ISVMA 2017 November, 2017

Canine Seizure Management: Panel Members Update on the ACVIM and IVETF Consensus Statements Dr. Michael Podell (Chair) Dr. Mette Berendt Dr. Wolfgang Löscher Dr. Karen Muñana Affiliate Professor, U of Chicago, Professor Professor Professor Michael Podell MSc, DVM, Diplomate ACVIM (Neurology) Pritzker School of Medicine ; University of University of Hannover NC State University, MedVet Chicago Chicago Veterinary Specialty Group, Copenhagen, Denmark Germany USA [email protected] USA 773-281-7110 Dr. Ned Patterson Dr. Simon Platt Dr. Holger Volk Associate Professor Professor Co-Chair University of University of Professor Minnesota, USA Georgia, USA The Royal Veterinary College, London, UK

Berendt et al. BMC Veterinary Research (2015) 11:182 International veterinary epilepsy task force consensus report on epilepsy definition, classification International Veterinary Epilepsy Task Force and terminology in companion animals

Hülsmeyer et al. BMC Veterinary Research (2015) 11:175 International Veterinary Epilepsy Task Force’s current understanding of idiopathic epilepsy of genetic or suspected genetic origin in purebred dogs

Rusbridge et al. BMC Veterinary Research (2015) 11:194 International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

De Risio et al. BMC Veterinary Research (2015) 11:148 International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs The International Veterinary Epilepsy TaskForce (IVETF) is formed by a mondial (among others Europe, United States Bhatti et al. BMC Veterinary Research (2015) 11:176 of America, Australia) group of (veterinary) scientists International Veterinary Epilepsy Task Force consensus proposal: medical treatment of interested and specialised in the field of epilepsy. Our canine epilepsy in Europe group consists of clinical veterinary neurologists, neuropharmacologists, and veterinary neuropathologists Potschka et al. BMC Veterinary Research (2015) 11:177 http://www.ivetf.org/ International veterinary epilepsy task force consensus proposal: outcome of therapeutic interventions in canine and feline epilepsy

International Approach CON-SEN-SUS ▪ Standardization of terminology ACVIM ▪ Latin from consentire (to allow) ▪ Provide foundation of scientific evaluation and recommendation ▪ General agreement: unanimity ▪ The judgment arrived at by most of those concerned ▪ Establish a framework for ECVIM veterinary clinical and human ▪ Group solidarity in sentiment and belief translation studies AND IVETF ▪ Parallel work with International ECVN Veterinary Epilepsy Task Force

Dr Michael Podell MedVet Chicago 1 ISVMA 2017 November, 2017

Guidelines for the Diagnosis and Treatment Our Approach of Canine Epilepsy Problems Objectives ▪ Seizure identification and diagnosis (not included in this paper) ▪ Decision making treatment strategies ▪ Epilepsy is a heterogeneous disease ▪ Present a working clinical consensus process statement for canine seizure 1. When should treatment be started? management 2. Which drug should be used first? ▪ Incomplete diagnostic capabilities ▪ Focus on epilepsy of undetermined 3. How should AED monitoring be performed? ▪ Unpredictable clinical outcome cause (idiopathic/genetic/primary) 4. What are the risks of treatment? ▪ Chronic treatment only ▪ Wide-variability in treatment 5. What is drug-resistance? approaches ▪ Recommendations based on published 6. When and which second AED should be started? reports and clinical expertise opinion ▪ Small database of strong evidence- ▪ Complimentary and alternative treatment strategies based clinical studies ▪ Establish a predetermined, concise and logical sequential approach to seizure ▪ Guidelines to enhance patient response and quality of life ▪ Use of antiepileptic drugs (AED) management established for people ▪ Emergency treatment strategies (not included in this paper)

