epilepsy may occur at any age, but it occurs most frequently in dogs or cats between 6 months and 5 years of age. Using idiopathic epilepsy as a reference point, a list of differential diagnoses for seizure disorders may be formed for each of three age groups: <6 months of age, 6 months to 5 years of age, and >5 years of age. A list of the most common diseases other than epilepsy that may occur in association with seizures in each of these age categories is included in Table 4. Additional Diagnostic Tests Selection of additional tests should be based on results of physical and neurological examinations and on the results of tests that comprise a minimum data base [Table 3]. The dog's or cat's age should also be considered because certain disorders that may result in seizures are more frequently associated with younger dogs and cats [Table 4]. An extracranial cause of seizures is most likely associated with an abnormal minimum data base [Table 3]. Additional tests may be selected to investigate such extracranial causes. For example, in 4 animals with serum chemistry abnormalities that are consistent with liver disease (eg, low BUN, elevated ALT and /or alkaline phosphatase, low glucose, low total protein, etc) further tests may be needed to assess liver function. Quantification of serum bile acids after a 12-hour fast, and 2 hours postprandially, provides a reliable indicator of liver function. After confirmation of an extracranial cause for seizures, specific therapy may be indicated. In certain instances, anticonvulsant medication may be instituted in addition to specific therapy of an extracranial disorder to control seizure activity during such therapy. Depending on the nature of the underlying extracranial disease, such anticonvulsant therapy may or may not be discontinued at some later date. It should be remembered that in rare instances both an extracranial and an intracranial disorder may be present, and yet the extracranial disorder may not be related to the cause of the seizures. For example, it is possible that a dog with seizures may have hepatic cirrhosis and a primary intracranial neoplasm. For this reason, it is essential to monitor closely the response of an animal to therapy for an extracranial cause of seizures. Should the seizures continue or worsen in the face of a response to therapy of the extracranial disease, then further diagnostic tests may be indicated. An intracranial cause of seizures is most likely associated with normal results of a minimum data base [Table 3]. An intracranial cause should also be considered if the results of additional tests completed to fully investigate abnormalities seen on a minimum data base prove to be normal. Cerebrospinal fluid (CSF) analysis is essential for any dog or cat in which an intracranial cause for seizures is suspected. In addition to submission of CSF for cytological examination and protein quantification, aerobic and anaerobic bacterial and/or mycotic culture and sensitivity testing may be done, and titers for infectious agents may be completed (eg, cryptococcosis, canine distemper, etc). Radiographs of the skull may be useful for detecting calvarial tumors, mineralised intracranial neoplasms, or fractures of the skull associated with head trauma. Electroencephalography (EEG) is helpful in the diagnosis of congenital malformations such as hydrocephalus or lissencephaly. The EEG can also be useful to evaluate electrical events associated with a seizure that may occur during recording and in the identification of paroxysmal electrical events that occasionally occur interictally in the recordings of some epileptic animals. Advanced imaging modalities, such as x-ray computed tomography or magnetic resonance imaging, may provide specific information regarding the location and extent of intracranial lesions such as neoplasms, granulomas, infarcts, or hemorrhages. Animals more than 6 months and less than 5 years of age that have a history of a seizure or of recurrent seizures, that have normal physical and neurological examinations, and that have normal results on a minimum data base most likely have a nonprogressive intracranial disorder. Ideally, additional diagnostic procedures should be done in such animals, however, consideration of costs inolved and potential for morbidity and mortality associated with anaesthesia may result in a decision to delay further tests pending assessment of response to anticonvulsant medication. If a response to therapy is not seen, if seizure frequency or severity increase, or if additional clinical signs develop, then further diagnostic tests to investigate progressive intracranial causes of seizures should be done. 5 Table 3: Diagnostic Approach for a Dog or Cat with Seizures 6 7 Table 4. Causes of Seizures Anticonvulsant Therapy Appropriate therapy for a seizure disorder depends on accurate determination of the cause of the seizures. Treatment with anticonvulsants is indicated for animals with idiopathic epilepsy. Seizures resulting from a structural brain disorder (progressive intracranial disease) require additional therapy, depending on the cause of the disease (eg, neoplasia or inflammation). Anticonvulsants usually are contraindicated in animals with extracranial causes of seizures, where therapy should be directed towards the primary cause of the seizures (eg, hypoglycemia). Objectives of Anticonvulsant Therapy. While the overall goal of anticonvulsant therapy is to eradicate all seizure activity, this goal is rarely achieved. Most dogs and cats benefit from anticonvulsant medication by reduction in frequency, severity, and duration of their seizures. A realistic goal is to reduce seizure frequency to a point that is acceptable to an owner without intolerable or lifethreatening adverse affects to the animal. General Principles of Anticonvulsant Therapy. Prevention of seizures in cats or dogs with epilepsy is a pharmacological problem in clinical veterinary medicine. Surgical therapy for uncontrolled epilepsy as applied in humans has not yet been reported for use in animals. Prior to initiation of therapy for seizures induced by epilepsy, every reasonable effort must be made to rule out either extracranial or progressive intracranial causes for the seizures. Decisions Regarding the Need for Anticonvulsant Therapy. Many factors must be considered prior to the initiation of anticonvulsant therapy. The most important considerations are seizure frequency, seizure character, and owner factors. 8 Seizure Frequency. The seizures observed in epileptic animals occur with varying frequency, and two general approaches exist regarding the institution of anticonvulsant therapy. Some authors state that therapy should not be started before the recurrent nature of the disease has been established. This means that at least two seizures should have been observed. Otherwise animals may be treated that would not have had additional seizures. However, there may be sound biological reasons for beginning treatment after the first seizure. Experience in human epilepsy indicates that when this is done, seizure control may be more effective. Character of Seizures. In certain instances, early and aggressive control of seizures is required. For example, in those animals where preictal and postictal phases are characterised by intolerable changes in personality (eg, aggression) or in excretory behavior. Owner Factors. In veterinary practice, the decision for or against anticonvulsant therapy ultimately must be made by the owner of an epileptic dog or cat. This decision should be based on information and advice provided by a veterinarian. An owner should be fully informed about the nature of the disease and its treatment in terms that are easily understandable. The owner should have a realistic knowledge of the objectives of anticonvulsant therapy because frequently an owner will expect successful therapy to be curative with complete elimination of seizures. An owner must appreciate the need for regular administration of an anticonvulsant drug and also understand that an animal may require medication for the remainder of its life. Cost of medication and regular assessments by a veterinarian should be discussed. Alterations in dosage without prior consultation must not occur. Omission of a single dose may result in severe relapses and sometimes status epilepticus. Although seizure frequency and severity will be reduced in the majority of cats or dogs that receive anticonvulsant medications, a proportion of animals (perhaps as high as 20-30%) may not be controlled adequately despite intensive medical management. With high dosages of anticonvulsant medications, the risk of drug-induced complications increases and must be weighed against the benefits of therapy. Once therapy has begun, a prescribed dosage schedule must be followed exactly. An owner should have a detailed knowledge of expected undesirable effects of anticonvulsant medications. Knowledge of these factors is essential for a high and intelligent degree of cooperation between an owner and veterinarian. Euthanasia of an animal should be considered when an owner cannot commit to supervision and lifetime treatment of a dog or cat with severe epilepsy. General Recommendations for Anticonvulsant Therapy In general, owners should be encouraged to begin anticonvulsant medication in epileptic dogs or cats that are known to have had one or more seizures within an eight week period. Treatment is not routinely advised in animals with seizures that occur less frequently than once every eight weeks, as owners of such animals often do not follow instructions diligently and may treat animals only intermittently. Certain owners, however, are so distressed by seizures that occur in their pet that they are willing to medicate an animal daily despite a history of infrequent seizures. In animals that have had only one seizure, institution of therapy may be delayed. Such a delay may permit the seizure interval to become apparent, thereby providing a basis for a decision regarding the need for therapy and also for an assessment of the efficacy of therapy once it is initiated. Exceptions to these recommendations are made for animals that have seizures in clusters or episodes of status epilepticus even though the interval between clusters may be greater than eight weeks. The seizure episodes have a tendency to become more frequent and severe in such animals when control is not attempted. When seizures have not occurred in a dog or cat for a period of 6-12 months, a cautious reduction of dosage may be attempted. Such a reduction must be done slowly. In rare instances, a dog or cat may remain free of seizures after withdrawal of drug therapy. There are few alternatives to the use of pharmacological agents in the control of seizures. Acupuncture, either as a sole therapy or in conjunction with conventional anticonvulsant therapy, has 9 been recommended by several authors. Results of these reports are encouraging, and it is likely that acupuncture will be used with increasing frequency as an adjunctive therapy to conventional anticonvulsant therapy in dogs in the future. Selection of an Anticonvulsant Medication The efficacy of an anticonvulsant depends on its serum concentration, because this determines its concentration in the brain. Therapeutic success can be achieved only when serum concentrations of a given anticonvulsant are consistently maintained within a therapeutic range. Therefore, anticonvulsants that are eliminated slowly must be employed. The elimination half-lives of the various anticonvulsants differ considerably between different species. Few of the anticonvulsant drugs used for the treatment of epilepsy in people are suitable for use in dogs and cats. This is largely because of differences in pharmacokinetics of antiepileptic drugs in animals and in humans. Some drugs are metabolised so rapidly that it is not possible to reach consistently high serum concentrations, even with very high doses. For many drugs, pharmacokinetic data and/or clinical experience is lacking in cats, which usually metabolise anticonvulsants more slowly than dogs. 10 SEIZURES: WHAT TO DO WHEN PHENOBARBITAL FAILS? Dr. Richard A. LeCouteur Professor of Neurology & Neurosurgery School of Veterinary Medicine University of California Davis CA 95616 USA PHENOBARBITAL Phenobarbital is a safe, effective, and inexpensive drug, suitable for long-term therapy of seizures in dogs and cats. Phenobarbital may be considered a broad spectrum anticonvulsant, in that it may be effective in many types of epileptic seizures observed in cats and dogs. It is particularly effective in delaying the progressive intensification of seizure activity that may accompany epilepsy. Clinical reports indicate that phenobarbital is effective in controlling seizures in 60% to 80% of epileptic dogs, provided serum concentrations of the drug are maintained within the recommended therapeutic range (20 to 45 ug/ml). Mechanism of action The exact anticonvulsant mechanism of