PRINCIPLE #1: THE BRAIN IS SIMILAR TO OTHER ORGANS IN THE BODY. ISVMA 2017 November 2017 DR. MICHAEL PODELL 1 PURPOSE

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1 Michael Podell MSc, DVM Diplomate ACVIM (Neurology) MedVet Chicago PURPOSE To provide 10 guiding principles to the diagnosis and management of an epileptic cat to improve treatment outcome measures Successful treatment is dependent upon the 3 D s: Diagnosis Drug selection Dose administration Update on novel theories on etiology Update on treatment strategies Update on the International Veterinary Epilepsy Task Force (IVETF) Consensus Statement International Veterinary Epilepsy Task Force The International Veterinary Epilepsy TaskForce (IVETF) is formed by a mondial (among others Europe, United States of America, Australia) group of (veterinary) scientists interested and specialised in the field of epilepsy. Our group consists of clinical veterinary neurologists, neuropharmacologists, and veterinary neuropathologists PRINCIPLE #1: THE BRAIN IS SIMILAR TO OTHER ORGANS IN THE BODY Signs parallel severity of illness Resiliency Responsive to therapy PRINCIPLE #2: BE CERTAIN THAT AN EPILEPTIC SEIZURE HAS OCCURRED Positive diagnosis is essential prior to therapy Epileptic seizures: Paroxysmal onset, finite duration, +/ post ictal changes Diagnosis of epilepsy = abnormal brain function DR. MICHAEL PODELL 1

2 SEIZURE TYPES Focal (partial) Sensory (psychic) Motor Elementary Automatisms Orofacial pain syndromes Generalized Tonic clonic Clonic Myoclonic Atonic Cluster seizures Status Epilepticus Kitz et al. J Vet Intern Med (3): Feline Audiogenic Reflex Seizures Lowrie et al J Feline Med and Surg (2016) 18: Seizures precipitated by sound High pitched (metal clinking, tin foil Repetitive (computer keys, phone ring) Myoclonic seizures predominant type (94%) Normal diagnostic testing Treatment Levetiracetam (93% success for myoclonic seizures) Avoidance (dec by 75%) PRINCIPLE #3: IDENTIFY THE SEIZURE ETIOLOGY SEIZURE ETIOLOGY CLASSIFICATION PREVALENCE BY ETIOLOGY SEIZURE EPILEPTIC SEIZURE NON-EPILPETIC SEIZURES STUDY TOTAL NUMBER IDIOPATHIC SYMPTOMATIC METABOLIC / TOXIC RECURRENT NON-RECURRENT Barnes et al JAVMA EPILEPSY PRIMARY SYMPTOMATIC PROBABLE SYMPTOMATIC REACTIVE PRIMARY SYMPTOMATIC REACTIVE Schriefl et al JAVMA 2008 Pakozdy et al J Feline Med Surg TOTALS (35%) 122 (52%) 31 (13%) IDIOPATHIC (PRIMARY) EPILEPSY Normal brain structure with abnormal function Less common than in dogs Age of onset typically < 6 years Not correlated with seizure type Normal neurologic exam and interictal periods (except for status epilepticus) SYMPTOMATIC EPILEPSY Structural brain disease Any age of onset (Raimondi et al Vet Rec 2017) < = 1 year: 9.4% 1 6 years: 5.4% >6 years: 23.1% Increase risk of 14% per year over 6 May OR may not be associated with abnormal exam or interictal period Typically shorter initial interictal interval Often associated with focal motor seizures SILENT DR. MICHAEL PODELL 2