Level Of Grade Of Type Of Evidence Evidence ≠Recommendation ▪ Random sequence generation METHODOLOGY I Appropriately designed, controlled trials Blinded, randomized clinical trials and A Cochrane Risk of ▪ Allocation concealment drug efficacy of ≥50% seizure reduction Published evidence in the peer-reviewed for at least 6 months High and likely to literature Bias Assessment ▪ Blinding of participants IB Blinded, randomized clinical trials and be effective • Standard electronic databases drug efficacy of ≥50% seizure reduction Tool for at < 6 months ▪ Personnel and outcome assessors • Pub Med (www.ncbi.nlm.nih.gov/PubMed) CAB Abstracts (www.cabdirect.org) and Web II Case-control or cohort studies (N > 15) B of Science (http://wok.mimas.ac.uk) search Moderate and ▪ Completeness of outcome data strategies included reference lists of Non-blinded, randomized, or non-blinded published papers and proceedings and non-randomized clinical trials and/or likely to be drug efficacy of ≥50% seizure reduction effective ▪ Selective reporting of outcome measures • Studies were included following modified for > 12 weeks criteria laid out in detail by Charalambous III Case-control or cohort studies: (N< 15) ▪ Other sources of bias et al. 2014 C Non-blinded and non-randomized clinical • Any peer-reviewed study without language trials with cohort size of less than 15 Low and may not Charalambous et al. Treatment in restrictions in which an antiepileptic drug and/or drug efficacy of ≥50% seizure be effective was used and in dogs with epilepsy reduction for < 12 weeks canine epilepsy- a systematic Expert opinion only without review. BMC Veterinary Research, IV D • Proceedings documentation by case reports or series 2014 Not • Annual Congresses of the European Society and College of Veterinary Neurology and the recommended American College of Veterinary Internal Medicine Levels of evidence and grades of recommendation. Table adapted from the National Institute for Health and Care Excellence (NICE) guidelines (Eccles & Mason 2001)

When Should Treatment Be Started? ACVIM Panel Recommendations: ▪ Decision to treat is a reflection of the ▪ Guidelines for people to start AED: The Reasons to Start AED Therapy treatment goals: ▪ Diagnosis of current or previous defined ▪ Identifiable structural lesion present or prior history of brain disease or injury ▪ Reduce or eliminate epileptic events cerebral lesions or trauma ▪ Reduce seizure severity ▪ Presence of inter-ictal EEG epileptic ▪ Acute repetitive seizures / status epilepticus has occurred discharges (up to 90 % recurrence rate) ▪ Avoid adverse effects ▪ Ictal event > 5 minutes or ▪ History of marked post-ictal adverse effects ▪ Reduce seizure-related mortality and morbidity ▪ 3 or more generalized seizures occur within a 24 hour period or ▪ First unprovoked, seizure for adult onset? ▪ 2 or more seizures without completely regaining consciousness between seizures ▪ Risk factors for seizure recurrence are not ▪ Individual risk and quality of life assessment well-established for dogs ▪ Recurrence risk 21-45% within first 2 years ▪ Two or more seizure events occur within a 6 month period ▪ Immediate treatment improves seizure free ▪ Seizure density is considered a strong risk prediction by 50% ▪ Prolonged, severe, or unusual post-ictal periods occur factor for seizure recurrence ▪ Packer et al. Clinical risk factors associated with AED American Academy of Neurology, ▪ IVETF : “The epileptic seizure frequency and/or duration is increasing and/or responsiveness in canine epilepsy, 2014 Summary of Evidence – Based Guidelines, 2015 seizure severity is deteriorating over 3 inter-ictal periods” http://journals.plos.org/plosone/

Dr Michael Podell MedVet Chicago 2 ISVMA 2017 November, 2017

Grade of Which AED Should Be Used First? Phenobarbital Monotherapy Level Evidence= I Recommendation = A High 8 studies (n = 311) Recommendation Moderate 6 studies: Treatment Risk of Higher Risk of Bias 5 studies (n > 15) Duration of 5 to 32 Complications months