action of barbiturates is not completely understood, although it is known that phenobarbital both increases the seizure threshold required for seizure discharge, and decreases the spread of discharge to surrounding neurons. Unlike other barbiturates (e.g., pentobarbital), phenobarbital suppresses seizure activity at subhypnotic doses. Four potential mechanisms of action are: 1) Increasing the activity of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in the central nervous system (CNS) at the post-synaptic membrane, hence increasing neuronal inhibition (by means of an allosteric effect, barbiturates increase the affinity of GABA for its own receptor, and as a result the chloride ion channel is open for a longer time, resulting in greater chloride flux and enhanced neuronal inhibition); 2) barbiturates may also interact with glutamate receptors to reduce neuronal excitotoxicity; 3) inhibition of voltage gaited calcium channels; and 4) competitive binding of the picrotoxin site of the chloride channel. For the chronic treatment of seizures, dosing should begin at 3-5 mg/kg/day per os divided BID or TID. In severely affected dogs with frequent, severe, or prolonged seizures, it may be necessary to commence therapy at a higher initial dosage. In some dogs or cats the starting dose may result in adverse effects. Should these adverse effects not resolve after two weeks of therapy, a reduction in dose may be indicated. Steady state serum phenobarbital concentrations may be determined after three weeks of therapy. If a patient’s seizures are adequately controlled, then serum concentrations may be determined again after three to six months, or more frequently, should seizure activity resume at an unacceptable frequency. If a patient’s seizures are not adequately controlled after three weeks of therapy, the dose of phenobarbital may be increased by 25%, and serum concentrations should be determined again after two weeks of therapy at this higher dose. This process should be continued until the patient’s seizures are controlled, or until a patient fails phenobarbital therapy (i.e. becomes refractory). Dogs or cats may be considered refractory to phenobarbital therapy should seizure activity or unacceptable effects persist after plasma concentrations reach 35 ug/ml. 11 Doses of phenobarbital as high as 18-20 mg/kg/day per os divided BID or TID rarely may be necessary to achieve seizure control in some patients, due to variations in individual drug metabolism. Adverse effects are commonly observed at doses above 20 mg/kg/day. Reductions in dosage should be made gradually as physical dependence to phenobarbital may develop, and withdrawal seizures may occur as serum levels decline. Therapy should not be discontinued suddenly, except in animals that develop fulminant liver dysfunction. Use of phenobarbital should be avoided in animals with hepatic dysfunction. Phenobarbital may be administered intravenously for the treatment of toxic seizures or status epilepticus, however a lag time of 20-30 minutes may be observed prior to control of seizures. Phenobarbital may be given as a loading dose of 12 to 24 mg/kg IV to achieve therapeutic plasma concentrations immediately. Phenobarbital may also be given as a bolus (2 - 4 mg/kg intravenously every 30 minutes) until a cumulative dose of 20 mg/kg has been given. The dose should be decreased proportionately if the patient is currently receiving phenobarbital. Pharmacokinetics Phenobarbital is fairly rapidly absorbed after oral administration, although variation exists between animals probably as a result of differences in tablet or capsule dissolution. Bioavailability is high (86-96%) and peak plasma levels are achieved at 46 hours after administration. Although phenobarbital is widely distributed into tissues, its lower lipid solubility means that it does not penetrate the CNS as rapidly as other barbiturates. After intravenous injection, therapeutic concentrations are reached in the CNS in 15-20 minutes. Administration of the drug with food reduces absorption by about 10%. Phenobarbital is primarily metabolised in the liver with only 25% excreted unchanged by the kidneys. Alkalinization of the urine will enhance elimination of phenobarbital and its metabolites. Plasma protein binding is approximately 45%. Reported elimination half-life of phenobarbital ranges from 30 to 90 hours in dogs and from 3 to 83 hours in cats. The wide range of values is a result of several variables, including the use of multiple drug doses in different studies, and more importantly, whether the drug was given as a single dose, a short course of several doses, or administered for a length of time. In addition drugs capable of stimulating drug metabolising enzyme systems were included in some studies. In studies in cats, the use of different populations of cats appeared to be a contributing factor in the reported variability in elimination half-life. In dogs, phenobarbital elimination half-life significantly decreases when the drug is administered chronically (47.3 10.7 hours when administered for 90 days vs 88.7 19.6 hours in a single dose study). The degree of autoinduction of hepatic metabolism of the drug that occurs may be dose dependent. Phenobarbital increases its own rate of metabolism, and therefore the drug concentration of phenobarbital may be expected to decrease in patients receiving long-term therapy, and a dose increase should be anticipated in patients after three to six months. In contrast, a study in cats comparing pharmacokinetics after single and multiple doses suggested that repeated phenobarbital administration did not alter serum steady state concentrations, but that large differences in phenobarbital elimination rates may exist between different populations of cats. In dogs the elimination half-life of phenobarbital is similar after oral or intravenous administration. Steady state concentrations are achieved within 18 days of initiation of therapy and therefore dosage adjustments should not be made until three weeks after 12 treatment has commenced, or been altered. The metabolism of phenobarbital is quite variable in dogs and similar oral dosage regimes can result in up to a six fold difference in peak serum concentrations. Beagles are reported to metabolise phenobarbital more quickly (32 hour elimination half-life) than cross-bred dogs. Clinical observations suggest that phenobarbital elimination half-life may be shorter in puppies. Since there may be extreme variations between the oral dosage of phenobarbital administered and the serum concentration of drug achieved, it is recommended that serum drug levels should be measured and used as a guide to alterations in drug therapy. Therapeutic serum phenobarbital concentrations for dogs and cats are estimated to be 15-45 &g/ml and 10-30 ug/ml respectively. Although monitoring of serum drug levels may be used as a guide to alterations in drug therapy, such monitoring is not a substitute for clinical judgement. Expected therapeutic serum drug levels are average values, and each animal will have an individual optimal value. In dogs this therapeutic range has been demonstrated to be achievable with a dose of 5.5 - 11 mg/kg/day. Due to the longer elimination half-life of phenobarbital in cats, a once daily dose of 2.5 mg/kg may be appropriate. Although pharmacokinetic studies in both cats and dogs suggest that once daily dosing should be adequate to maintain appropriate serum concentrations, twice or even three times a day dosing is usually recommended to decrease the fluctuations in serum drug levels and minimise adverse effects. In measuring serum drug levels it has been recommended that blood be collected at a similar time in the daily administration cycle of phenobarbital. A blood sample should be collected within one hour before the next scheduled drug administration time (so called trough levels). In a recent study, epileptic dogs receiving chronic phenobarbital therapy were shown to have minimal variations in serum phenobarbital concentrations throughout the day. Should other studies confirm these results, it may be acceptable to measure phenobarbital blood levels anytime during the day in chronically treated dogs. In dogs that have an unacceptable level of seizure control, serum phenobarbital concentrations should be maintained between 30 to 40 ug/ml for 1-2 months before the maximal effects of the drug may be fully assessed. After this time should frequency and/or severity of the seizures remain unacceptable, additional or alternative anticonvulsant medications should be considered. Serum separation tubes have been shown to falsely reduce drug concentrations, and should be avoided for therapeutic drug monitoring. Methylphenobarbital is available in several countries. It requires hepatic demethylation for activation. Dosage recommendations are usually similar to those recommended for phenobarbital. However, it is possible that serum concentrations of the active constituent, phenobarbital, may not be as high at equivalent milligram doses of phenobarbital. Adverse effects Adverse effects that may be observed initially with phenobarbital therapy include sedation, ataxia, polydipsia, polyuria, polyphagia and weight gain. Polyuria is due to an inhibitory effect on the release of antidiuretic hormone. Polyphagia is believed to be due to suppression of the satiety center in the hypothalamus. Most dogs develop a tolerance to these effects after two to four weeks of therapy. Unless sedation is extreme or persistent beyond four weeks, it should not be considered evidence of toxicity and does not warrant an adjustment in the dose. Sedation at the initiation of therapy has been reported to be more severe in cats. Occasionally, a dog may appear 13 hyperactive during the initial phase of therapy, however this effect usually may be overcome by increasing the dose. Although there have been reports of hepatotoxicity in dogs associated with chronic phenobarbital treatment, the reported incidence is extremely low. Hepatotoxicity has not been reported in cats. The incidence of liver toxicity may be reduced significantly in both species by avoiding combination therapy (i.e. use of more than one drug metabolised by the liver), by using therapeutic monitoring to achieve adequate serum concentrations at the lowest possible dosage, and by evaluating clinical pathology alterations every six months while an animal is receiving phenobarbital. Induction of liver enzymes will commonly occur in dogs, and elevations of ALT, ALP and GGT are frequently present in association with phenobarbital therapy. In one study, serum albumin concentrations were demonstrated to decrease initially, but then increased back to pretreatment levels in most patients. The significance of hypoalbuminaemia without other indications of hepatic dysfunction is unknown at this time. Enzyme elevations do not imply hepatic damage or dysfunction, although if ALT is disproportionately elevated in comparison to ALP, phenobarbital toxicity is possible. Phenobarbital does not induce elevations in ALP in cats. If there is doubt about whether hepatic dysfunction is present in an animal receiving anticonvulsant therapy, measurement of serum bile acids is recommended, as these apparently are not increased by anticonvulsant therapy. Blood dyscrasias such as neutropaenia, thrombocytopaenia , anaemia and in some cases, pancytopaenia have been reported in dogs receiving phenobarbital. These adverse effects appear to be idiosyncratic or allergic, and resolve once the drug is discontinued. Phenobarbital may increase the metabolism of thyroid hormones in liver and peripheral tissues, and may also adversely impact thyroid stimulating hormone concentrations. Regular monitoring of animals receiving anticonvulsants by a veterinarian is important to reduce the potential adverse effects of the drug. Animals receiving phenobarbital should be examined at least once every six months. A complete blood count, serum chemistry panel, urinalysis and serum phenobarbital concentration should be completed at least annually, and ideally more frequently. It is recommended that blood levels of phenobarbital be maintained at 35 ug/ml and below to reduce hepatotoxicity. Drug interactions Hepatic microsomal P-450 enzyme activity is accelerated by phenobarbital. This dose-related effect may enhance the biotransformation of other drugs such as digoxin, glucocorticoids, phenylbutazone and certain anaesthetic drugs. As a result, the therapeutic efficacy of these drugs may be reduced in patients also receiving phenobarbital. In contrast, drugs that inhibit hepatic microsomal enzymes may inhibit phenobarbital metabolism and cause toxicity. Several cases of chloramphenicol-induced phenobarbital toxicity in dogs have been documented. Although to the authors' knowledge clinical toxicity has not been documented in dogs receiving phenobarbital concurrently with cimetidine or valproic acid, the combination is best avoided. Phenobarbital may impair the absorption