3 SYMPTOMATIC CAUSES Infectious FIP Protozoal Neoplasia Meningioma Vascular Head trauma < 6 % risk Grohmann et al JAVMA 2012 T2W TRANSVERSE MRI SCAN R Developmental Anomaly Hydrocephalus Porencephaly Cortical dysplasia Functional disturbance (kindling) REACTIVE EPILEPTIC SEIZURES Normal brain structure Age of onset: younger Portosystemic shunt Pre ligation: > 80% Post ligation: >35% Lipscomb et al Vet Rec 2007 Toxicity Permethrin Nutritional Thiamine depletion Cardiogenic A V block May not be syncopal Feline Hippocampal Necrosis Syndrome Adult cats with high frequency seizure activity Histopathologic evidence of selective hippocampal necrosis Difficult to treat cases Temporal Lobe Epilepsy in People Anatomy Neocortex (6 layer) Hippocampus (3 layer) Subcortical nuclei Complex partial seizures Ambulatory automatisms Hallucinatory phenomenon Hippocampal sclerosis Highest degree of medically intractable epilepsy Scharfman and Pedley, 2007 DR. MICHAEL PODELL 3

4 Limbic Encephalitis Autoimmune disease in adult people CSF autoantibody Onconeuronal Voltage gated potassium channels MRI scan of hyperintense hippocampal lesions on T2W and FLAIR images Normal CSF analysis Progression to temporal lobe epilepsy and hippocampal sclerosis Treatment of primary disease may prevent need for chronic antiepileptic drug therapy 23 yo woman Bien et al Neurol 2007;69: Feline Limbic Encephalitis 35 yo man with hippocampal 6 yo MC DSH cat with sclerosis and LE refractory epilepsy Podell and Oglesbee 2008 Bien et al Neurol 2007;69: /10 cats with serum & CSF VGKC AB Pakozdy et al JVIM /14 cats with serum VGKC AB PRINCIPLE #4: ALWAYS TREAT THE UNDERLYING DISEASE Antiepileptic drug therapy manages the signs ONLY Reversal of metabolic abnormalities often prevents the need for chronic AED therapy Symptomatic epilepsy may still need to be treated with AEDs despite removal of the inciting cause PRINCIPLE #5: SEIZURES BEGET SEIZURES William Gowers Accurate history and documentation is essential The earlier AED therapy is started, the better the potential outcome for seizures control Earlier therapy may reduce the need for multiple drug therapy Progression of clinical and EEG seizures induced by repeated activation in neural pathways Critical period exists (< 6 months) for onset of sustained temporal lobe epilepsy Early treatment results in more favorable prognosis Shouse et al. Brain Res 1027:126, 2004 Kindling Realistic Goals of Therapy Balance between seizure control and quality of life Seizure control, not necessarily seizure elimination Decrease in frequency and severity of seizures Prevention of cluster seizure events Decrease post ictal severity DR. MICHAEL PODELL 4

5 Realistic Expectations by Owners Life long commitment Daily medication commitment Potential for emergency treatment Inherent risks of therapy Time for another pill?!! Reasons to Start Antiepileptic Drug Therapy Identifiable structural lesion present (symptomatic epileptic seizures) Status epilepticus has occurred More than 3 generalized seizures occurred within a 24 hour period Reasons to Start Antiepileptic Drug Therapy Two or more cluster seizure events (2 or more seizures) occur within a 12 month period Two or more isolated seizure events occur within a 6 month period The first seizure is within 6 months of head trauma Prolonged, severe, or unusual post ictal periods occur PRINCIPLE #6: Start with the Appropriate AED First Generation Phenobarbital Benzodiazepines Bromide Second Generation Levetiracetam Zonisamide Topiramate Gabapentin IVETF Recommendations High Phenobarbital Levetiracetam Moderate Zonisamide Diazepam Gabapentin Pregabalin Low Clonazepam Topiramate Propentofylline Taurine Efficacious Well tolerated Consistent in its effect Can be monitored Can be given as an injectable or oral formulation Relatively rapid acting Can serve as a cerebral protectant Inexpensive PHENOBARBITAL Phenobarbital Is the Drug of Choice for the Majority of Cases DR. MICHAEL PODELL 5