Primidone Imepitoin Potassium •Approved in US •Approved in 82% with > 50% 15% with no Phenobarbital and Europe Europe Levetiracetam Zonisamide 3% with > 0 and < Low Risk of Moderate High Risk of bromide seizure reduction improvement Bias Risk of Bias Bias (N=255) (N=47) 50% seizure reduction (N=9) •2 studies •1 study •4 studies

31% with seizure free status (N=96) Cochrane Risk of Bias Assessment (Charalambous et al, 2014)

Potassium Bromide Monotherapy Grade of Primidone Monotherapy Level Evidence= II Recommendation Grade of = D Level Evidence= I Recommendation = B (n= 1) Not Recommended 6 studies (n = 103) Moderate 1 study RISK OF Higher Treatment Recommendation High Higher Risk of BIAS Risk of Bias Moderate 5 studies: Complications Lower Risk of Bias 5 studies (n > 15) Treatment Risk of Duration of 6 to 35 (n=1) months Complications N = 23 6 months duration 21% with no 38% with > 50% 41% with > 0 and < seizure reduction improvement 50% seizure reduction Low Risk of Moderate Risk High Risk of (N=39) (N=22) Low Risk Moderate High Risk of Bias Bias of Bias Bias (N=42) Risk of Bias •1 •0 •0 74% with > 50% •0 studies •3 studies •3 studies 16% with >0 and < 35% with seizure seizure reduction 50% seizure reduction free status (N=36)

Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Cochrane Risk of Bias Assessment (Charalambous et al, 2014)

Grade of Imepitoin Monotherapy Level Evidence = I Recommendation Grade of = A Levetiracetam Level Evidence= IV Recommendation = C High Monotherapy 4 studies (n = 205) Recommendation Insufficient Data to Recommend Low Treatment Low to Moderate Low Treatment Risk of Unknown Risk of 4 studies: Risk of Bias No published reports evaluating the Risk of 2 studies (n > 15) Complications Bias Duration of 5 to 8 months use of levetiracetam as first line Complications therapy in dogs with epilepsy

38% with > 50% 2 % with no 60% with > 0 and < seizure reduction improvement 50% seizure reduction Low Risk Moderate Risk High Risk of Bias (N=78) (N=3) Low Risk of Moderate Risk High Risk of Bias of Bias (N=123*) Bias of Bias •0 studies •0 studies •0 studies •2 studies •2 studies •0 studies 40% with seizure free status (N=82) * = Estimated Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Cochrane Risk of Bias Assessment (Charalambous et al, 2014)

Dr Michael Podell MedVet Chicago 3 ISVMA 2017 November, 2017

Grade of ACVIM Panel Monotherapy Recommendations: Zonisamide Monotherapy Level Evidence= III Recommendation = C DRUG LEVEL OF EVIDENCE GRADE OF Insufficient Data to RECOMMENDATION 1 study (n = 10) Recommend Low Treatment Phenobarbital I A Higher Risk of Risk of Bias Duration of 12 to 36 Complications 0 studies (n > 15) months Bromide I B

60% with > 40% with no 0% with > 0 and Low Risk Moderate High Risk of Bias Primidone II D 50% seizure improvement < 50% seizure Risk of Bias reduction (n=6) (N=4) reduction •0 studies •0 studies •1 study Imepitoin I A

0 % with seizure free status Levetiracetam IV C Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Zonisamide III C

ACVIM Panel Grade of Recommendations How Should AED Monitoring Be Performed? (Level of Evidence) for AED Monotherapy ▪ Objectives ▪ Determine effective drug levels after initiation of successful therapy (as appropriate ) A (HIGH) B (MODERATE) C (LOW) D (NO) ▪ Determine if drug failure is due to: ▪ Pharmacokinetic factors to focus on a change •Bromide (I) •Levetiracetam •Primidone (II) in dose (metabolic tolerance) or •Phenobarbital ▪ Pharmacodynamic factors to focus on a (I) (IV) change of drugs (functional tolerance) •Zonisamide •Imepitoin (I) ▪ Determine if treatment failure is due to (III) poor compliance, an inadequate or a TOLERANCE change in drug level DOSE ▪ Prevent toxic effects from occurring [SERUM]