of griseofulvin, and therefore reduce blood levels and efficacy of this antifungal agent. Chronic phenobarbital treatment has been reported to influence the results of ACTH response tests, suggesting that this test should not be used to screen for hyperadrenocorticism in dogs receiving phenobarbital. Although plasma ACTH levels 14 are reported to be unchanged, not all studies have confirmed this observation. Similarly, dexamethasone suppression tests may also be influenced in some, but not all, dogs chronically treated with phenobarbital. Total and free serum thyroxine concentrations have been reported to be significantly reduced in dogs receiving phenobarbital. BROMIDE Bromide is a halide element, discovered in 1826 by Balard, and first reported for use as an anticonvulsant in people by Sir Charles Locock in 1857. Until 1912 when phenobarbital was introduced, bromide was the only effective anticonvulsant available. There are reports of the use of bromide in dogs as early as 1907, but it was not until 1986 that interest in its use clinically to control seizures was reported. Until recently, bromide was used only as an adjunct to phenobarbital therapy for the management of dogs with refractory epilepsy. More recently, its use as a sole anticonvulsant therapy in epileptic dogs has been recommended by some neurologists, particularly in dogs with hepatic dysfunction. Although bromide is an effective anticonvulsant, it is not approved for use for medical purposes in any species. Dosage and formulations Bromide is available as a potassium or a sodium salt. Bromide may be formulated as a 200 mg/ml or 250 mg/ml solution of reagent grade potassium bromide in syrup or distilled water. Potassium bromide is available in tablet form in some countries. Alternatively, the powder may be placed in gelatin capsules. In solution in distilled water, bromide has been found to be stable for more than one year at room temperature or refrigerated, and in glass, plastic, clear or brown containers. Information concerning stability of bromide in solution in syrup is not available, however current recommendations include keeping the solution refrigerated, and discarding it after three months. Bromide may also be administered as the sodium salt to dogs that dislike the taste of potassium or cannot tolerate it (e.g., due to hypoadrenocortism). Sodium bromide should not be used in dogs with congestive heart failure, hypertension or liver disease. The dose of sodium bromide should be reduced by 15% to account for the higher bromide content per gram (KBr = 67% bromide, NaBr = 78% bromide). The primary indication for bromide has been in combination with phenobarbital in refractory epileptics or in patients that have developed liver disease. Bromide is also the drug best suited for use by noncompliant owners because of its long half-life. Bromide may also be used as the sole drug in patients whose seizure history is limited to mild seizure activity. Because reaching a steady state may require two to three months, a loading dose is recommended to achieve therapeutic concentrations more rapidly. The maintenance dose is designed to maintain concentrations achieved after loading. Alternatively the maintenance dose may be given without a loading dose to allow more gradual accommodation to effective serum concentrations. The appropriate dose of bromide depends on concurrent anticonvulsants, diet, and renal function. The maintenance dose of potassium bromide as a first line anticonvulsant is 20-40 mg/kg/day PO once daily or in divided doses in both dogs and cats. Steady state concentrations are not achieved for two to three months in dogs. Steady state concentrations in dogs following administration of 30 mg/kg per day are about 0.8 to 1.2 mg/ml. When used in conjunction with other anticonvulsants, the 15 recommended dose is 22-30 mg/kg PO once daily or divided. The author’s protocol for a loading dose of potassium bromide is 400-600 mg/kg divided into four doses, given over 24 hours. Distribution of bromide is to the extracellular space. Bromide is eliminated slowly (perhaps due to marked reabsorption) in the kidney. Its rate of elimination can change with salt administration. Increased dietary salt will increase the rate of elimination of bromide, and decreased dietary salt will result in the opposite effect. The elimination of bromide in cats appears to be faster than that in dogs, with a mean half-life of approximately six weeks. Following administration of 30 mg/kg orally for eight weeks, mean bromide concentrations were 1.2 mg/ml at steady state. Cats developed no adverse effects to bromide administration in one report. Serum bromide concentrations may be determined one month after a maintenance dose is instituted, regardless of whether a loading dose was given. This approach will enable modification prior to steady state and prior to therapeutic failure or signs of adverse reactions. Recommended target ranges are controversial and depend on whether phenobarbital is being given concurrently. Most laboratories use 1-3 mg/ml regardless of whether bromide is being given as a sole agent or in combination with phenobarbital. Mechanism of action The exact mechanisms of anticonvulsant action of bromide are incompletely understood. The action appears to involve chloride ion channels. These channels are an important part of the inhibitory neuronal network of the CNS. Their function is modulated by GABA, the most important inhibitory neurotransmitter in the mammalian CNS. Increased chloride ion flow as a result of activation of GABA receptors by barbiturates, or benzodiazepines results in increased neuronal inhibition and increases the threshold for seizures. Bromide appears to cross neuronal chloride channels more readily than chloride because it has a smaller hydrated diameter. It is therefore believed that bromide, by competing with chloride ions, hyperpolarises post-synaptic neuronal membranes and facilitates the action of inhibitory neurotransmitters. Barbiturates may act synergistically with bromide to raise the seizure threshold by enhancing chloride conductance via GABA-ergic activity. Pharmacokinetics The pharmacokinetics of bromide have not been well established. Bromide is absorbed from the small intestine with peak absorption achieved 1.5 hours after oral administration. It is not protein bound or metabolised and does not undergo hepatic metabolism. Therefore bromide does not affect hepatic enzymes and is a useful anticonvulsant for dogs with hepatic disease. Elimination of bromide from the body is via the kidneys. Although bromide replaces chloride throughout the body, the sum of these two halides remains constant. Lower concentrations of bromide are found in the brain than would be expected based on the chloride concentration, as it appears there is a barrier to the free passage of bromide. However, the concentration of bromide in the brain of dogs is higher than that found in humans. In humans after bromide treatment the CSF to serum ratio is 31% whereas in dogs the ratio is 87%. As a result, seizure control may be achieved in dogs at a lower serum bromide concentration than in humans, and the potential for toxicity is much reduced. The half-life of bromide is longer in dogs than in humans (24.9 vs 12 days). Two to three weeks of therapy are required before serum bromide levels enter the therapeutic 16 range, and steady state levels are achieved in four months. Higher serum concentrations are required if dogs are treated with bromide alone as compared to dogs treated with bromide and phenobarbital. The therapeutic range for potassium bromide when administered with phenobarbital is 0.8-2.4 mg/ml and 0.8 - 3.0 mg/ml when it is used alone. Adverse effects Clinical signs of bromide toxicity appear to be dose dependent, and include polyphagia, vomiting, anorexia, constipation, pruritis, muscle pain, sedation, and pelvic limb weakness. Ataxia and sedation have been reported to be the major dose limiting side effects in dogs. Other infrequently reported adverse effects include pancreatitis, increased attention seeking, aggression, coprophagia and hyperactivity. High dose bromide therapy has been associated with thyroid disfunction in people and rats. Bromide toxicity has been reported in a dog with renal insufficiency, which resulted in decreased clearance of bromide and therefore higher plasma levels. Reduced efficacy of the drug has been reported in a dog fed a high chloride diet. Toxic concentrations of bromide may be reached rapidly when chloride intake is decreased. Bromide readily crosses the placenta is people, and there are a few reports of neonatal bromism. Due the lack of information in dogs, bromide should be avoided in breeding animals. Drug interactions Because bromide is not protein bound and not metabolized, it does not interact with many drugs. However, chloride containing foods, food supplements, fluids, drugs, and loop diuretics may enhance bromide elimination and lower serum bromide concentrations. Bromide is a product of halothane metabolism in dogs, and therefore small increases in serum bromide may be apparent after halothane anaesthesia. In people, bromide administration has be reported to be associated with increased visualisation of cerebral vessels with non-contrast computed tomography. Pseudohyperchloraemia occurs with bromide administration as bromide ions interfere with colourimetric and automated ion-specific electrolyte analysers used to measure chloride. Treatment of bromide toxicity includes chloride loading (intravenous sodium chloride) to increase bromide elimination. Table 1: Recommended Anticonvulsant Drug Dosages DRUG RECOMMENDED DOSES Phenobarbital Dogs: 2 - 5 mg/kg divided BID (up to 18 - 20 mg/kg BID if necessary) Cats: 0.5 - 1.5 mg/kg divided BID Potassium bromide Dogs and Cats: 20 - 40 mg/kg PO SID or divided BID Dogs: Loading dose 400-600 mg/kg divided into four doses, given over 24 hours. Sodium Bromide Dogs: 20-40 mg/kg PO SID, reduce by 15% Dogs: 1200-1500 mg/kg over 24 hours as a continuous rate infusion of 3% NaBR in D5W. 17 Phenobarbital Resistant Epilepsy Using multiple anti-convulsant drugs has several potential disadvantages, including the increased cost, the need to monitor and to interpret serum concentrations of multiple drugs, potential drug interactions, and more complicated dosing schedules. Indications for such 'polytherapy' include failure of diligent monotherapy and the treatment of cluster seizures. Before polytherapy is started, all reasonable options for monotherapy should be tried. If the initial drug is ineffective, a second drug should be added. If the dog responds, the veterinarian should attempt to withdraw the first drug gradually and continue with polytherapy if this is unsuccessful. Factors to consider when choosing an add-on medication include 1) mechanism of action, with preference given to drugs with a differing mechanism, 2) side effects, 3) the potential for drug interactions among antiepileptic drugs, 4) the required frequency of administration, which in turn may influence compliance, and 5) the cost. Potassium Bromide (KBr) Potassium bromide has no known hepatic toxicity and all the adverse effects of KBr are completely reversible once the drug is discontinued. Potassium bromide is excreted unchanged in the urine and is not metabolised by the liver. There have been no liver enzyme alterations or thyroid axis effects after administration of this drug. KBr controls approximately 70-80% of the epileptic dogs it is used to treat and is often effective in dogs that fail phenobarbital therapy. When high dose KBr and low dose PB are used together, approximately 95% of epileptic dogs can be controlled. Where do you turn when an epileptic dog responds poorly to PB and/or KBr? Management of refractory epilepsy presents a considerable challenge to veterinary practitioners and pet owners. Appropriate therapy and monitoring should be used to optimise treatment results. Ongoing patient follow-up is critical. With the approval of several new antiepileptic drugs for the management of human epilepsy over the last two decades, the treatment options available for dogs and cats have increased. Although information on the use of these novel antiepileptic drugs in animals is lacking, studies and clinical experience available to date suggest that they have the potential to improve seizure control and minimise adverse effects. Continued evaluation of these drugs in veterinary patients should provide additional details on their use in managing canine epilepsy. Aspects of these new antiepileptic drugs have been summarised by Munana.1 Newer anticonvulsant drugs to consider include: Felbamate Gabapentin Pregabalin Zonisamide Levetiracetam Efficacy of new anticonvulsant drugs When recommending a novel treatment, it is helpful if you can provide information on the expected effectiveness of the treatment, especially when the treatment involves a considerable investment of time or money on the pet owner's part. Unfortunately, extensive data of this nature are not available for the use of the new antiepileptic drugs in canine or feline epilepsy. Rather, information on drug use has been obtained by administering the new antiepileptic drug in an open-label fashion: Dogs with poorly controlled seizures were given a new antiepileptic drug, and seizure frequency during administration of the new drug was compared with seizure frequency before the new drug was initiated. Because the studies were not placebo-controlled, the information obtained regarding drug efficacy may be inaccurate. This has been called the placebo effect. 