6 PHENOBARIBITAL TREATMENT PEARLS 2.5 mg/kg PO daily at night to start Elimination half life hours No hepatic enzyme autoinduction IV loading dose: Total mg IV = (Body weight [kg] X (0.8 L/kg) X 10 ug/ml) = 8 mg/kg over 3 minutes Therapeutic range: mg/dl Hepatot0xicity is very rare POTASSIUM BROMIDE PEARLS Not recommended for use in cats due to potential for allergic bronchitis syndrome which can be fatal PRINCIPLE # 7: MONITOR AED CONCENTRATIONS (Be Proactive Rather Than Reactive) Determine if therapeutic level present at lowest daily time point (trough) Document steadystate concentration Prevent toxic effects Individualize therapy PHENOBARBITAL MONOTHERAPY Range: Initial goal is mg/dl Maximum: 50 mg/dl Measure at: Trough times 14, 45, 90, 180, and 360 days after the initiation of treatment At 6 months intervals thereafter If pet has more than two seizure events between these times 14 days after the last dosage adjustment Benzodiazepine Therapy Diazepam Oral: 2.5 to 5 mg q 12 hours IV: 0.5 mg/kg bolus CRI IV: 0.25 mg/kg/hr in saline Per rectal: Not recommended Clonazepam Oral: 0.25 to 0.5 mg q hours Evaluate liver panel 2 weeks post chronic treatment for idiosyncratic hepatic necrosis PRINCIPLE # 8: KNOW HOW AND WHEN TO ADJUST AED DOSAGE TOLERANCE= LOSS OF EFFECTIVENESS ACQUIRED DOSE [SERUM] TIME ENZYME INDUCTION METABOLIC CROSS- TOLERANCE POSITIVE TIME DOWN REGULATION OF RECEPTORS FUNCTIONAL DECREASED BBB DELIVERY NEGATIVE UP REGULATION OF RECEPTORS PROGRESSION OF DISEASE Weight based dosing used on initial therapy only Follow established therapeutic serum concentration ranges Adjust after steady state concentrations achieved Adjust for metabolic tolerance Gradual increments are most effective DR. MICHAEL PODELL 6

7 Phenobarbital Dose Adjustments Monitor trough serum concentrations Consistent time point for comparison Time period of highest risk for relapse Comparison to peak levels for toxicity New total mg phenobarbital per day= (desired concentration / actual concentration) X total mg per day Differential dosing for animals with more frequent night/early AM seizures PRINCIPLE # 9: CHECK ON OWNER COMPLIANCE Seizure records Review of dosing schedule and method 20% drop of trough steady state concentration can be an indicator of poor compliance MONTH 1 MONTH 2 MONTH 3 DAY 1 SEIZURE # DAY 2 DAY 3 TOTAL SINGLE SHEET RECORD FOR 1 YEAR PRINCIPLE # 10: KNOW WHEN TO ADD, CHANGE, OR STOP MEDICATIONS Reasons for adjustments Refractory epilepsy: Recurrent seizure activity at a rate of >1 per 8 weeks Toxicities Expense Discontinuation is always a gamble Higher probability of success with longer history of control Gradual reductions are important to avoid withdrawal seizures IVETF BMC Vet Res. 2015; 11: 177. LEVETIRACETAM PHARMACOKINETICS Low protein binding results in minimal drug interactions Renal excreted (70%) Minimal hepatic metabolism Elimination half life of 2.9 hr ( range) Bailey et al JAVMA 2008:232: Pharmacodynamic effect > pharmacokinetic effect DR. MICHAEL PODELL 7

8 LEVETIRACETAM TREATMENT Primary drug Liver disease or older cats Dose: 20 mg/kg po TID with gradual up titration Best add on drug Best tolerated of all new AED in cats Excellent add on option for all seizure types Dose: Dose: 20 mg/kg po TID with gradual uptitration Best used with orofacial complex partial seizures/pain syndrome Monitoring drug levels not recommended due to high therapeutic index Maximal dose: 50 mg/kg PO TID or adverse effects ZONISAMIDE ZONISAMIDE Blocks Na+ and Ca+2 channels to reduce depolarization Long elimination half life of 30 + hours Dose 5 mg/kg/day 25, 50, 100 mg capsules Therapeutic range mcg/ml Metabolic acidosis prevalent PROGNOSIS EPILEPSY OF UNDETERMINED CAUSE SYMPTOMATIC EPILEPSY 4 mo Wahle AM et al JVIM (1): SAPERE VADERE DR. MICHAEL PODELL 8