▪ Aid with individualization of therapy TIME TIME METABOLIC FUNCTIONAL

▪ Pharmacology Drug Monitoring ▪ Elimination half-life of 24-40 hours ▪ Auto-induction of hepatic metabolism results in enhanced . Reference range is established by clearance over 6 weeks laboratory /clinical study for a Phenobarbital ▪ High degree of drug-drug interactions due to hepatic population metabolism and higher protein binding . Sub-therapeutic: Lower limit below which ▪ Panel recommendations therapeutic response is unlikely Evidence level: I ▪ Initial dose of 2.5 mg/kg q 12 hours . Toxicity: Upper limit below which toxic ▪ Monitor levels at 2 and 6 weeks and every 6 months, response is likely Grade of Recommendation ▪ 2 weeks after a dose change or with increase in seizure frequency for Monitoring: A . Therapeutic range is the range of drug ▪ Monitor if signs of toxicity concentrations associated with best ▪ Patient therapeutic range of 15-35 ug/ml achievable results in an individual ▪ Collect trough sample for dogs with recurrent seizures 6 weeks . Initial Start •Steady clearance . Target

2 weeks •Steady state

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▪ Pharmacology ▪ Pharmacology ▪ Elimination half-life 15 -20 days ▪ Rapidly metabolized to its major active metabolite ▪ Renal elimination phenobarbital that is responsible for more than 85% of the total anticonvulsant activity ▪ No protein binding ▪ Panel recommendations : ▪ Similar pharmacokinetic profile as phenobarbital Potassium Bromide ▪ Initial dose or 30 to 40 mg/kg /day (single or divided) Primidone ▪ Panel recommendations ▪ Monitor at 8 to 12 weeks after initiation and every 12 months ▪ Initial dose of 10 mg/kg q 12 hours ▪ 1 month after a dose change, or if increase in seizure frequency ▪ Monitor levels at 2 and 6 weeks and every 6 months, Evidence level: I ▪ Monitor if signs of toxicity ▪ 2 weeks after a dose change or with increase in seizure Evidence level: I frequency Grade of Recommendation for ▪ Patient therapeutic range is 1000 to 3000 ug/ml for Monitoring: A monotherapy and 800 to 2500 ug/ml for combined therapy Grade of Recommendation for ▪ Monitor if signs of toxicity ▪ Collect sample after 2 hours of dosing Monitoring: A ▪ Patient therapeutic range of 15-35 ug/ml ▪ Avoid peak concentration ▪ Collect trough sample for dogs with recurrent seizures 6 to 12 months Start 6 weeks •Cumulative effect Start •Steady clearance

2 months 2 weeks •Steady state •Steady state

▪ Pharmacology ▪ Pharmacology ▪ Elimination half-life of approximately 2 hours ▪ Elimination half-life ▪ Monotherapy: 4-8 hours ▪ No known therapeutic concentration Imepitoin ▪ With phenobarbital = 2-4 hours ▪ Low inter-individual metabolism variability Levetiracetam ▪ Low hepatic metabolism ▪ Low drug-drug interaction ▪ No indication of drug-drug interaction Evidence level: I ▪ Panel recommendations: ▪ Panel recommendation: Grade of Recommendation: C Evidence level: I ▪ Initial dose of 20 mg/kg q 8 hours ▪ Initial dose of 10-30 mg/kg q 12 hours Approved in Europe Grade of Recommendation ▪ Monitoring is not routinely recommended ▪ Drug monitoring is not recommended except in for Monitoring: C ▪ Monitoring may be indicated with concomitant rare cases of concern for owner compliance phenobarbital treatment if satisfactory seizure control is not achieved. ▪ Trough and Peak levels are most helpful