18 From the information available to date, a veterinarian can recommend a trial with a new antiepileptic drug, but, no representation should be made with respect to efficacy. As experience with these drugs grows in veterinary medicine and more research is performed on their applicability to dogs and cats, additional information will become available to further guide recommendations on their use. Factors to consider when choosing an add-on medication include: 1. Mechanism of action, with preference given to drugs with a differing mechanism, 2. Adverse effects, 3. Potential for drug interactions among antiepileptic drugs, 4. Required frequency of administration, which in turn may influence compliance, and, 5. Cost. New antiepileptic drugs approved for use in people that may be considered for extralabel use in dogs are summarised in Table 1.1 Levetiracetam Levetiracetam is one of the more recently approved human antiepileptic drugs. Points of interest regarding levetiracetam are as follows: 1. levetiracetam has a unique mechanism of action, which is a potential advantage when the drug is used in combination with other antiepileptic drugs, 2. Levetiracetam has minimal hepatic metabolism in dogs, with more than 80% of the drug excreted in the urine, 3. The half-life in dogs is three to four hours, which necessitates frequent administration, 4. The recommended oral dose is 20 mg/kg every eight hours. A recent study2 evaluated levetiracetam as an add-on medication in dogs with idiopathic epilepsy that was refractory to phenobarbital and potassium bromide. Nine of 14 dogs responded, and the only adverse effect was sedation (observed in one dog). The main factor limiting the use of levetiracetam in dogs has been its expense, although a generic form of this drug recently has become available. Levetiracetam also is available in a parenteral formulation. Levetiracetam may prove useful in treating cluster seizures and status epilepticus in dogs, with the option of administering the drug intramuscularly if venous access cannot be obtained. The disposition of levetiracetam has been evaluated in six dogs after intravenous and intramuscular administration.3 A dose of 20 mg/kg IV resulted in desirable serum concentrations in a short period; with intramuscular administration, peak concentrations were reached in 40 minutes. Felbamate Felbamate was the first of the newer antiepileptic drugs to be approved in the United States for epilepsy in people. Side effects of aplastic anemia and hepatotoxicosis have since been reported in people, so its use has declined. Points of interest regarding felbamate are as follows: 1. The half-life of felbamate in dogs is five to eight hours, 19 2. The recommended oral dosage is 15 to 60 mg/kg every eight hours. 3. Treatment should be initiated at the low end of the dosage range, and the dosage should be increased as needed to control seizures. 4. Felbamate serum concentrations are not routinely monitored, as is the case for many of the newer antiepileptic drugs. Rather, the drug is used to effect, and dosage adjustments are based on seizure frequency and side effects, 5. Felbamate is mostly excreted in the urine in dogs, although some hepatic metabolism occurs, increasing the potential for drug interactions when phenobarbital and felbamate are administered concurrently. Felbamate is used infrequently in veterinary patients because of the potential for adverse effects and drug interactions, and because of the expense. It is recommended that complete blood counts and liver enzyme activities be measured every two or three months during treatment to assess for adverse effects. Felbamate was evaluated as a sole antiepileptic drug in six dogs with partial onset seizures.4 Dosages ranged from 60 to 220 mg/kg/day, and all dogs showed reduced seizure frequency. Two dogs developed blood dyscrasias, characterised by thrombocytopenia, lymphopenia, and leukopenia, which resolved after the drug was discontinued. One dog developed keratoconjunctivitis sicca, although it was not determined that this problem was drug-related. The use of felbamate as an add-on therapy has been reported in 16 dogs refractory to phenobarbital and potassium bromide.5 Twelve dogs had improved seizure control, but four of these dogs developed signs of liver dysfunction. Other side effects anecdotally reported in dogs receiving felbamate in combination with phenobarbital include sedation, nausea, and vomiting.6 Gabapentin Gabapentin was approved in the United States for use in people as an antiepileptic drug shortly after felbamate. Since its introduction, gabapentin has also been approved to treat neuropathic pain. In people, gabapentin is eliminated entirely by the kidneys. 1. In dogs gabapentin undergoes partial hepatic metabolism, 2. The elimination half-life in dogs is two to four hours, requiring frequent drug administration to achieve steady-state concentrations, 3. The recommended oral dosage is 10 to 20 mg/kg every six to eight hours. Two studies have examined the use of gabapentin in refractory canine epilepsy. The first study involved 11 dogs administered gabapentin (10 mg/kg t.i.d.) in addition to phenobarbital and potassium bromide.7 A positive response to gabapentin, defined as ≥ 50% reduction in seizure frequency, was reported in six of the 11 dogs. The second study evaluated 17 dogs with refractory seizures that were administered gabapentin at a dose of 35 to 50 mg/kg/day divided twice or three times daily, also in conjunction with phenobarbital and potassium bromide (16 dogs) or phenobarbital alone (1 dog).8 This study found no significant decrease in the number of seizures over the study period for the entire population of dogs. However, seizures resolved in three dogs while they were receiving the medication. The adverse effects reported in both studies were sedation and ataxia. The availability of a generic form of gabapentin has made it affordable relative to other antiepileptic drugs used in veterinary medicine. 20 A liquid formulation (50 mg/ml) of gabapentin exists, which facilitates the administration of lower doses to smaller patients. However, the liquid product contains 300 mg xylitol/ml, so it has the potential of causing adverse effects associated with the ingestion of this sugar alcohol.9 Pregabalin Pregabalin is a newer-generation drug in the same class as gabapentin. Limited information exists on its use in dogs for the treatment for epilepsy. Based on pharmacokinetic data in normal dogs, a dose of 2 to 4 mg/kg orally every eight hours has been recommended and was administered to six dogs with idiopathic epilepsy refractory to treatment with phenobarbital, potassium bromide, or both drugs.10 One dog was considered a drug failure, and four of the five remaining dogs had a mean seizure reduction of 59.3%. Five dogs exhibited side effects (sedation and ataxia) attributed to pregabalin. Zonisamide Zonisamide is a sulfonamide-derived antiepileptic drug introduced in the United States in 2000. Points of interest are as follows: 1. The half-life of zonisamide in dogs is 15 to 20 hours, which is relatively long when compared with the other new antiepileptic drugs, 2. Zonisamide requires only twice-daily administration 3. Most of the drug is excreted unchanged by the kidneys, although some hepatic metabolism occurs, 4. The dosage in dogs is 5 to 10 mg/kg given orally every 12 hours. The high end of the dose range is recommended when the drug is used in combination with phenobarbital since phenobarbital appears to facilitate zonisamide clearance.11 For this reason, it may also be helpful to measure serum zonisamide concentrations in dogs being treated concurrently with Phenobarbital, 5. A therapeutic range of 10 to 40 μg/ml has been suggested,12 which is similar to the therapeutic range in people, 6. Zonisamide is a known teratogen in dogs, so its use should be avoided in pregnant animals. A generic form of zonisamide is available, which has reduced the cost considerably since its introduction. Two recent reports on zonisamide as add-on therapy in dogs with refractory epilepsy demonstrated a favorable response in seven of 12, and nine of 11 dogs, respectively.13,14 Reported side effects included sedation, ataxia, and loss of appetite. Efficacy of new antiepileptic drugs – The placebo effect15 Extensive data are not available regarding the effectiveness of treatment of the new antiepileptic drugs in canine epilepsy. Rather, the information on drug use described above was obtained by administering the new antiepileptic drug in an open-label fashion: Dogs with poorly controlled seizures were given a new antiepileptic drug, and seizure frequency during administration of the new drug was compared with seizure frequency before the new drug was initiated. Because the studies were not placebocontrolled, the information obtained regarding drug efficacy may be inaccurate. A reduction in seizure frequency during placebo administration has been documented in people with epilepsy,15 and, a similar phenomenon may occur in dogs. One likely cause for this placebo effect is regression to the mean, which is a statistical term used 21 to describe the fluctuations that occur in biological variables over time and take the form of a sine wave around the mean. Epilepsy is a waxing and waning disorder, and fluctuations in seizure frequency are common over the course of the disease. Clients are most likely to seek a change in therapy for their pets when seizures are poorly controlled. Over time, improvement in the seizure frequency is probable, regardless of the treatment administered. However, this improvement may be erroneously attributed to a recently instituted change in therapy. Open-label studies cannot account for this bias, and, consequently, the efficacy reported in such studies may be falsely elevated. Thus, from the information available to date, a veterinarian may recommend a trial with a new antiepileptic drug, but should not make any representation with respect to efficacy. As experience with these drugs grows in veterinary medicine and more research is performed on their applicability to dogs, additional information will become available to further guide recommendations on their use. Conclusion The management of refractory seizures can pose a considerable challenge to practitioners and pet owners. Ongoing patient follow-up is critical, and directed, appropriate therapy and monitoring should be used to optimize treatment results. With the approval of several new antiepileptic drugs for the management of human epilepsy over the last two decades, the treatment options available for our canine patients have also increased. Although our knowledge is still somewhat limited on these novel antiepileptic drugs, studies and clinical experience available to date suggest that they have the potential to improve seizure control and minimize adverse effects in affected dogs. Continued evaluation of these drugs in veterinary patients should provide additional details on how to use these therapies most effectively in managing canine epilepsy. References 1. Munana KR. Newer options for medically managing refractory canine epilepsy. http://veterinarymedicine.dvm360.com/vetmed/ArticleStandard/Article/detail/608398 2. Volk HA, Matiasek LA, Reliu-Pascual AL, et al. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J 2008;176(3):310-319. 3. Patterson EE, Goel V, Cloyd JC, et al. Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics. J Vet Pharmacol Ther 2008;31(3):253-258. 4. Ruehlmann D, Podell M, March P. Treatment of partial seizures and seizure-like activity with felbamate in six dogs. J Small Anim Pract 2001;42(8):403-408. 5. Boothe DM. Anticonvulsant therapy in small animals. Vet Clin North Am Small Anim Pract 1998;28(2):411-448. 6. Dayrell Hart B, Tiches D, Vite C, et al. Efficacy and safety of felbamate as an anticonvulsant in dogs with refractory seizures (abst). J Vet Intern Med 1996;10:174 7. Platt SR, Adams V, Garosi LS, et al. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec 2006;159(26):881-884. 8. Govendir M, Perkins M, Malik R. Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent. Aust Vet J 2005;83(10):602-608. 9. Dunayer EK, Gwaltney-Brant SM. Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs. J Am Vet Med Assoc 2006;229(7):11131117. 10. Dewey CW, Cerda-Gonzalez S, Levine JM, et al. Pregabalin therapy for refractory idiopathic epilepsy in dogs (abst). J Vet Intern Med 2008;22:765. 