▪ Pharmacology ▪ Elimination half-life of 15-20 hours What Are The Risks Of Treatment? ▪ Hepatic metabolism but without hepatic autoinduction ▪ Increased clearance with concomitant phenobarbital use ▪ Type 1: Predictable and directly ▪ Weak carbonic anhydrase inhibitor related to pharmacological effects in a dose dependent fashion Zonisamide ▪ Panel recommendations with the following criteria: EFFICACY ▪ Initial dose ▪ Type 2: Unpredictable Therapeutic Index ▪ Monotherapy: 5 mg/kg q 12 hours (idiosyncratic) and may be life- ▪ With phenobarbital : 10 mg/kg q 12 hours threatening Evidence level: II ▪ Monitor levels at 2 weeks and then every 6 months, TOXICITY ▪ 2 weeks after a dose change or with increase in seizure frequency ▪ Type 3: Cumulative effects with Grade of ▪ Collect trough time if used as monotherapy longer term therapy and may be Recommendation for life-threatening Monitoring: A ▪ Collect trough and peak (3 hours) if used with phenobarbital ▪ Patient therapeutic range of 10-40 ug/ml ▪ Type 4: Delayed consequences (carcinogenic/teratogenic) and Start 6-12 weeks life-threatening

2 weeks

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Type 1 Type 2 Type 3 Type 4 Phenobarbital Behavioural changes • Immune-mediated anemia, • Psychogenic polydipsia with associated Not reported neutropenia or thrombocytopenia, polyuria • Acute, idiosyncratic hepatotoxic • Elevation of the serum alkaline phosphatase What is Drug-Resistant Epilepsy? reactions level • Superficial necrolytic dermatitis in • Factitious decrease in serum total and free International League Against Epilepsy Task Force dogs thyroxine (T4) • Drug-induced hepatotoxicity (>35 ug/ml) Kwan et al, Epilepsia 52:1069-1077, 2010 • Physical dependence and associated withdrawal effects Drug Treatment Success Drug-Resistant Epilepsy Potassium Increased lethargy and • Pancreatitis and gastrointestinal • Polydipsia and polyphagia Not reported bromide mild ataxia with intolerance • Pelvic limb ataxia and weakness increasing serum • Idiosyncratic allergic bronchitis • Altered behaviour ▪ Seizure free duration at least 3 times ▪ Level 1 concentration • Panniculitis • Megaesophagus the longest seizure free period prior to • Caution should be used when treating dogs onset of treatment ▪ Undetermined outcome with underlying renal insufficiency ▪ Inadequate time or drug dose Primidone Similar to Phenobarbital Similar to phenobarbital • Higher prevalence of hepatotoxicity than Not reported ▪ Minimum duration of 12 months phenobarbital ▪ Monotherapy failure Imepitoin • Somnolence/sedation Not reported None reported Imepitoin is not ▪ Continued seizure recurrence despite • Polyphagia, polyuria genotoxic, appropriate drug selection, time of and polydipsia teratogenic or treatment and serum concentration • Hyperactivity immune toxic • Ataxia ▪ Level 2 Levetiracetam Ataxia only parameter to Not reported Not reported Not reported differ from baseline ▪ Failure of adequate trials of 2 tolerated and appropriately chosen AEDs Zonisamide Sedation, ataxia and • KCS • Lower total T4 levels Not reported gastrointestinal upset • Polyarthropathy • Lower total C02 • Acute toxic hepatic necrosis • Renal tubular acidosis

What Causes Drug- Resistance? When Should a Second AED Be Started? ▪ ▪ Strict criteria for decision-making strategy Transporter hypothesis (1) on starting a second AED is lacking in ▪ Panel Recommendations: ▪ Reduced AED CSF concentration veterinary medicine ▪ Documentation of appropriate drug ▪ Target hypothesis (2) ▪ Risk factors associated with poorer and maximal level of first AED for a minimum of 3 months ▪ Decrease AED action at receptor seizure control include male dogs and prior cluster seizure activity ▪ > 50% increase in seizure frequency ▪ Network hypothesis (3) ▪ (Packer et al. 2014) over 3 months ▪ Altered connectivity ▪ Factors to consider ▪ New onset of status epilepticus ▪ Gene variant hypothesis ▪ Selection of an AED with a different ▪ New onset of cluster seizures ▪ Genetic protein alteration mechanism of action ▪ ▪ Minimizing drug-drug interactions, avoiding Presence of drug-toxicity ▪ Intrinsic severity hypothesis additive toxicity ▪ High seizure density and/or ▪ Determination of risk-benefit of frequency correlated with poorer polypharmacy versus quality of life prognosis

Kwan P et al. Drug-Resistant Epilepsy N Engl J Med 2011; 365:919-926

Grade of Phenobarbital: Level Evidence= IV Recommendation Add-on Therapy = B Moderate ▪ No reported studies evaluating Recommendation phenobarbital as an add-on AED Moderate treatment were found Treatment Risk of Higher Risk of Bias ▪ Recommendation is based on Complications knowledge of efficacy as monotherapy treatment Low Risk of Moderate Risk High Risk of Bias of Bias Bias

•0 studies •0 studies •0 studies

Cochrane Risk of Bias Assessment (Charalambous et al, 2014)

Perucca et al Epil Beh, 2012

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Potassium Bromide: Add-on Therapy Primidone: Grade of Level Evidence= IV Recommendation Grade of Add-on Therapy = D Level Evidence= II Recommendation = 5 studies (n=232) B All with phenobarbital or Not recommended primidone as primary AED RISK OF Moderate High ▪ No reported studies evaluating BIAS Recommendation phenobarbital as an add-on High Treatment Moderate All studies >6 AED treatment were found Risk of Higher Risk of Bias 4 studies (N months Treatment Risk of Higher Risk of Bias >15) Complications duration Complications ▪ Recommendation is based on knowledge of efficacy as 49% with > 50% 6 % with no 46% with >0 and < monotherapy treatment Low Risk of Moderate Risk High Risk of seizure reduction improvement 50% seizure Bias of Bias Bias (N=114) (N=14) reduction (N=118)* Low Risk of Moderate Risk High Risk of Bias of Bias Bias •0 studies •0 studies •0 studies •0 studies •2 studies •3 studies 6% seizure free (N=10) * Estimated Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Cochrane Risk of Bias Assessment (Charalambous et al, 2014)

Imepitoin: Add-On Therapy Levetiracetam: Add-on Therapy Grade of Grade of Level Evidence= IB Recommendation Level Evidence= III Recommendation = = B C (n= 1) 3 studies (n = 71) Moderate 1 study RISK OF Insufficient Data for Recommendation Recommendation High BIAS N= 1 > 6 months 2 studies (n > 15) Low Treatment Low Treatment (Duration of 9-95 months ) Higher Risk of Bias Risk of Low Risk of Bias Risk of N = 17 6 months duration (n=1) Complications Complications 48% with > 50% 3 % with no 49% with > 0 and < seizure reduction improvement (N=2) 50% seizure (n=34) reduction

41% with >50% 35% with no 24% with >0 and Moderate Risk High Risk of Low Risk of Low Risk Moderate Risk High Risk of Bias seizure reduction improvement < 50% seizure Bias of Bias Bias NOTE: 67% (6/9) increase of Bias 7 % with seizure (N=7) (N=6) reduction (N=4) frequency 4-8 months •0 •0 •1 free status (N=5) •1 study •1 study •1 study (Volk et al, 2008)

6% seizure free NOTE: No statistical difference (N=1) Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Cochrane Risk of Bias Assessment (Charalambous et al, 2014) from placebo (Munana, et al 2012)

Grade of ACVIM Panel Add-on Therapy Recommendations: Zonisamide: Add-on Therapy Level Evidence= III Recommendation = B DRUG LEVEL OF EVIDENCE GRADE OF RECOMMENDATION Moderate 3 studies (n = 33) Recommendation Phenobarbital IV B Low Treatment Moderate Risk of Risk of Bias 3 studies > 6 months Complications 0 studies N > 15) (Duration of 4-18 Bromide II B months ) Primidone II D