11. Orito K, Saito M, Fukunaga K, et al. Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs. J Vet Pharmacol Ther 2008;31(3):259-264. 22 12. Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004;40(4):285-291. 13. von Klopmann T, Rambeck B, Tipold A. Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs. J Small Anim Pract 2007;48(3):134-138. 14. Burneo JG, Montori VM, Faught E. Magnitude of the placebo effect in randomised trials of antiepileptic agents. Epilepsy Behav 2002;3(6):532-534. 15. Munana KR, Zhang D, Patterson EE. Placebo effect in canine epilepsy trials. J Vet Intern Med 2010; 24:166-170. Table 1 . Characteristics of new anticonvulsant drugs used to treat canine epilepsy1 Drug Dosage Mechanism of Action Time to reach Hepatic steady state Metabolism concentrations Adverse Effects Levetiracetam 20 mg/kg PO t.i.d. Binds to synaptic vesicle protein, modulating release of neurotransmitter 15-20 hours No Sedation, ataxia Felbamate 15-60 mg/kg PO t.i.d. Inhibits glutamine by blocking calcium channels; Potentiates GABA 25-40 hours Yes Sedation, ataxia, blood dyscrasias, vomiting, hepatic disease Gabapentin 10-20 mg/kg PO t.i.d. to q.i.d. Inhibits voltagegated calcium channels 10-20 hours Partial Sedation, ataxia Pregabalin 2-4 mg/kg PO t.i.d. Inhibits voltagegated calcium channels 30-40 hours Partial Sedation. ataxia Zonisamide 5-10 mg/kg PO b.i.d. Inhibits voltagegated calcium & sodium channels 15-20 hours Yes Sedataion, ataxia, vomiting, appetite loss 23 INFLAMMATORY BRAIN DISEASES “YOU, ME, AND GME” Dr. Richard A. LeCouteur Professor of Neurology & Neurosurgery School of Veterinary Medicine University of California Davis CA 95616 USA Definition • Inflammatory central nervous system (CNS) diseases are a group of sporadic inflammatory diseases that affect the brain and/or spinal cord of dogs in the absence of an infectious cause (ie, pathogen-free). • Based on histopathological findings, 3 distinct forms of inflammatory CNS disease have been identified in dogs: 1. Granulomatous meningoencephalomyelitis (GME): Canine GME is the current term for an idiopathic CNS disease (most likely first described in 1936). GME still attracts a confusing and lengthy number of synonyms reflecting changes only in immunologic terminology (eg, inflammatory reticulosis, lymphoreticulosis, neoplastic reticulosis). 2. Necrotizing meningoencephalitis (NME): Canine NME was originally recognized in dogs in the U.S. in the 1970’s as a breed-specific disease of pug dogs (colloquially known as “pug dog encephalitis”). Since 1989, based on morphologically defined lesion patterns and histology, NME has been recognized in other small-breed dogs, including Maltese, Chihuahua, Pekinese, Boston terrier, Shih Tzu, Coton de Tulear, and Papillon. 3. Necrotizing encephalitis (NE): Canine NE was first described in 1993 in Yorkshire terriers and has been reported in other breeds, including French bulldogs. Signalment • GME affects dogs older than 6 months of age, and is most prevalent in dogs between 4 and 8 years of age. • Onset of NME is 6 months to 7 years of age, with a mean age of 29 months. • NE typically manifests between 4 months and 10 years of age, with 4.5 years as a mean onset age. Breed & Gender Predilection • GME affects all sizes and breeds of dog (with toy and terrier breeds overrepresented), whereas NME and NE affect predominantly small-breed dogs. • Both males and females are affected, although females may be at higher risk of developing the disease. Causes • Obscure, although an autoimmune or immune-mediated/immune-dysregulatory cause is suspected. • PCR-based screening for viral DNA (eg, herpes, adeno- or parvoviruses ) has been negative. Pathophysiology Suggested possible mechanisms include autoimmune encephalitis induced by anti-GFAP (glial fibrillary acidic protein) antibodies in CSF and T-cell-mediated delayed hypersensitivity mechanisms. 24 Clinical Signs • Signs of neurologic dysfunction reflect the location of the lesion(s) within the CNS. • Multifocal involvement of the cerebrum, brainstem, cerebellum, and spinal cord (GME only) is common. • Clinical signs of GME may include visual disturbances (ie, the ophthalmic form of GME affects the optic nerve), cranial nerve deficits (particularly central vestibular signs), seizures, apparent cervical pain, ataxia, and paresis. • NME and NE frequently affect the forebrain, resulting in abnormal mentation, seizures, blindness, circling, and behavior changes, or brainstem, resulting in cranial nerve deficits, changes in mentation, and difficulty walking. Diagnosis A tentative antemortem diagnosis may be based on analysis of a combination of the patient’s signalment, history, clinical signs, neurological examination findings, results of bloodwork, infectious disease titers, CSF analysis (including culture and PCR analysis), and advanced imaging (CT and MRI). Neurological signs, results of CSF analysis, and neuro-imaging findings will vary with intensity and location of the pathological lesions. • Definitive antemortem diagnosis is based on characteristic findings on histopathology of brain and/or spinal cord tissue obtained by surgical biopsy. • Definitive postmortem diagnosis is based on characteristic findings on histopathology of brain and spinal cord. Differential Diagnosis • Other causes of focal and multifocal CNS dysfunction of dogs (see Table 1). Laboratory findings • CSF from dogs with inflammatory CNS disease usually is abnormal, although normal CSF may be present (particularly should corticosteroids have been administered up to 6 weeks prior to CSF collection). • Typical findings consist of an elevated total nucleated cell count and an elevated CSF protein. The predominant cell type is lymphocytes, with smaller numbers of neutrophils and macrophages present (Figure 1). • Infectious causes of the CSF abnormalities should be considered, and culture, serological testing, electrophoresis or PCR analysis (of CSF and/or serum) for the presence of infectious agents may be appropriate, although results of these tests are unlikely to contribute to a diagnosis. Imaging • Characteristic findings on MRI include asymmetric, bilateral (often multifocal) lesions in the forebrain, brainstem, and/or spinal cord (Figure 2). These lesions variably enhance with intravenous contrast administration. Cystic areas may be seen in areas of the brain that are necrotic. • The classical lesions in GME, NME, and NE may be distinctly different based on both distribution pattern and microscopic lesions. While this information may be helpful in differentiating between the 3 forms of inflammatory CNS disease, it may not be possible to differentiate GME, NME, and NE based on imaging characteristics alone (except that spinal cord involvement is only present with GME). Postmortem findings • A unique histopathological appearance is present in each of the inflammatory CNS disorders. 25 • • • GME is characterized by a unique angiocentric granulomatous encephalitis consisting of a perivascular accumulation of macrophages often intermixed with lymphocytes and plasma cells. Three major patterns of histologic lesion distribution in brain and spinal cord have been described for GME: 1. The disseminated form, in which the most intense lesions occur in the upper cervical spinal cord, brainstem, and midbrain, often with less severe extension involving white matter of the rostral cerebrum (Figure 3A). 2. A disseminated form with angiocentric expansion forming multiple coalescing mass lesions of similar distribution. 3. A focal form, in which single discrete mass lesions occur in either the spinal cord, brainstem, midbrain, thalamus, optic nerves, or cerebral hemispheres, without dissemination. It remains contentious whether this form is a neoplastic rather than an immunoproliferative process. NME has both a characteristic anatomic distribution pattern and unique histological lesions. Gross lesions occur as asymmetrical, multifocal bilateral areas of either acute encephalitis or chronic foci of malacia, necrosis, and collapse of hemispheric gray and white matter decreasing in intensity rostrocaudally. Histologically, there is a unique combination of focal meningitis and polio- and leukoencephalitis of adjacent white matter. The lesions are intensely inflammatory with meningitis and parenchymal histiocytic, microglial infiltrates accompanied by perivascular cuffing of lymphocytes and plasma cells. Coexisting with chronic lesions can be acute nonsuppurative encephalitis in the hippocampus, septal nuclei, and thalamus. Usually, few inflammatory lesions are present in cerebellum, brainstem, and spinal cord (Figure 3B). In canine NE, grossly the large focal asymmetric bilateral malacic necrotizing lesions are confined mostly to the white matter of the cerebral hemispheres. There is an intense histiocytic, microglial and macrophage cellular infiltrate with loss of white matter and thick perivascular lymphocytic cuffing. Other areas have acute exudation, severe edema, necrosis, and eventual cyst formation, with a dramatic gemistocytic astrogliosis, histiocytes, and gitter cells intermixed with thick perivascular lymphocytic cuffing. Characteristically, the overlying cortex and meninges are not involved. Multifocal intense inflammatory cell infiltrates of macrophages with dramatically thick perivascular lymphocytic cuffing are seen in the midbrain, brainstem, and cerebellum (Figure 3C). Treatment • Therapy is based on the use of immunomodulatory drugs at immunosuppressive doses. • The most common therapy utilized is corticosteroids. Dogs often have a favorable response to corticosteroid monotherapy. Response to corticosteroids may be temporary. • Other immunomodulatory drugs may be used if the dog does not tolerate corticosteroids, to reduce the dose of corticosteroids, or if there is inadequate clinical response to corticosteroids. Many drugs have been recommended, including cyclosporine, procarbazine, lomustine (CCNU), leflunomide, mycophenolate mofetil (MMF), azathioprine, and cytosine arabinoside. All have been used by different authors in relatively small numbers of patients. There is no published evidence of the risks and benefits of these treatments when compared to the use of immunosuppressive regimens of corticosteroids alone for the same diseases. <Reviewer comment: Regarding the use of drugs such as cytosine arabinoside, it seems that many feel that it may be very effective in acute encephalititis in improving clinical signs when corticosteroids alone are ineffective.> 26 • The author recommends starting treatment with immunosuppressive doses of prednisone, giving the patient 1.5 mg/kg BID for 3 weeks; then 1.0 mg/kg BID for 6 weeks; then 0.5 mg/kg BID for 3 weeks; then 0.5 mg/kg once daily for 3 weeks. The patient then receives 0.5 mg/kg every other day indefinitely. After the first 4–6 weeks of prednisone therapy, cytosine arabinoside may be added at 3–6 week intervals (administered as a subcutaneous injection at a dose of 50 mg/m2 Q 12 H for 2 consecutive days). Precautions • Adverse effects of long-term high dose corticosteroid therapy include polyuria/polydipsia, polyphagia, weight gain, hepatotoxicity, gastrointestinal ulceration, pancreatitis, and iatrogenic hyperadrenocorticism. • Adverse effects of cytosine arabinoside are dose dependent, and include myelosuppression, vomiting, diarrhea, and hair loss. Nutritional aspects • Avoid weight gain associated with prolonged corticosteroid administration. Activity • Exercise restrictions are not recommended. Client Education • Clients should be informed that there is no definitive treatment for inflammatory CNS diseases of dogs. Therapy is aimed at suppressing the dog’s immune system for as long as possible. • Prognosis is extremely guarded to poor. Patient Monitoring • Regular rechecks (suggested at monthly intervals or as needed) to assess progress of disease and to assess adverse effects of medications. • Repeat blood counts, chemistry panels, urinalysis, CSF analysis and advanced imaging procedures may be necessary. Complications • Complications usually are related to adverse effects of immunomodulatory drugs. Relative Cost • Diagnosis and long-term management are costly due to need for specialized diagnostic procedures, immunomodulatory drug maintenance, and repeated assessments. Prognosis • Prognosis for dogs with inflammatory CNS disease is poor, and most affected dogs eventually die from the disease, or are euthanized. Some survive only a short time, while others have a more prolonged clinical course, from 6 months to, rarely, years. Future considerations • Research to date on canine inflammatory CNS diseases, and the nature of the histopathologic lesions, suggests the likelihood of an autoimmune or immunemediated/immune-dysregulatory disease. In people, many autoimmune diseases have strong associations with certain MHC genotypes and this information may be used to assist in diagnosis or patient counseling. It is now possible to determine the MHC haplotype of dogs, and some disease associations with MHC haplotype 27 in dogs already have been demonstrated. Assessment of MHC haplotype in dogs with GME may help to determine if there is a genetic component to disease susceptibility and development. References 1. Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: A systematic review of 457 published cases from 1962 to 2008. Granger N, Smith PM, Jeffery ND. Vet J 184(3):290-7, 2010. 2. Idiopathic granulomatous and necrotizing inflammatory disorders of the canine central nervous system: A review and future perspectives. Talarico LR, Schatzberg SJ. J Small Anim Pract 51(3):138-49, 2010. 3. Dog leukocyte antigen class II association in Chihuahuas with necritotizing meningoencephalitis. Vernau KM, Liu H, Higgins RJ, et al. J Vet Intern Med 24(3):736, 2010. Figure 1. Cytofuge smear of CSF from a 5-year-old spayed female Maltese. Total nucleated cell count was 1,057/mcL (reference range: <3/mcL) with 1% neutrophils, 93% small mononuclear cells, and 6% large mononuclear cells. Protein content was 576 mg/dL (reference range: <25 mg/dL). These findings are consistent with a diagnosis of GME. (Wright’s stain x100). Figure 2. Transverse, FLAIR MRI at the level of the midbrain and cerebral hemispheres of a 4-year-old, castrated male Maltese with acute onset of mild obtundation and generalized ataxia caused by GME. Note the localized hyperintensity 28 of the white matter throughout the cerebral cortex, with bilateral periventricular edema. Ill-defined multifocal hyperintensity is also identified in the brainstem. These findings are consistent with a diagnosis of GME. A. B. C. Figure 3. A: GME. Perivascular accumulation of macrophages, lymphocytes, and plasma cells (H&E X 130); B: NME. Focal meningitis with polio- and leukoencephalitis of adjacent white matter. The lesions are intensely inflammatory with parenchymal histiocytic, microglial infiltrates accompanied by perivascular cuffing of lymphocytes and plasma cells (H&E X 110); C: NE. Acute exudation, edema, and necrosis, with gemistocytic astrogliosis. Histiocytes and gitter cells are intermixed with perivascular lymphocytic cuffing (H&E X 265). 29 Table 1: Possible causes of brain dysfunction in dogs Degenerative Lysosomal storage diseases Leukodystrophy/spongy degeneration Cognitive dysfunction syndrome Anomalous/Developmental Congenital hydrocephalus Caudal occipital malformation Intracranial arachnoid cyst Metabolic Hepatic encephalopathy Renal-associated encephalopathy Hypoglycemic encephalopathy Electrolyte-associated encephalopathy Endocrine-related encephalopathies Encephalopathy associated with acid-base disturbances Mitochondrial encephalopathy Neoplastic Primary brain tumors Secondary brain tumors Nutritional Thiamine deficiency Inflammatory/Infectious/Immune-mediated Bacterial meningoencephalitis Fungal encephalitis Viral meningoencephalitis Protozoal meningoencephalitis Rickettsial meingoencephalitis Verminous meningoencephalitis Granulomatous meningoencephalomyelitis Necrotizing meningoencephalitis Necrotizing encephalitis Eosinophilic meningoencephalitis Toxic Vascular Ischemic encephalopathy Hemorrhagic encephalopathy 30 UPDATE ON BRAIN DISEASES IN DOGS & CATS Dr. Richard A. LeCouteur Professor of Neurology & Neurosurgery School of Veterinary Medicine University of California Davis CA 95616 USA The term encephalopathy refers to any disorder or disease affecting the brain. In its broadest interpretation, this includes disorders affecting the cerebrum (cerebral cortex and basal nuclei), brainstem (thalamus, hypothalamus, midbrain, pons and medulla), and cerebellum. This lecture will concentrate on disorders affecting the cerebrum. Clinical Signs The principal clinical signs associated with cerebral dysfunction are as follows; Altered mental status (obtundation, stupor (semi-coma) or coma) Change in behavior (loss of trained habits, failure to recognize owner, aggression, or hyperexcitability) Abnormal movements/postures such as pacing, wandering, circling, head pressing, twisted head and trunk (pleurothotonus) Postural reaction deficits in contralateral limbs Visual impairment (e.g. bumping into objects, menace deficit contralateral to side of lesion) with normal pupillary light reflexes Seizures On the basis of signalment, history, and the results of a physical and neurologic examination, it may be possible to localize a lesion to the brain and occasionally to determine an approximate location. A similar neurologic syndrome will result from any one of a number of different diseases occurring at a given location. Many degenerative, metabolic, infectious, inflammatory, toxic, and vascular diseases may result in clinical signs of cerebral dysfunction. The cerebral cortex coordinates voluntary movements and reactions. Clinical signs of cerebral cortex dysfunction include changes in behavior (lethargy, loss of trained habits, irritable, aggressive) or mental status (obtundation, semicoma, coma), and visual and postural reaction deficits. Behavioral changes usually result from a lesion of the limbic system or frontal lobe of the cerebral cortex. Since the frontal lobe has an inhibitory effect on some motor functions, a lesion here removes this inhibition and as a result the animal may continually pace. When as animal reaches a barrier pacing may be replaced with head pressing. Some animals circle, usually to the side of the lesion. Seizures may be partial or generalized. Conscious visual perception requires intact visual pathways to the occipital lobes of the cerebral cortex. Unilateral lesions of the occipital cortex result in visual deficits in 31 the contralateral temporal visual field, with intact pupillary light reflexes. Bilateral lesions produce blindness. Although the motor cortex is important for voluntary motor activity, it is not necessary for relatively normal gait and posture. Animals with lesions here may be able to stand, walk and run with minimal deficits, but control of finer movements is lost and they may have difficulty avoiding obstacles and contralateral postural reactions are usually deficient. Although it is possible to localize a problem to the brain and sometimes to the approximate location within the brain, it must be remembered that clinical signs may be the same regardless of the underlying cause. Brain tumors, infections, congenital disorders, trauma, vascular disorders, degeneration, immunologic and metabolic disorders, toxicities, and idiopathic disorders may result in similar clinical signs. For this reason it is essential to follow a logical diagnostic plan for a cat or dog with signs of brain dysfunction. Some Common Disorders Affecting the Cerebrum of Dogs and Cats 1. 2. 3. 4. 5. Degenerative a. Lysosomal storage diseases: Fucosidosis - Springer spaniel Gangliosidosis - cats, dogs Ceroid lipofuscinosis - dogs Anomalous/ Developmental a. Hydrocephalus b. Lissencephaly - small smooth brain with absent gyri and abnormal arrangement of cells in cerebral cortex c. Hydranencephaly - virtual absence of cerebral hemispheres and basal nuclei, with remnants of mesencephalic structures d. Porencephaly - a circumscribed cerebral defect that communicates with the ventricular system e. Meningoencephalocele - herniation of part of the brain and meninges through a defect in the skull Metabolic a. Hepatic encephalopathy b. Miscellaneous Hypoglycemia Neoplastic a. Primary brain tumor b. Secondary brain tumor Local extensions from skull, middle ear, pituitary, nasal cavity Metastasis Inflammatory/Infectious a. Viral Canine distemper Old dog encephalitis Feline infectious peritonitis Parvovirus encephalitis b. Unknown cause Granulomatous meningoencephalomyelitis Eosinophilic meningoencephalitis c. Protozoal Toxoplasmosis 32 Neosporosis Mycotic Cryptococcus neoformans Others - Blastomyces dermititidis, Histoplasma capsulatum, Coccidioides immitis, Cladosporium trichoides, paecilomyces, Aspergillus spp., etc e. Bacterial Abcessation Sub-dural empyema f. Miscellaneous Verminous encephalitis Foreign body migration Traumatic Vascular a. Hemorrhage b. Infarction Feline ischemic encephalopathy d. 6. 7. Diagnostic Plan Patient signalment, history and physical and neurological examination findings will help to localize a lesion to the brain and possibly a particular area of the brain. Further diagnostic tests are required to localize the affected area within the brain, and to obtain an accurate diagnosis. These tests include CSF analysis, CT or MR imaging, and brain biopsy. Following a complete history and physical and neurologic examination, a minimum data base for an animal with signs of brain dysfunction should be obtained. This should include a hemogram, serum chemistry panel, and urinalysis. Survey thoracic radiographs and abdominal ultrasound help to rule out problems elsewhere. The major objective in doing these tests is to exclude disease outside the brain as a cause of the signs of cerebral dysfunction. Plain skull radiographs are useful for detecting problems of the skull or nasal cavity that may have extended to the brain. Occasionally, lysis or hyperostosis of the skull may accompany a primary brain tumor (e.g., meningioma of cats) or there may be mineralization of a neoplasm. Skull radiographs are of little value in detecting dysfunction within the brain. Cerebrospinal Fluid Analysis of cerebrospinal fluid (CSF) is recommended as an aid in the diagnosis of a brain disorders. The results of CSF analysis may help to identify inflammatory causes of cerebral dysfunction, and in some cases may support diagnosis of a brain tumor. CSF bathes the entire CNS, both internally (the ventricles and central canal) and externally (the subarachnoid space). CSF composition may be affected by many nervous system diseases and the ease with which this fluid may be collected has made it a useful diagnostic tool in the diagnosis of CNS disease. Unfortunately, for cells to be shed into the CSF a disease must involve the ventricular system or the subarachnoid space. Disorders involving deeper brain structures (e.g. neoplasms) may not shed cells into the CSF. Frequently these diseases disrupt the blood-brain barrier allowing protein to leak into the CSF and resulting in an increased protein level. CSF must be evaluated keeping in mind history and clinical signs. Neoplasms and some other non-inflammatory diseases may result in inflammatory changes in CSF composition. CSF composition may also change as a disease becomes more chronic. Also, following various therapies CSF may no longer accurately reflect an etiology Care should be used in the collection of CSF, because frequently an increased intracranial pressure (ICP) may be present in association with a brain tumor, and 33 pressure alterations associated with CSF removal may cause brain herniation. Because CSF pressure measurements are of limited usefulness, it is often desirable to utilize techniques such as hyperventilation to decrease intracranial pressure prior to CSF collection. CSF may be collected at either the cerebellomedullary cistern or by lumbar puncture. In general the cerebellomedullary cistern is easier to perform, allows collection of a larger volume and generally collection from this area results in less blood contamination. All patients undergoing CSF collection should be anesthetized appropriately. If it is suspected that intracranial pressure is elevated the patient should be hyperventilated for several minutes prior to collection as well as during and after collection in order to decrease arterial CO2 and intracranial pressure. Complications of CSF collection include needle injury to the brain and herniation of the brain, usually due to high intracranial pressure. Both these complication may be fatal if appropriate steps to reduce intracranial pressure (hyperventilation and mannitol administration) are not instituted immediately. CT and MRI CT and MRI allow imaging of brain tissue rather than just the surrounding bony skull. Both can distinguish lesions which have only slightly different densities than the surrounding tissues and this can be further enhanced by contrast agents allowing the identification of masses and other abnormal tissues within the brain. Images obtained by means of MRI may be superior to those of CT especially in certain areas such as the brain stem, although CT is usually better for bony lesions (e.g. middle ear studies). While the major tumor types are reported to have characteristic CT or MRI appearances , non neoplastic lesions may mimic the CT or MRI appearance of a neoplasm, and occasionally a metastasis may resemble a primary brain tumor on CT or MRI images. Patients for either CT or MRI must be anesthetized, intubated, and hyperventilated whenever an increase in ICP is even suspected. Proper patient positioning is extremely important. The animals should be placed in sternal recumbency with the head extended. The entire calvaria should be examined in the non contrast series of images. This should be followed by a post contrast series of images. Cerebrovascular Disease of Dogs & Cats Cerebrovascular disease is defined as any abnormality of the brain resulting from a pathologic process affecting its blood supply. Stroke or cerebrovascular accident (CVA) is the most common clinical manifestation of cerebrovascular disease, and may be broadly divided into (1) ischemic stroke and (2) hemorrhagic stroke. Ischemic stroke results from occlusion of a cerebral blood vessel by a thrombus or embolism, depriving the brain of oxygen and glucose, whereas hemorrhagic stroke results from rupture of a blood vessel wall within the brain parenchyma or subarachnoid space. Ischemic strokes are more common, and an underlying cause is found in about 50% of cases. The most common concurrent medical conditions found in dogs are hyperadrenocorticism, chronic kidney disease, hypothyroidism and hypertension. Hemorrhagic strokes are rare and have been reported secondary to rupture of congenital vascular abnormalities, brain tumors, intravascular lymphoma, cerebral amyloid angiopathy and impaired coagulation. Signs are typically peracute in onset, and then they plateau. Worsening edema can sometimes lead to progression of neurologic signs MRI is the imaging modality of choice. CT can detect hemorrhage and is useful for ruling out mimics of stroke, but it is not very sensitive in detecting ischemic changes. Ancillary diagnostic tests for ischemic strokes include CBC, chemistry, UA, serial blood pressure measurements, urine protein/creatinine ratio, d-dimers, endocrine testing, thoracic radiographs, abdominal ultrasound and echocardiography. 34 Ancillary diagnostic tests for hemorrhagic stroke include serial blood pressure measurement, CBC, chemistry, BMBT, PT/PTT, thoracic radiographs and abdominal ultrasound. Treatment, regardless of type, includes supportive care and management of neurologic and non-neurologic complications, as well as treating any underlying causes. Most cases of ischemic stroke recover within a few weeks with just supportive care. Hemorrhagic stroke is far less common, but associated with higher mortality. The risk of neurologic deterioration is highest in the first 24 hours. Dogs with concurrent medical conditions have significantly shorter survival times and are more likely to suffer from subsequent infarcts. Previously considered uncommon, CVA is being recognized with greater frequency in veterinary medicine since magnetic resonance imaging (MRI) has become more readily available. Once the diagnosis of ischemic or hemorrhagic stroke is confirmed, potential underlying causes should be investigated and treated accordingly. Hippocampal Necrosis of Cats A profound encephalopathy of cats, caused by necrosis of the hippocampus, has been described. The syndrome is characterized by progressive, partial or generalized seizures, behavior changes (particularly aggression), and pathological features confined to the limbic system (including hippocampus and piriform lobe of the cerebrum). In one study, the clinical records of 38 cats (1985-1995) with a neuropathologically confirmed diagnosis of necrosis of the hippocampus and occasionally the piriform lobe of the cerebrum were evaluated retrospectively. There was no sex or breed predisposition. Most cats were between 1 and 6 years of age (mean age 35 months) and had either generalized or complex-partial seizures of acute onset and rapid progression. The seizures had a tendency to become recurrent and to present as clusters or even status epilepticus later in the course of the disease. Fourteen cats died spontaneously, and 24 were euthanized. Histopathologic examination revealed bilateral lesions restricted to the hippocampus and occasionally the piriform lobe of the cerebrum. The lesions seemed to reflect different stages of the disease and consisted of acute neuronal degeneration to complete malacia, affecting mainly the layer of the large pyramidal cells but sometimes also the neurons of the dentate gyrus and the piriform lobe. The clinical, neuropathologic, and epidemiologic findings suggest that the seizures in these cats were triggered by primary structural brain damage, perhaps resulting from excito-toxicity. The cause remains unknown, but epidemiologic analysis suggests an environmental factor, probably a toxin. Brain Tumors of Dogs & Cats The Past: Surgery, Irradiation and Chemotherapy The major goals of therapy for a brain tumor have been to control secondary effects, such as increased intracranial pressure or cerebral edema, and to eradicate the tumor or reduce its size. Beyond general efforts to maintain homeostasis, palliative therapy for dogs or cats with a brain tumor has consisted of glucocorticoids for edema reduction, and in some cases (e.g., lymphoma), for retardation of tumor growth. Some animals with a brain tumor will demonstrate dramatic improvement in clinical signs for weeks or months with sustained glucocorticoid therapy. Should anti-seizure medications be needed, phenobarbital or bromide are the drugs best suited for the control of generalized seizures. Three major methods of therapy for a brain tumor have been available for use in dogs and cats: surgery, irradiation, and chemotherapy. 35 Surgery In association with the availability of CT and MRI, and the development of advanced neurosurgical, anesthetic, and critical care techniques, complete or partial surgical removal of intracranial neoplasms is being practiced with increasing frequency. Neurosurgical intervention is an essential consideration in the management of intracranial neoplasms of cats or dogs, whether for complete excision, partial removal, or biopsy. Radiation Therapy The use of radiation therapy for the treatment of primary brain tumors of dogs and cats is well established. Irradiation may be used either alone or in combination with other treatments. Radiation therapy also is recommended for the treatment of secondary brain tumors. Metastases, pituitary macroadenomas or macrocarcinomas, and skull tumors have been successfully managed by means of either radiation therapy alone or as an adjunct to surgery. Lymphoma may also be sensitive to radiation therapy. Chemotherapy Traditionally, cytotoxic drugs have had a limited role in the treatment of dogs or cats with brain tumors, and progress in the development of truly effective chemotherapeutic protocols for humans or companion animals has been slow. Several factors affect the use of chemotherapeutic agents for the treatment of brain tumors in dogs or cats. The first, unique to the brain, is that the blood-brain barrier (BBB) may prevent exposure of all or some of the tumor to a chemotherapeutic agent injected parenterally. Second, tumor cell heterogeneity may be such that only certain cells within a tumor are sensitive to a given agent. Third, a tumor may be sensitive only at dosages that are toxic to the normal brain or other organs (kidney or liver). The Present: Therapeutic Delivery Strategies for Canine Brain Tumors The use of Surgery, irradiation and chemotherapy remains the mainstay of brain tumor therapy today. Development of novel therapeutic strategies to combat primary brain tumors has followed closely behind elucidation of the basic molecular and genetic mechanisms underlying both tumorigenesis and subsequent progression. Despite the wealth of data documenting successful treatment of experimental tumors, translation into the clinical setting has been slow. Many existing therapeutics are rendered ineffective in the treatment of brain tumors due to the inability to effectively deliver and sustain them within the brain. The major obstacle to therapeutic delivery via the vascular route (following either orally administration or direct vascular administration) is the BBB. Transport across the brain vascular endothelium is essentially trans-cellular, therefore the ideal substance to be transported should be: Small (< 400Da) Lipophilic (lipid soluble) Non-polar at physiological pH Non-protein bound Unfortunately, a majority of chemotherapeutic agents are large positively charged, hydrophilic molecules. Many therapeutic molecules such as cyclosporine, doxorubicin and vincristine have poor BBB penetration despite being lipophilic (cyclosporine A is more lipophilic than diazepam). This is the result of additional “barriers” such as high levels of degrading enzymes within the endothelial cells, and high concentrations of efflux transporter proteins such as P-glycoprotein, multiple organic anion transporter proteins (MOAT) and multi-drug-resistance proteins (MRP). In addition to barriers preventing movement of therapeutic agents from the blood into the brain parenchyma, mechanisms are also present to limit movement into the 36 cerebrospinal fluid (CSF). Passage of substances through the arachnoid membrane is prevented by tight junctions and is generally impermeable to hydrophilic molecules. While the capillaries of the choroids plexus are fenestrated, non-continuous and allow free movement of small molecules, the adjacent choroidal epithelial cells form tight junctions preventing the passage of most macromolecules. An active organic acid transporter system in the choroid plexus also is capable of driving therapeutic organic acids such as penicillin or methotrexate back into the blood from the CSF. Entry of drugs into the CSF does not necessarily guarantee that they will reach the interstitial fluid in the brain, suggesting the presence of the so-called CSF-brain barrier, mainly attributed to insurmountable diffusion distances required to equilibrate CSF with brain interstitial fluid. Although the BBB may be inconsistently compromised in tumor vasculature, a variety of obstacles still restrict delivery of therapeutic agents. Tumor microvascular supply often is heterogeneous and chaotic, with significant areas of inefficient or poor blood flow, vascular shunting, blind-ending vessels, etc., resulting in erratic distribution of drugs that are able to penetrate the BBB. Improving delivery of therapeutic agents to brain tumors in the face of these obstacles has focused on the following areas of research: Improve entry through the BBB by modification of therapeutic drugs. a. Increase influx. b. Decrease efflux. c. Utilization of carriers/receptors. Disruption of the BBB. a. A variety of approaches have been used to disrupt BBB integrity including: i. Chemical (often toxic), DMSO, ethanol, aluminium, irradiation, hypertension, hypercapnia, hypoxia. ii. Osmotic agents such as mannitol and arabinose. iii. Biochemical agents such as leukotriene C4, bradykinin, histamine etc. Circumventing the BBB. a. Using non-vascular delivery of therapeutic agents directly into the CNS is appealing in many ways. Apart from removing the BBB as a restriction to delivery of many potent anticancer therapies, targeting the drugs directly potentially reduces systemic toxicity, degradation and immunological stimulation (particularly with protein and virally based therapies). However strategies are generally more invasive requiring craniotomy or insertion of catheters. i. Intraventricular/intrathecal infusion. ii. Wafers/microspheres/microchips. iii. Delivery from biological tissues b. Delivery of therapies directly from living cells within the brain or tumor itself can provide sustained levels of drugs in specific targeted regions. The two main strategies examined to date are: i. Implantation of transfected cell lines. ii. Transduction of resident CNS cells or brain tumor cells with gene therapy constructs. Interstitial delivery. a. Both gene therapies and direct acting drugs, such as chemotherapeutics, can be delivered directly into tumor or brain parenchyma. AAV vectors carrying thymidine kinase suicide constructs and antiangiogenic agents have been shown to be efficacious in both in vitro and in vivo models, and direct 37 injection into canine primary brain tumors has been done. Results in clinical tumors however have been disappointing mainly due to limited distribution of the therapy beyond the local region of the injection site. The Future: Biopsy and Convection Enhanced Delivery Brain Biopsy Biopsy remains the sole method available for the ante mortem definitive diagnosis of brain tumor type in cats or dogs, and is an essential step prior to consideration of any type of therapy. However, biopsy is not always attempted because of practical considerations, such as cost and morbidity. The most recent advance in the biopsy of brain tumors of dogs and cats has been the development of CT-guided stereotactic brain biopsy systems for use in cats and dogs. These CT-guided stereotactic biopsy systems provide a relatively rapid and extremely accurate means of tumor biopsy, with a low rate of complications. Cytological evaluation of brain tumor smear preparations, rapidly fixed in 95% alcohol and stained with hematoxylin and eosin, may be done within minutes of biopsy collection. Diagnostically accurate information from this rapid technique is generally available from both primary and metastatic