64% with > 50% 27 % with no 9 %with > 0 and Low Risk Moderate High Risk of Bias seizure reduction improvement < 50% seizure Risk of Bias (n=21) (N=9) reduction (N=3) •0 studies •2 studies •1 study Imepitoin III C

24 % with Levetiracetam IB B seizure free status (N=8) Cochrane Risk of Bias Assessment (Charalambous et al, 2014) Zonisamide III B

Dr Michael Podell MedVet Chicago 7 ISVMA 2017 November, 2017

•1 clinical study (N= 6) (III) ACVIM Panel Grade of Recommendations Felbamate •6/6 with > 50% reduction for 6 months (CP seizures) (Level of Evidence) for Add-On AED Therapy Additional AED •2 clinical studies N=25 (III) Information for Gabapentin •11/25 with > 50% reduction for 3 or 4 months

A (HIGH) B (MODERATE) C (LOW) D (NO) Use •1 clinical study (n =9) (III) Pregabalin •7/9 with > 50% reduction for 3 months •Levetiracetam •Imepitoin (III) •Primidone (II) (IB) •Bromide (II) •1 clinical study (n =10) (III) Insufficient Data •5/10 dogs with > 50% reduction for 6-15 months •Zonisamide Topiramate (III) For Treatment Recommendations •Phenobarbital •No clinical studies (IV) Lacosamide

Rufinamide •No clinical studies

Vagal Nerve • Placebo-controlled, cross-over study evaluating the What Alternative use of VNS in 10 dogs with medically refractory Stimulation (VNS) idiopathic epilepsy (Muñana et al, 2002) Vagal Nerve Non-Pharmacological Stimulation • Treatment and control periods were both 13 weeks Treatments Are in duration • No significant difference seizure frequency Available? between groups over the total study time period • Significant decrease in seizure frequency of 34% Homeopathy Complimentary Diet was detected with VNS for the final 4 weeks of and Alternative treatment Medicine

Acupuncture

Courtesy of Dr. Munana

Diet Acupuncture Fatty acid Ketogenic (MCT) Hypoallergenic (Gold Bead Homeopathy supplementation Eastern Based Implantation) Alternative

Level of evidence: IB Level of evidence: IB Level of evidence: IV Therapy Insufficient Data to Insufficient Data to Insufficient Data to Evidence level = III Evidence level = III Recommend Recommend Recommend Insufficient Data for Insufficient Data for Recommendation Recommendation

Randomized placebo cross-over for Single blinded randomized, 6 months (N=11) placebo cross over for 3 months (N=15) One retrospective non-controlled •Patterson et al, 2005 study (abstract N =8) with report of Overall decrease in Belladonna +/- •No difference in seizure control •Matthews et al 2012 improvement (Luján et al, 2004) mean seizure Cocculus 6C (N=10) for •3 cases pancreatitis •No difference in seizure control frequency of 38.7% up to 8 months with (N= 15 with 7 on AED) variable degree of Randomized, blinded placebo control for for 15 weeks (Goiz- improvement (Varshney, 3 months (N=21) (Law et al. 2015) Marquez et al, 2009) 2007) •7 with > 50% improvement

Dr Michael Podell MedVet Chicago 8 ISVMA 2017 November, 2017

What Are The Guidelines for Success And Quality of Life Parameters? What We Accomplished Etiology •Symptomatic Treatment ▪ Developed a working clinical consensus statement for canine seizure management Tolerance •Breed risks ▪ Demonstrated that a collaborative international approach is achievable

▪ Established a predetermined, concise and logical sequential approach to seizure Seizure severity Owner Considerations management •Cluster •Restrictive lifestyle •Prolonged post-ictal •Cost ▪ Established a framework for future veterinary clinical and translational epilepsy treatment •Emotional stress studies •Family stress ▪ Revealed a great need for controlled clinical trials Efficacy •Frequency Quality Client Education International Veterinary League Against Epilepsy ? •Nocturnal of Life and Support

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