nervous system tumors. Convection enhanced delivery (CED CED is a local delivery technique that utilizes a bulk-flow mechanism to deliver and distribute macromolecules over clinically relevant volumes of targeted tissue. Unlike local injection techniques, CED uses a pressure gradient established at the tip of an infusion catheter that pushes the infusate through the interstitial space. Volumes of distribution of infused molecules are significantly increased compared to local injection or surgical implantation methods that rely primarily on diffusion and are limited by concentration gradients and molecular weight of the delivered substance. Distribution of infusates over centimeters, rather than millimeters, has been reported in a variety of experimental model systems using CED. Real time in vivo imaging of CED is an essential consideration if adequate drug distribution is to be confirmed ante mortem. Additionally, the ability to detect and minimize distribution or leakage of drugs to normal tissues during delivery has the potential to significantly decrease toxicity and increase therapeutic effectiveness. Several surrogate marker systems have been described, facilitating image-guided CED, including magnetic resonance imaging (MRI) systems utilizing T2 imaging correlated with 123I-labelled serum albumin, single photon emission computed tomography (SPECT), and liposomes co-labeled with gadolinium. Liposomes are phospholipid nanoparticles composed of a bi-layered membrane capable of encapsulating a variety of therapeutic molecules. Liposomal encapsulation of a variety of drugs, including chemotherapeutics, has been shown to result in prolonged half-life, sustained release, and decreased toxicity. CED of liposomes, containing therapeutic drugs, directly into targeted brain tissue offers several advantages over systemic delivery of un-encapsulated drug, including bypassing of the BBB, increased volume of distribution within the target tissue, and increased therapeutic index as a result of both liposomal encapsulation and minimal systemic exposure. Irinotecan/CPT-11 is a camptothecin derivative and topoisomerase I inhibitor with activity against a variety of cancer types, including brain tumors. The efficacy and safety of direct delivery of liposomally encapsulated camptothecin analogs in rodent models of glioma has been reported. Translation of this promising therapeutic approach into clinical trials will require demonstration of the safety and efficacy of combined real time gadolinium based imaging and liposomally encapsulated CPT-11 treatment in a large animal model system. The advantages of a canine model system over established rodent and primate models are several and include the ability to investigate aspects of feasibility and toxicity on a scale relevant to 38 human clinical patients, and the unique potential to investigate CED efficacy, and adverse effects in large, spontaneously occurring tumors. Thiamine Deficiency of Cats Cats are susceptible to thiamine deficiency because of their high-dietary requirement for thiamine, and because fish-based diets that contain thiaminases before processing are often fed to cats. In people, thiamine requirement is directly related to both total caloric intake and the proportion of calories provided as carbohydrates. All of the published reports to date of thiamine deficiency in cats eating commercially available diets have involved canned foods. Canned foods are more susceptible to thiamine loss because of the high temperature involved in the processing of these diets, in particular when the pH is above 5. The primary sources of thiamine supplementation in commercially available pet foods are synthetic (thiamine mononitrate and thiamine hydrochloride), and these sources are more susceptible to destruction than the thiamine present in plant and animal tissues. Thiamine can be destroyed by sulfate trace minerals and sulfite preserved meats which cleave the thiamine at the methylene bridge. In addition, thiamine is oxidized by ultraviolet and gamma irradiation and degraded by thiaminase enzyme activity found predominantly in shellfish, fish viscera, and some bacteria. Thiaminase is destroyed by heat processing; however, if raw ingredients are not promptly or properly cooked, destruction could result in lower than expected concentrations of thiamine. Given there are no real safety concerns regarding increased dosages of thiamine in either the cat or dog, and processing losses can exceed 90%, fortification in diet premixes warrants careful consideration to ensure appropriate thiamine concentrations in the final product. Thiamine deficiency is a readily reversible neurological disorder that warrants consideration in any cat manifesting compatible clinical and neurological signs. The differential diagnoses for the multifocal intracranial disease suspected in all cats based on their neurological examinations included toxic and metabolic disease. Foods should also be evaluated for their adequacy as the sole or primary diet, as many unbalanced canned products are widely available and are marketed and labeled similarly to complete diets. Further studies assessing thiamine content of canned feline diets are warranted. Abscessation of the Central Nervous System in Cats Infection of the CNS may result in an abscess formation (a circumscribed collection of purulent material within the CNS, its surrounding membranes, or in the epidural space) and/or much less frequently, empyema (collection of pus in subdural or epidural locations). The term "pyocephalus" refers to a purulent effusion within the cranium and is synonymous with "pyencephalus". In animals, the empyema tends to be in cranial subdural sites and in spinal epidural locations. Abscesses within the CNS are uncommon in cats but may arise as a result of either metastasis from distant foci of infection (e.g., lung abscesses and bacterial endocarditis), by direct extension from sinuses, ears, and eyes, as a result of trauma (e.g., bite wound), or from contaminated surgical instruments (e.g., spinal needle). Brain abscess may also result from penetration of the cranial cavity and brain substances by an exopharyngeal foreign body (e.g., sewing needle). Several instances of spinal epidural infection in the cat have followed tail fracture or a purulent granulomatous dermatitis involving the tail. The common sites for direct extension are the cribriform plate and the inner ear, resulting in abscess formation in the frontal lobe and the cerebellopontine angle, respectively. Spinal epidural infections also may result from vertebral osteomyelitis or paraspinal abscess. Abscesses of hematogenous origin, such as those that spread from pulmonary infection, bacterial endocarditis, or congenital heart disease with right to left shunting, appear to have a predilection for 39 the CNS parenchyma, especially in the hypothalamus and cerebral cortex, and particularly in less vascularized areas such as white matter and junctions of gray and white matter. It is thought that neuraxial abscessation occurs preferentially in areas of focal ischemia or necrosis. Typically, CNS abscesses are associated with bacteria, but are occasionally caused by fungi. Aerobic bacteria such as Streptococcus, Staphylococcus, Pasteurella, and Nocardia may be more common than anaerobic bacteria as causes of CNS infection in dogs and cats. Nevertheless, anaerobic bacteria such as Bacteroides, Fusobacterium, Peptostreptococcus, Actinomyces, and Eubacterium are reported to be important pathogens in cats, casuing either brain abscesses or subdural empyema. Actinomyces typically spreads by direct extension, although brain and possibly vertebral abscesses may result from hematogenous dissemination. Otogenic Intracranial Infection Extension of otitis media/interna into the central nervous system is a serious complication that may occur in cats of any age, breed or gender. Most intracranial complications originate from sub-acute to chronic ear infections, resulting in abscess formation in the brain. Cerebral Phaeohyphomycosis Phaeohyphomycosis refers to invasive disease caused by several species of dematiaceous fungi. Cognitive Dysfunction Syndrome Cognitive dysfunction syndrome (CDS) is an age-related neurodegenerative disease that impairs memory and learning. CDS may manifest itself in multiple nonspecific clinical signs that increase in frequency and severity over time in affected cats. Cognitive dysfunction is an age-related neurodegenerative disease that impairs memory and learning. Cognitive dysfunction can cause various behavioral changes. Make sure to rule out diseases that can mimic these signs. There are many forms of cognitive dysfunction and often they involve the depletion of neurotransmitters or disruption of neural pathways. The common denominator in all cases of neurodegeneration and cognitive decline is oxidative stress and mitochondrial dysfunction. Alterations in cell function and neurotransmission in the brain of the CDS patients lead to malfunctions of short-term memory, loss of learned behavior, impairment of the processing of sensory information, reduction in cognitive capacity, and alterations of mood. The progression of CDS is related to the general rate of aging of cats and dogs. Quite significant changes may occur in the space of weeks or months. Worsening of the condition may be precipitated by stressful events such as hospitalization, kenneling, surgery or a house move. Ideally, cats should be behaviorally assessed before these events. Emotional changes: mild emotional changes may be the first signs of the onset of dementia. Signs include depression (reduction in activity, play and interest in activities the cat formerly enjoyed). Increases in anxiety and fear leading to irritability and aggressiveness. Defects of short-term memory: the animal repeatedly performs certain actions such as asking for attention, food and other rewards. Malfunction of short-term memory is at the root of many of the problems seen in CDS. 40 Disorientation: the animal has trouble recognizing people, locations, or objects. This may lead to secondary problems, such as house soiling and difficulty finding locations in the home (e.g., door to outside, cat flap, water and food dish). Changes in sleep-wake cycle: the animal tends to sleep mostly during the day and appears restless at night, often waking up and crying out loudly. Pain and illness are also significant factors in night-time restlessness (e.g., chronic arthritic pain may make rest uncomfortable, and deafness can result in the cry becoming loader than previously). Loss of learned behaviors: failure to respond to commands and social signals that inhibit unwanted behavior. This contributes to loss of social inhibition and alterations in relationships with people and other animals in the home. Loss of house training (example of a learned behavior): a previously house trained animal will suddenly urinate and/or defecate inside the house and/or outside its littler box. This clinical sign can be caused by numerous medical and behavioral problems that have to be ruled out, especially osteoarthritis, hyperthyroidism and hypertension. Changes in interaction with the environment: reduced greeting of the owner, familiar persons or pets, decreased response to commands. A depressed mood and lack of interaction tends to isolate animal from their owners, who may not instigate play or give attention. Through a loss of stimulation and reward of normal activity the degradation of the human-animal bond leads to social isolation that contributes to worsening signs of CDS. Neurological : in the latter stages of CDS, neurological impairment may be seen. These include ataxia, apparent sensory loss (loss of vision/hearing) and changes in locomotion. Any neurological signs must be investigated thoroughly as there are numerous other potential medical causes. Treatment The drug Anipryl (selegiline), used by humans to treat Parkinson’s disease, has been reported to dramatically improve clinical signs and the quality of life for many dogs with cognitive dysfunction syndrome. An additional benefit may come from feeding the therapeutic diet Hill’s b/d. This diet is specifically formulated with extra antioxidants for older dogs. Older dogs may also benefit from treatment with acupuncture and Chinese herbs. References Dickinson PJ, LeCouteur RA, Higgins RJ et al. 2008. Canine model of convectionenhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation. J Neurosurg 108, 989-98. Dickinson PJ, LeCouteur RA, Higgins RJ et al. 2010. Canine spontaneous glioma: a translational model system for convection-enhanced delivery. Neuro Oncol 12, 928-40. Thomas R, Duke SE, Wang HJ, et al. 2009. 'Putting our heads together': insights into genomic conservation between human and canine intracranial tumors. J Neurooncol 94, 333-49. Wisner ER, Dickinson PJ, Higgins RJ. 2011. Magnetic resonance imaging features of canine intracranial neoplasia. Vet Radiol Ultrasound.52(1 Suppl 1):S52-61. 41